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InternalMed_Harrison. the intrapancreatic portion of the common bile duct. Twenty years after the diagnosis of calcific chronic pancreatitis, the cumulative risk of pancreatic carcinoma is 4%. Patients with hereditary pancreatitis are at a 10-fold higher risk for pancreatic cancer.


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InternalMed_Harrison. The treatment of steatorrhea with pancreatic enzymes is straightforward even though complete correction of steatorrhea is unusual. Enzyme therapy usually brings diarrhea under control and restores absorption of fat to an acceptable level and affects weight gain. Thus, pancreatic enzyme replacement has been the cornerstone of therapy. In treating steatorrhea, it is important to use a potent pancreatic formulation that will deliver sufficient lipase into the duodenum to correct maldigestion and decrease steatorrhea. In an attempt to standardize the enzyme activity, potency, and bioavailability, the U.S. Food and Drug Administration (FDA) required that all pancreas enzyme drugs in the United States obtain a New Drug Application (NDA) by April 2008. Table 371-8 lists frequently used formulations, but availability will be based on compliance with the FDA mandate. Recent data suggest that dosages up to ComPliCATionS of CHRoniC PAnCREATiTiS


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InternalMed_Harrison. ComPliCATionS of CHRoniC PAnCREATiTiS Enzyme Content/Unit Dose, U.S. Pharmacopeia Units Note: The FDA has mandated all enzyme manufacturers to submit New Drug Applications (NDAs) for all pancreatic extract drug products after reviewing data that showed substantial variations among currently marketed products. Numerous manufacturers have investigations under way to seek FDA approval for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions under the new guidelines for this class of drugs (www.fda.gov). 80,000–100,000 units of lipase taken during the meal may be necessary to normalize nutritional parameters in malnourished chronic pancreatitis patients, and some may require acid suppression with proton pump inhibitors. The management of pain in patients with chronic pancreatitis is problematic.


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InternalMed_Harrison. The management of pain in patients with chronic pancreatitis is problematic. Recent meta-analyses have shown no consistent benefit of enzyme therapy at reducing pain in chronic pancreatitis. In some patients with idiopathic chronic pancreatitis, conventional nonenteric-coated enzyme preparations containing high concentrations of serine proteases may relieve mild abdominal pain or discomfort. The pain relief experienced by these patients actually may be due to improvements in the dyspepsia from maldigestion. Gastroparesis is also quite common in patients with chronic pancreatitis. It is important to recognize and treat with prokinetic drugs because treatment with enzymes may fail simply because gastric dysmotility is interfering with the delivery of enzymes into the upper intestine. A recent prospective study reported that pregabalin can improve pain in chronic pancreatitis and lower pain medication requirement.


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InternalMed_Harrison. Endoscopic treatment of chronic pancreatitis pain may involve 2101 sphincterotomy, stenting, stone extraction, and drainage of a pancreatic pseudocyst. Therapy directed to the pancreatic duct would seem to be most appropriate in the setting of a dominant stricture, especially if a ductal stone has led to obstruction. The use of endoscopic stenting for patients with chronic pain, but without a dominant stricture, has not been subjected to any controlled trials. It is now appreciated that significant complications can occur from stenting (i.e., bleeding, cholangitis, stent migration, pancreatitis, and stent clogging). In patients with large-duct disease usually from alcohol-induced chronic pancreatitis, ductal decompression with surgical therapy has been the therapy of choice. Among such patients, 80% seem to obtain immediate relief; however, at the end of 3 years, one-half of the patients have recurrence of pain. Two randomized prospective trials comparing endoscopic to surgical


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InternalMed_Harrison. patients, 80% seem to obtain immediate relief; however, at the end of 3 years, one-half of the patients have recurrence of pain. Two randomized prospective trials comparing endoscopic to surgical therapy for chronic pancreatitis demonstrated that surgical therapy was superior to endoscopy at decreasing pain and improving quality of life in selected patients with dilated ducts and abdominal pain. This would suggest that chronic pancreatitis patients with dilated ducts and pain should be considered for surgical intervention. The role of preoperative stenting prior to surgery as a predictor of response has yet to be proven.


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InternalMed_Harrison. A Whipple procedure, total pancreatectomy, and autologous islet cell transplantation have been used in selected patients with chronic pancreatitis and abdominal pain refractory to conventional therapy. The patients who have benefited the most from total pancreatectomy have chronic pancreatitis without prior pancreatic surgery or evidence of islet cell insufficiency. The role of this procedure remains to be fully defined but may be an option in lieu of ductal decompression surgery or pancreatic resection in patients with intractable, painful small-duct disease, particularly as the standard surgical procedures tend to decrease islet cell yield. Celiac plexus block has not resulted in long-lasting pain relief.


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InternalMed_Harrison. Hereditary pancreatitis is a rare disease that is similar to chronic pancreatitis except for an early age of onset and evidence of hereditary factors. A genomewide search using genetic linkage analysis identified the hereditary pancreatitis gene on chromosome 7. Mutations in ion codons 29 (exon 2) and 122 (exon 3) of the cationic trypsinogen gene cause autosomal dominant forms of hereditary pancreatitis. The codon 122 mutations lead to a substitution of the corresponding arginine with another amino acid, usually histidine. This substitution, when it occurs, eliminates a fail-safe trypsin self-destruction site necessary to eliminate trypsin that is prematurely activated within the acinar cell. These patients have recurring attacks of severe abdominal pain that may last from a few days to a few weeks. The serum amylase and lipase levels may be elevated during acute attacks but are usually normal. Patients frequently develop pancreatic calcification, diabetes mellitus, and steatorrhea;


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InternalMed_Harrison. a few weeks. The serum amylase and lipase levels may be elevated during acute attacks but are usually normal. Patients frequently develop pancreatic calcification, diabetes mellitus, and steatorrhea; in addition, they have an increased incidence of pancreatic carcinoma, with the cumulative incidence being as high as 40% by age 70 years. A recent natural history study of hereditary pancreatitis in more than 200 patients from France reported that abdominal pain started in childhood at age 10 years, steatorrhea developed at age 29 years, diabetes at age 38 years, and pancreatic carcinoma at age 55 years. Such patients often require surgical ductal decompression for pain relief. Abdominal complaints in relatives of patients with hereditary pancreatitis should raise the question of pancreatic disease.


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InternalMed_Harrison. PSTI, or SPINK1, is a 56-amino-acid peptide that specifically inhibits trypsin by physically blocking its active site. SPINK1 acts as the first line of defense against prematurely activated trypsinogen in the acinar cell. Recently, it has been shown that the frequency of SPINK1 mutations in patients with idiopathic chronic pancreatitis is markedly increased, suggesting that these mutations may be associated with pancreatitis. Pancreatic endocrine tumors are discussed in Chap. 113.


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InternalMed_Harrison. When the ventral pancreatic anlage fails to migrate correctly to make contact with the dorsal anlage, the result may be a ring of pancreatic tissue encircling the duodenum. Such an annular pancreas may cause intestinal obstruction in the neonate or the adult. Symptoms of postprandial fullness, epigastric pain, nausea, and vomiting may be present for years before the diagnosis is entertained. The radiographic findings are symmetric dilation of the proximal duodenum with bulging of the recesses on either side of the annular band, effacement but not destruction of the duodenal mucosa, accentuation of the findings in the right anterior oblique position, and lack of change on repeated examinations. The differential diagnosis should include duodenal webs, tumors of the pancreas or duodenum, postbulbar peptic ulcer, regional enteritis, and adhesions. Patients with annular pancreas have an increased incidence of pancreatitis and peptic ulcer. Because of these and other potential


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InternalMed_Harrison. duodenum, postbulbar peptic ulcer, regional enteritis, and adhesions. Patients with annular pancreas have an increased incidence of pancreatitis and peptic ulcer. Because of these and other potential complications, the treatment is surgical even if the condition has been present for years. Retrocolic duodenojejeunostomy is the procedure of choice, although some surgeons advocate Billroth II gastrectomy, gastroenterostomy, and vagotomy.


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InternalMed_Harrison. Pancreas divisum is present in 7–10% of the population and occurs when the embryologic ventral and dorsal pancreatic anlagen fail to fuse, so that pancreatic drainage is accomplished mainly through the accessory papilla. Pancreas divisum is the most common congenital anatomic variant of the human pancreas. Current evidence indicates that this anomaly does not predispose to the development of pancreatitis in the great majority of patients who harbor it. However, the combination of pancreas divisum and a small accessory orifice could result in dorsal duct obstruction. The challenge is to identify this subset of patients with dorsal duct pathology. Cannulation of the dorsal duct by ERCP is not as easily done as is cannulation of the ventral duct. Patients with pancreatitis and pancreas divisum demonstrated by MRCP or ERCP should be treated with conservative measures. In many of these patients, pancreatitis is idiopathic and unrelated to the pancreas divisum. Endoscopic or surgical


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InternalMed_Harrison. divisum demonstrated by MRCP or ERCP should be treated with conservative measures. In many of these patients, pancreatitis is idiopathic and unrelated to the pancreas divisum. Endoscopic or surgical intervention is indicated only if pancreatitis recurs and no other cause can be found. If marked dilation of the dorsal duct can be demonstrated, surgical ductal decompression should be performed. It should be stressed that the ERCP/MRCP appearance of pancreas divisum (i.e., a small-caliber ventral duct with an arborizing pattern) may be mistaken as representing an obstructed main pancreatic duct secondary to a mass lesion.


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InternalMed_Harrison. In macroamylasemia, amylase circulates in the blood in a polymer form too large to be easily excreted by the kidney. Patients with this condition demonstrate an elevated serum amylase value and a low urinary amylase value. The presence of macroamylase can be documented by chromatography of the serum. The prevalence of macroamylasemia is 1.5% of the nonalcoholic general adult hospital population. Usually macroamylasemia is an incidental finding and is not related to disease of the pancreas or other organs. Macrolipasemia has now been documented in a few patients with cirrhosis or non-Hodgkin’s lymphoma. In these patients, the pancreas appeared normal on ultrasound and CT examination. Lipase was shown to be complexed with immunoglobulin A. Thus, the possibility of both macroamylasemia and macrolipasemia should be considered in patients with elevated blood levels of these enzymes.


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InternalMed_Harrison. This chapter represents a revised version of chapters by Drs. Norton J. Greenberger, Phillip P. Toskes, and Bechien Wu that were in previous editions of Harrison’s. Introduction to the Immune System Barton F. Haynes, Kelly A. Soderberg, Anthony S. Fauci 372e Sec tIon 1 the Immune SyStem In health and dISeaSe ParT 15: Immune-mediated, Inflammatory, and Rheumatologic Disorders Adaptive immune system—recently evolved system of immune responsesmediated by TandBlymphocytes.Immuneresponsesby these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during development and throughout the life of the organism. Additional cells of the adaptive immune system include various types of antigen-presenting cells.


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InternalMed_Harrison. Antibody—B cell–produced molecules encoded by genes that rearrange during B cell development consisting of immunoglobulin heavy and light chains that together form the central component of the B cell receptor for antigen. Antibody can exist as B cell–surface antigen-recognition molecules or as secreted molecules in plasma and other body fluids. Antigens—foreign or self-molecules that are recognized by the adaptive and innate immune systems resulting in immune cell triggering, T cell activation, and/or B cell antibody production. Antimicrobial peptides—small peptides <100 amino acids in length that are produced by cells of the innate immune system and have anti-infectious agent activity.


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InternalMed_Harrison. Antimicrobial peptides—small peptides <100 amino acids in length that are produced by cells of the innate immune system and have anti-infectious agent activity. Apoptosis—the process of programmed cell death whereby signaling through various “death receptors” on the surface of cells (e.g., tumor necrosis factor [TNF] receptors, CD95) leads to a signaling cascade that involves activation of the caspase family of molecules and leads to DNA cleavage and cell death. Apoptosis, which does not lead to induction of inordinate inflammation, is to be contrasted with cell necrosis, which does lead to induction of inflammatory responses. Autoimmune diseases—diseases such as systemic lupus erythematosus and rheumatoid arthritis in which cells of the adaptive immune system such as autoreactive T and B cells become over-reactive and produce self-reactive T cell and antibody responses.


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InternalMed_Harrison. Autoinflammatory diseases—hereditary disorders such as hereditary periodic fevers (HPFs) characterized by recurrent episodes of severe inflammation and fever due to mutations in controls of the innate inflammatory response, i.e., the inflammasome (see below and Table 372e-6). Patients with HPFs also have rashes and serosal and joint inflammation, and some can have neurologic symptoms. Autoinflammatory diseases are different from autoimmune diseases in that evidence for activation of adaptive immune cells such as autoreactive B cells is not present. B cell receptor for antigen—complex of surface molecules that rearrange during postnatal B cell development, made up of surface immunoglobulin (Ig) and associated Ig αβ chain molecules that recognize nominal antigen via Ig heavy-and light-chain variable regions, and signal the B cell to terminally differentiate to make antigen-specific antibody.


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InternalMed_Harrison. B lymphocytes—bone marrow-derived or bursal-equivalent lymphocytes that express surface immunoglobulin (the B cell receptor for antigen) and secrete specific antibody after interaction with antigen. CD classification of human lymphocyte differentiation antigens—the development of monoclonal antibody technology led to the discovery of a large number of new leukocyte surface molecules. In 1982, the First International Workshop on Leukocyte Differentiation Antigens was held to establish a nomenclature for cell-surface molecules of human leukocytes. From this and subsequent leukocyte differentiation workshops has come the cluster of differentiation (CD) classification of leukocyte antigens. Chemokines—soluble molecules that direct and determine immune cell movement and circulation pathways.


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InternalMed_Harrison. Chemokines—soluble molecules that direct and determine immune cell movement and circulation pathways. Complement—cascading series of plasma enzymes and effector proteins whose function is to lyse pathogens and/or target them to be phagocytized by neutrophils and monocyte/macrophage lineage cells of the reticuloendothelial system. Co-stimulatory molecules—molecules of antigen-presenting cells (such as B7-1 and B7-2 or CD40) that lead to T cell activation when bound by ligands on activated T cells (such as CD28 or CD40 ligand). Cytokines—soluble proteins that interact with specific cellular receptors that are involved in the regulation of the growth and activation of immune cells and mediate normal and pathologic inflammatory and immune responses.


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InternalMed_Harrison. Dendritic cells—myeloid and/or lymphoid lineage antigen-presenting cells of the adaptive immune system. Immature dendritic cells, or dendritic cell precursors, are key components of the innate immune system by responding to infections with production of high levels of cytokines. Dendritic cells are key initiators both of innate immune responses via cytokine production and of adaptive immune responses via presentation of antigen to T lymphocytes. Ig Fc receptors—receptors found on the surface of certain cells including B cells, natural killer cells, macrophages, neutrophils, and mast cells. Fc receptors bind to antibodies that have attached to invading pathogen-infected cells. They stimulate cytotoxic cells to destroy microbe-infected cells through a mechanism known as antibody-dependent cell-mediated cytotoxicity (ADCC). Examples of important Fc receptors include CD16 (FcγRIIIa), CD23 (FcεR), CD32 (FcγRII), CD64 (FcγRI), and CD89 (FcαR).


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InternalMed_Harrison. Inflammasome—large cytoplasmic complexes of intracellular proteins that link the sensing of microbial products and cellular stress to the proteolytic activation of interleukin (IL)-1β and IL-18 inflammatory cytokines. Activation of molecules in the inflammasome is a key step in the response of the innate immune system for intracellular recognition of microbial and other danger signals in both health and pathologic states. Innate immune system—ancient immune recognition system of host cells bearing germline-encoded pattern recognition receptors that recognize pathogens and trigger a variety of mechanisms of pathogen elimination. Cells of the innate immune system include natural killer cell lymphocytes, monocytes/macrophages, dendritic cells, neutrophils, basophils, eosinophils, tissue mast cells, and epithelial cells.


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InternalMed_Harrison. Large granular lymphocytes—lymphocytes of the innate immune system with azurophilic cytotoxic granules that have natural killer cell activitycapableofkillingforeignandhostcellswithfewornoself-major histocompatibility complex(MHC) class I molecules. Natural killer (NK) cells—large granular lymphocytes that kill target cells expressing few or no human leukocyte antigen (HLA) class I molecules, such as malignantly transformed cells and virally infectedcells.NKcellsexpressreceptorsthatinhibitkillercellfunction when self-MHC class I is present. Introduction to the Immune System NK T cells—innate-like lymphocytes that use an invariant T cell receptor (TCR)-α chain combined with a limited set of TCR-β chains and coexpress receptors commonly found on NK cells. NK T cells recognize lipid antigens of bacterial, viral, fungal, and protozoal infectious agents.


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InternalMed_Harrison. Pathogen-associated molecular patterns (PAMPs)—Invariant molecular structures expressed by large groups of microorganisms that arerecognized by host cellular pattern recognition receptors in the mediation of innate immunity. Pattern recognition receptors (PRRs)—germline-encoded receptors expressedbycellsoftheinnateimmunesystemthatrecognizePAMPs. Polyreactive natural antibodies—preexistinglow-affinity antibodies produced by B cells that cross-react with multiple antigens and are available at the time of infection to bind to and coat the invading pathogen and harness innate responses to slow the infection until anadaptivehigh-affinityprotectiveantibodyresponsecanbemade. T cell exhaustion—state of T cells when the persistence of antigen disrupts memory T cell function, resulting in defects in memory T cell responses. Most frequently occurs in malignancies and in chronic viral infections such as HIV-1 and hepatitis C.


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InternalMed_Harrison. T cell receptor (TCR) for antigen—complex of surface molecules that rearrange during postnatal T cell development made up of clonotypicTCR-αand-βchainsthatareassociatedwiththeCD3complex composed of invariant γ, δ, ε, ζ, and η chains. TCR-α and -β chains recognize peptide fragments of protein antigen physically bound in antigen-presentingcell MHC class I or II molecules, leading to signaling via the CD3 complex to mediate effector functions. T follicular helper T cells (Tfh)—CD4 T cells in B cell follicle germinal centers that produce IL-4 and IL-21 and drive B cell development and affinity maturation in peripheral lymphoid tissues such as lymph node and spleen. TH17 T cells—CD4 T cells that secrete IL-17, IL-22, and IL-26 and play roles in autoimmune inflammatory disorders as well as defend against bacterial and fungal pathogens.


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InternalMed_Harrison. TH17 T cells—CD4 T cells that secrete IL-17, IL-22, and IL-26 and play roles in autoimmune inflammatory disorders as well as defend against bacterial and fungal pathogens. T lymphocytes—thymus-derived lymphocytes that mediate adaptive cellular immune responses including T helper, T regulatory, and cytotoxic T lymphocyte effector cell functions. Tolerance—B and T cell nonresponsiveness to antigens that results from encounter with foreign or self-antigens by B and T lymphocytes in the absence of expression of antigen-presenting cell co-stimulatory molecules. Tolerance to antigens may be induced and maintained by multiple mechanisms either centrally (in the thymus for T cells or bone marrow for B cells) or peripherally at sites throughout the peripheral immune system.


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InternalMed_Harrison. The human immune system has evolved over millions of years from both invertebrate and vertebrate organisms to develop sophisticated defense mechanisms to protect the host from microbes and their virulence factors. The normal immune system has three key properties: a highly diverse repertoire of antigen receptors that enables recognition of a nearly infinite range of pathogens; immune memory, to mount rapid recall immune responses; and immunologic tolerance, to avoid immune damage to normal self-tissues. From invertebrates, humans have inherited the innate immune system, an ancient defense system that uses germline-encoded proteins to recognize pathogens. Cells of the innate immune system, such as macrophages, dendritic cells, and NK lymphocytes, recognize PAMPs that are highly conserved among manymicrobesanduseadiversesetofPRRmolecules.Importantcomponents of the recognition of microbes by the innate immune system include recognition by germline-encoded host molecules, recognition of


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InternalMed_Harrison. among manymicrobesanduseadiversesetofPRRmolecules.Importantcomponents of the recognition of microbes by the innate immune system include recognition by germline-encoded host molecules, recognition of key microbe virulence factors but not recognition of self-molecules, and nonrecognition of benign foreign molecules or microbes. Upon contact with pathogens, macrophages and NK cells may kill pathogens directlyor,inconcertwithdendriticcells,mayactivateaseriesofevents that both slow the infection and recruit the more recently evolved arm of the human immune system, the adaptive immune system.


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InternalMed_Harrison. Adaptive immunity is found only in vertebrates and is based on the generation of antigen receptors on T and B lymphocytes by gene rearrangements, such that individual T or B cells express unique antigen receptors on their surface capable of specifically recognizing diverse antigens of the myriad infectious agents in the environment. Coupled with finely tuned specific recognition mechanisms that maintain tolerance (nonreactivity) to self-antigens, T and B lymphocytes bring both specificity and immune memory to vertebrate host defenses. This chapter describes the cellular components, key molecules (Table 372e-1), and mechanisms thatmakeup theinnateand adaptive immune systems and describes how adaptive immunity is recruited to the defense of the host by innate immune responses. An appreciation of the cellular and molecular bases of innate and adaptive immune responses is critical to understanding the pathogenesis of inflammatory, autoimmune, infectious, and immunodeficiency diseases.


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InternalMed_Harrison. All multicellular organisms, including humans, have developed the use of a limited number of surface and intracellular germline-encoded molecules that recognize large groups of pathogens. Because of the myriad human pathogens, host molecules of the human innate immune system sense “danger signals” and either recognize PAMPs, the common molecular structures shared by many pathogens, or recognize host cell molecules produced in response to infection such as heat shock proteins and fragments of the extracellular matrix. PAMPs must be conserved structures vital to pathogen virulence and survival, such as bacterial endotoxin, so that pathogens cannot mutate molecules of PAMPs to evade human innate immune responses. PRRs are host proteins of the innate immune system that recognize PAMPs as hostdangersignalmolecules (Tables 372e-2 and 372e-3).Thus,recognition of pathogen molecules by hematopoietic and nonhematopoietic cell types leads to activation/production of the complement cascade,


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InternalMed_Harrison. hostdangersignalmolecules (Tables 372e-2 and 372e-3).Thus,recognition of pathogen molecules by hematopoietic and nonhematopoietic cell types leads to activation/production of the complement cascade, cytokines,andantimicrobial peptides aseffectormolecules.Inaddition, pathogen PAMPs as host danger signal molecules activate dendritic cells to mature and to express molecules on the dendritic cell surface that optimize antigen presentation to respond to foreign antigens.


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InternalMed_Harrison. Major PRR families of proteins include transmembrane proteins, such as the Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), and cytoplasmic proteins, such as the retinoic acid–inducible gene (RIG)-1-like receptors (RLRs) and NOD-like receptors (NLRs) (Table 372e-3). A major group of PRR collagenous glycoproteins with C-type lectin domains are termed collectins and include the serum protein mannose-binding lectin (MBL). MBL and other collectins, as well as two other protein families—the pentraxins (such as C-reactive protein and serum amyloid P) and macrophage scavenger receptors—all have the property of opsonizing (coating) bacteria for phagocytosis by macrophages and can also activate the complement cascade to lyse bacteria. Integrins are cell-surface adhesion molecules that affect attachment between cells and the extracellular matrix and mediate signal transduction that reflects the chemical composition of the cell environment. For example, integrins signal after cells


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InternalMed_Harrison. affect attachment between cells and the extracellular matrix and mediate signal transduction that reflects the chemical composition of the cell environment. For example, integrins signal after cells bind bacterial lipopolysaccharide (LPS) and activate phagocytic cells to ingest pathogens.


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InternalMed_Harrison. There are multiple connections between the innate and adaptive immune systems; these include (1) a plasma protein, LPS-binding protein, that binds and transfers LPS to the macrophage LPS receptor, CD14; (2) a human family of proteins called Toll-like receptor proteins (TLRs), some of which are associated with CD14, bind LPS, and signal epithelial cells, dendritic cells, and macrophages to produce cytokines andupregulatecell-surfacemolecules thatsignaltheinitiationofadaptive immune responses (Fig. 372e-1, Tables 372e-3 and 372e-4), and (3) families of intracellular microbial sensors called NLRs and RLRs. Proteins intheTollfamily can beexpressedonmacrophages,dendritic cells, and B cells as well as on a variety of nonhematopoietic cell types, including respiratory epithelial cells. Eleven TLRs have been identified in humans, and 13 TLRs have been identified in mice (Tables 372e-4 and 372e-5). Upon ligation, TLRs activate a series of intracellular events that lead to the killing of


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InternalMed_Harrison. TLRs have been identified in humans, and 13 TLRs have been identified in mice (Tables 372e-4 and 372e-5). Upon ligation, TLRs activate a series of intracellular events that lead to the killing of bacteria-and viral-infected cells as well as to the recruitment and ultimate activation of antigen-specific T and B lymphocytes (Fig. 372e-1). Importantly, signaling by massive


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InternalMed_Harrison. Introduction to the Immune System Molecular Mass, (Other Names) Family kDa Distribution Ligand(s) Function CD64 (FcγRI) Ig 45–55 Macrophages and Fc portion of IgG Mediates phagocytosis and ADCC monocytes CD80 (B7-1, BB1) Ig 60 CD86 (B7-2, B70) Ig 80 CD89 (FCαR) Ig 55–100 CD95 (APO-1, Fas) TNFR 43 Activated B and T, MP, DC Subset B, DC, EC, activated T, thymic epithelium Neutrophils, eosinophils, monocytes, and MP Activated T and B Activated T Activated CD4+ T, subset CD8+ T, NK, M, basophil B, T, TfH CD28, CD152 CD28, CD152 Fc portion of IgG Fas ligand CD80, CD86 CD40 PD-L1, PD-L2 Co-regulator of T cell activation; signaling through CD28 stimulates and through CD152 inhibits T cell activation Co-regulator of T cell activation; signaling through CD28 stimulates and through CD152 inhibits T cell activation Mediates phagocytosis and ADCC of IgA-coated pathogens Co-stimulatory for T cell activation, B cell proliferation and differentiation


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InternalMed_Harrison. Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CTLA, cytotoxic T lymphocyte–associated protein; DC, dendritic cells; EBV, Epstein-Barr virus; EC, endothelial cells; ECM, extracellular matrix; Fcγ RIII, low-affinity IgG receptor isoform A; FDC, follicular dendritic cells; G, granulocytes; GC, germinal center; GPI, glycosyl phosphatidylinositol; HTA, human thymocyte antigen; Ig, immunoglobulin; IgG, immunoglobulin G; LCA, leukocyte common antigen; LPS, lipopolysaccharide; MHC-I, major histocompatibility complex class I; MP, macrophages; Mr, relative molecular mass; NK, natural killer cells; P, platelets; PBT, peripheral blood T cells; PD-1, programmed cell death-1; PI, phosphatidylinositol; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PTP, protein tyrosine phosphatase; TCR, T cell receptor; TfH, T follicular helper cells; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor. For an expanded list of cluster of differentiation (CD) human


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InternalMed_Harrison. phosphatase; TCR, T cell receptor; TfH, T follicular helper cells; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor. For an expanded list of cluster of differentiation (CD) human antigens, see Harrison’s Online at http://www.accessmedicine.com; and for a full list of CD human antigens from the most recent Human Workshop on Leukocyte Differentiation Antigens (VII), see http://mpr.nci.nih.gov/prow/.


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InternalMed_Harrison. Source: Compiled from T Kishimoto et al (eds): Leukocyte Typing VI. New York: Garland Publishing, 1997; R Brines et al: Immunology Today 18S:1, 1997; and S Shaw (ed): Protein reviews on the Web. http://mpr.nci.nih.gov/prow/. Abbreviation: NK, natural killer. Toll-like receptors (TLRs), C-type lectin receptors (CLRs), retinoic acid– inducible gene (RIG)-1-like receptors (RLRs), and NOD-like receptors (NLRs) α-Defensins, β-defensins, cathelin, protegrin, granulysin, histatin, secretory leukoprotease inhibitor, and probiotics Macrophages, dendritic cells, NK cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells Classic and alternative complement pathway, and proteins that bind complement components


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InternalMed_Harrison. Classic and alternative complement pathway, and proteins that bind complement components Autocrine, paracrine, endocrine cytokines that mediate host defense and inflammation, as well as recruit, direct, and regulate adaptive immune responses amounts of LPS through TLR4 leads to the release of large amounts of cytokines that mediate LPS-induced shock. Mutations in TLR4 proteins in mice protect from LPS shock, and TLR mutations in humans protect from LPS-induced inflammatory diseases such as LPS-induced asthma (Fig. 372e-1). Twootherfamiliesofcytoplasmic PRRsarethe NLRsand the RLRs. These families, unlike the TLRs, are composed primarily of soluble intracellular proteins that scan host cell cytoplasm for intracellular pathogens (Tables 372e-2 and 372e-3).


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InternalMed_Harrison. Theintracellularmicrobialsensors,NLRs,aftertriggering,formlarge cytoplasmic complexes termed inflammasomes, which are aggregates of molecules including NOD-like receptor pyrin (NLRP) proteins that are members of the NLR family (Table 372e-3). Inflammasomes activate inflammatorycaspasesandIL-1βinthepresenceofnonbacterialdanger signals (cell stress) and bacterial PAMPs. Mutations in inflammasome proteins can lead to chronic inflammation in a group of periodic febrile diseases called autoinflammatory syndromes (Table 372e-6). Cells of the innate immune system and their roles in the first line of host defense are listed in Table 372e-5. Equally important as their roles in the mediation of innate immune responses are the roles that each cell type plays in recruiting T and B lymphocytes of the adaptive immune system to engage in specific pathogen responses.


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InternalMed_Harrison. Monocytes-Macrophages Monocytes arise from precursor cells within bone marrow (Fig. 372e-2) and circulate with a half-life ranging from 1 to 3 days. Monocytes leave the peripheral circulation via capillaries and migration into a vast extravascular cellular pool. Tissue macrophages arise from monocytes that have migrated out of the circulation and by in situ proliferation of macrophage precursors in tissue. Common locations where tissue macrophages (and certain of their specialized forms) are found are lymph node, spleen, bone marrow, perivascular connective tissue, serous cavities such as the peritoneum, pleura, skin connective tissue, lung (alveolar macrophages), liver (Kupffer cells), bone (osteoclasts), central nervous system (microglia cells), and synovium (type A lining cells).


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InternalMed_Harrison. In general, monocytes-macrophages are on the first line of defense associated with innate immunity and ingest and destroy microorganisms through the release of toxic products such as hydrogen peroxide (H2O2) and nitric oxide (NO). Inflammatory mediators produced by macrophages attract additional effector cells such as neutrophils to the site of infection. Macrophage mediators include prostaglandins; leukotrienes; platelet activating factor; cytokines such as IL-1, TNF-α, IL-6, and IL-12; and chemokines (Tables 372e-7 to 372e-9).


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InternalMed_Harrison. Although monocytes-macrophages were originally thought to be the major antigen-presenting cells (APCs) of the immune system, it is now clear that cell types called dendritic cells are the most potent and effective APCs in the body (see below). Monocytesmacrophages mediate innate immune effector functions such as destruction of antibody-coated bacteria, tumor cells, or even normal hematopoietic cells in certain types of autoimmune cytopenias. Monocytes-macrophages ingest bacteria or are infected by viruses, and in doing so, they frequently undergo programmed cell death or apoptosis. Macrophages that are infected by intracellular infectious agents are recognized by dendritic cells as infected and apoptotic cells and are phagocytosed by dendritic cells. In this manner, dendritic cells “cross-present” infectious agent antigens of macrophages


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InternalMed_Harrison. Abbreviations: CLR, C-type lectin receptors; dsRNA, double-strand RNA; iE-DAP, D-glutamyl-meso-diaminopimelic acid moiety; LGP2, Laboratory of Genetics and Physiology 2 protein encoded by the gene DHX58; MDA5, melanoma differentiation-associated protein 5; MDP, MurNAc-L-Ala-D-isoGln, also known as muramyl dipeptide; MINCLE, macrophage-inducible C-type lectin; NLR, NOD-like receptor; NOD, NOTCH protein domain; RIG, retinoic acid–inducible gene; RLR, RIG-like receptors; TLR, Toll-like receptor. Source: Adapted from O Takeuchi, S Akira: Cell 140:805, 2010, with permission. Introduction to the Immune System


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InternalMed_Harrison. Source: Adapted from O Takeuchi, S Akira: Cell 140:805, 2010, with permission. Introduction to the Immune System FIGUrE 372e-1 Overview of major TLR signaling pathways. All TLRs signal through MyD88, with the exception of TLR3. TLR4 and the TLR2 subfamily (TLR1, TLR2, TLR6) also engage TIRAP. TLR3 signals through TRIF. TRIF is also used in conjunction with TRAM in the TLR4-MyD88independent pathway. Dashed arrows indicate translocation into the nucleus. dsRNA, double-strand RNA; IFN, interferon; IRF3, interferon regulatory factor 3; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; ssRNA, single-strand RNA; TLR, Toll-like receptor. (Adapted from D van Duin et al: Trends Immunol 27:49, 2006, with permission.) TLRs TLR2 (heterodimer with TLR1 or 6) Env of HIV; core protein of HCV; components of Mycobacterium tuberculosis; Helicobacter pylori, Lewis Ag Muramyl dipeptide of peptidoglycan of bacteria


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InternalMed_Harrison. TLRs TLR2 (heterodimer with TLR1 or 6) Env of HIV; core protein of HCV; components of Mycobacterium tuberculosis; Helicobacter pylori, Lewis Ag Muramyl dipeptide of peptidoglycan of bacteria Mannosylated lipoarabinomannans from bacillus Calmette-Guérin and M. tuberculosis Low IL-12p70 TH1 High IL-10 TH2 IL-6 T regulatory IL-12p70 TH1 IFN-α IL-6 High IL-12p70 TH1 Intermediate IL-10 IL-6 High IL-12p70 TH1 Low IL-12p70 TH2 High IL-12p70 TH1 IFN-α IL-6 High IL-12p70 TH1 Low IL-10 IL-6 IFN-α ?? ?? H. pylori, Lewis Ag TH2 Suppresses IL-12p70 T regulatory Suppresses TLR signaling in DCs Induces IL-10 in DCs Weak T cell response (tolerogenic?) Suppresses IL-12 and TLR signaling in DCs Weak T cell response? (tolerogenic?)


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InternalMed_Harrison. Abbreviations: CpG, sequences in DNA recognized by TLR-9; DC, dendritic cell; DC-SIGN, DC-specific C-type lectin; dsRNA, double-strand RNA; HCV, hepatitis C; HIV, human immunodeficiency virus; LPS, lipopolysaccharide; MALP, macrophage-activating lipopeptide; NOD, NOTCH protein domain; ssRNA, single-strand RNA; TH1, helper T cell; TH2, helper T cell; TLR, Toll-like receptor. Source: B Pulendran: J Immunol 174:2457, 2005. Copyright 2005 The American Association of Immunologists, Inc., with permission. to T cells. Activated macrophages can also mediate antigen-nonspecific lytic activity and eliminate cell types such as tumor cells in the absence of antibody. This activity is largely mediated by cytokines (i.e., TNF-α and IL-1). Monocytes-macrophages express lineage-specific molecules (e.g., the cell-surface LPS receptor, CD14) as well as surface receptors for a number of molecules, including the Fc region of IgG, activated complement components, and various cytokines (Table 372e-7).


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InternalMed_Harrison. Dendritic Cells Human dendritic cells (DCs) contain several subsets, including myeloid DCs and plasmacytoid DCs. Myeloid DCs can differentiate into either macrophages-monocytes or tissue-specific DCs. In contrast to myeloid DCs, plasmacytoid DCs are inefficient APCs but are potent producers of type I interferon (IFN) (e.g., IFN-α) in response to viral infections. The maturation of DCs is regulated through cell-to-cell contact and soluble factors, and DCs attract immune effectors through secretion of chemokines. When DCs come in contact with bacterial products, viral proteins, or host proteins released as danger signals from distressed host cells (Figs. 372e-2 and 372e-3), infectious agent molecules bind to various TLRs and activate DCs to release cytokines and chemokines that drive cells of the innate immune system to become activated to respond to the invading organism, and recruit T and B cells of the adaptive immune system to respond. Plasmacytoid DCs produce antiviral IFN-α that


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InternalMed_Harrison. of the innate immune system to become activated to respond to the invading organism, and recruit T and B cells of the adaptive immune system to respond. Plasmacytoid DCs produce antiviral IFN-α that activates NK cell killing of pathogen-infected cells; IFN-α also activates T cells to mature into antipathogen cytotoxic (killer) T cells. Following contact with pathogens, both plasmacytoid and myeloid DCs produce chemokines that attract helper and cytotoxic T cells, B cells, polymorphonuclear cells, and naïve and memory T cells as well as regulatory T cells to ultimately dampen the immune response once the pathogen is controlled. TLR engagement on DCs upregulates MHC class II, B7-1 (CD80), and B7-2 (CD86), which enhance DC-specific antigen presentation and induce cytokine production (Table 372e-7). Thus, DCs are important bridges between early (innate) and later (adaptive) immunity. DCs also modulate and determinethetypes ofimmuneresponsesinducedbypathogensviatheTLRs


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InternalMed_Harrison. production (Table 372e-7). Thus, DCs are important bridges between early (innate) and later (adaptive) immunity. DCs also modulate and determinethetypes ofimmuneresponsesinducedbypathogensviatheTLRs expressedonDCs(TLR7–9onplasmacytoidDCs,TLR4onmonocytoid DCs) and via the TLR adapter proteins that are induced to associate with TLRs (Fig. 372e-1, Table 372e-4). In addition, other PRRs, such as C-type lectins, NLRs, and mannose receptors, upon ligation by pathogenproducts,activatecellsoftheadaptiveimmunesystemand,likeTLR stimulation, by a variety of factors, determine the type and quality of the adaptive immune response that is triggered (Table 372e-4).


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InternalMed_Harrison. Large Granular Lymphocytes/Natural Killer Cells Large granular lymphocytes (LGLs) or NK cells account for ~5–15% of peripheral blood lymphocytes.NK cells are nonadherent, nonphagocytic cells withlarge azurophilic cytoplasmic granules. NK cells express surface receptors for the Fc portion of IgG (FcR) (CD16) and for NCAM-I (CD56), and many NK cells express T lineage markers, particularly CD8, and proliferatein response toIL-2. NK cellsarise in both bonemarrow and thymic microenvironments.


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InternalMed_Harrison. Functionally, NK cells share features with both monocytes-macrophages and neutrophils in that they mediate both ADCC and NK cell activity.ADCCisthebindingofanopsonized(antibody-coated)target celltoanFcreceptor-bearingeffectorcellviatheFcregionofantibody, resulting in lysis of the target by the effector cell. NK cell cytotoxicity is the nonimmune (i.e., effector cell never having had previous contact with the target), MHC-unrestricted, non-antibody-mediated killing of target cells, which are usually malignant cell types, transplanted foreign cells, or virus-infected cells. Thus, NK cell cytotoxicity may play Abbreviations: IL-4, IL-5, IL-6, IL-10, and IL-12, interleukin 4, 5, 6, 10, and 12, respectively; MHC, major histocompatibility complex: LPS, lipopolysaccharide; PAMP, pathogen-associated molecular patterns; TH, helper T cell; TNF-α, tumor necrosis factor-alpha.


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InternalMed_Harrison. Source: Adapted from R Medzhitov, CA Janeway: Curr Opinion Immunol 9:4, 1997. Copyright 1997, with permission from Elsevier. an important role in immune surveillance and destruction of malig-to uninfected, nonmalignant self-cells; however, they are activated nant and virus-infected host cells. NK cell hyporesponsiveness is also to attack malignant and virally infected cells (Fig. 372e-4). Recent observed in patients with Chédiak-Higashi syndrome, an autosomal evidence suggests that NK cells, although not possessing rearranging recessive disease associated with fusion of cytoplasmic granules and immune recognition genes, may be able to mediate recall for NK cell defective degranulation of neutrophil lysosomes. responses to viruses and for immune responses such as contact hyper-


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InternalMed_Harrison. NK cells have a variety of surface receptors that have inhibitory sensitivity. or activating functions and belong to two structural families. These Some NK cells express CD3 and invariant TCR-α chains and are families include the immunoglobulin superfamily and the lectin-like termed NK T cells. TCRs of NK T cells recognize lipid molecules type II transmembrane proteins. NK immunoglobulin superfamily of intracellular bacteria when presented in the context of CD1d receptors include the killer cell immunoglobulin-like activating or molecules on APCs. Upon activation, NK T cells secrete effector inhibitory receptors (KIRs), many of which have been shown to have cytokines such as IL-4 and IFN-γ. This mode of recognition of intra-HLA class I ligands. The KIRs are made up proteins with either two cellular bacteria such as Listeria monocytogenes and Mycobacterium (KIR2D) or three (KIR3D) extracellular immunoglobulin domains tuberculosis by NK T cells leads to induction of activation of DCs


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InternalMed_Harrison. two cellular bacteria such as Listeria monocytogenes and Mycobacterium (KIR2D) or three (KIR3D) extracellular immunoglobulin domains tuberculosis by NK T cells leads to induction of activation of DCs (D). Moreover, their nomenclature designates their function as either and is thought to be an important innate defense mechanism against inhibitory KIRs with a long (L) cytoplasmic tail and immunoreceptor these organisms. tyrosine-based inhibitory motif (ITIM) (KIRDL) or activating KIRs The receptors for the Fc portion of IgG (FcγRs) are present on NK with a short (S) cytoplasmic tail (KIRDS). NK cell inactivation by KIRs cells, B cells, macrophages, neutrophils, and mast cells and mediate isacentralmechanismtopreventdamagetonormalhostcells.Genetic interactions of IgG with antibody-coated target cells, such as virally studies have demonstrated the association of KIRs with viral infection infected cells. Antibody-NK interaction via antibody Fc and NK cell outcome and autoimmune disease


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InternalMed_Harrison. target cells, such as virally studies have demonstrated the association of KIRs with viral infection infected cells. Antibody-NK interaction via antibody Fc and NK cell outcome and autoimmune disease (Table 372e-10). FcR links the adaptive and innate immune systems and regulates the


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InternalMed_Harrison. In addition to the KIRs, a second set of immunoglobulin superfam-mediation of IgG antibody effector functions such as ADCC. There ily receptors includes the natural cytotoxicity receptors (NCRs), which are both activation and inhibitory FcγRs. Activation FcRs, such as include NKp46, NKp30, and NKp44. These receptors help to mediate FcγRI (CD64), FcγRII (CD32), and FcγRII (CD64), are character-NK cell activation against target cells. The ligands to which NCRs bind ized by the presence of an immunoreceptor tyrosine-based activating on target cells have been recently recognized to be comprised of mol-motif (ITAM) sequence, whereas inhibitory FcRs, such as FcγRIIb, ecules of pathogens such as influenza, vaccinia, and malaria as well as contain an immunoreceptor tyrosine-based inhibitory motif (ITIM) host molecules expressed on tumor cells. sequence. There is evidence that dysregulation in IgG-FcγR interac-


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InternalMed_Harrison. NK cell signaling is, therefore, a highly coordinated series of inhib-tions plays a role in arthritis, multiple sclerosis, and systemic lupus iting and activating signals that prevent NK cells from responding erythematosus. Introduction to the Immune System


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InternalMed_Harrison. Introduction to the Immune System Neutrophils, Eosinophils, and Basophils Granulocytes are present in nearly all forms of inflammation and are amplifiers and effectors of innate immune responses (Figs. 372e-2 and 372e-3). Unchecked accumulation and activation of granulocytes can lead to host tissue damage, as seen in neutrophil-and eosinophil-mediated systemic necrotizing vasculitis. Granulocytes are derived from stem cells in bone marrow. Each type of granulocyte (neutrophil, eosinophil, or basophil) is derived from a different subclass of progenitor cell that is stimulated to proliferate by colony-stimulating factors (Table 372e-7). During terminal maturation of granulocytes, class-specific nuclear morphology and cytoplasmic granules appear that allow for histologic identification of granulocyte type.


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InternalMed_Harrison. Neutrophils express Fc receptor IIIa for IgG (CD16) as well as receptors for activated complement components (C3b or CD35). Upon interaction of neutrophils with antibody-coated (opsonized) bacteria or immune complexes, azurophilic granules (containing myeloperoxidase, lysozyme, elastase, and other enzymes) and specific granules (containing lactoferrin, lysozyme, collagenase, and other enzymes) are released, and microbicidal superoxide radicals (O2 -) are generatedattheneutrophilsurface.Thegenerationofsuperoxideleads to inflammation by direct injury to tissue and by alteration of macromolecules such as collagen and DNA.


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InternalMed_Harrison. Eosinophils express Fc receptor II for IgG (CD32) and are potent cytotoxic effector cells for various parasitic organisms. In Nippostrongylus brasiliensis helminth infection, eosinophils are important cytotoxic effector cells for removal of these parasites. Key to regulation of eosinophil cytotoxicitytoN. brasiliensis wormsareantigen-specificThelpercellsthat produce IL-4, thus providing an example of regulation of innate immune responsesbyadaptiveimmunityantigen-specificTcells.Intracytoplasmic contents of eosinophils, such as major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin, are capable of directly damaging tissues and may be responsible in part for the organ system dysfunction in the hypereosinophilic syndromes (Chap. 80). Because the eosinophil granule contains anti-inflammatory types of enzymes (histaminase, arylsulfatase, phospholipase D), eosinophils may homeostatically downregulate or terminate ongoing inflammatory responses.


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InternalMed_Harrison. Basophils and tissue mast cells are potent reservoirs of cytokines suchasIL-4andcanrespondtobacteriaandviruseswithantipathogen cytokine production through multiple TLRs expressed on their surface. Mast cells and basophils can also mediate immunity through the binding of antipathogen antibodies. This is a particularly important host defense mechanism against parasitic diseases. Basophils express high-affinity surface receptors for IgE (FcεRII) (CD23) and, upon cross-linking of basophil-bound IgE by antigen, can release histamine, eosinophil chemotactic factor of anaphylaxis, and neutral protease— all mediators of allergic immediate (anaphylaxis) hypersensitivity responses (Table 372e-11). In addition, basophils express surface receptors for activated complement components (C3a, C5a), through IL-12 antigen presentation Myeloid dendritic cell IL-1,IL-6 phagocytosis of microbes


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InternalMed_Harrison. IL-12 antigen presentation Myeloid dendritic cell IL-1,IL-6 phagocytosis of microbes CD8+ cytotoxic T cell CD4+, CD8+ regulatory cells TH1 TH2 TH0 TR IL-12 IL-4 IFN-°intracellular microbes IL-4,IL-5 extracellular microbes Phagocytosis of microbes; secretion of inflammatory products Neutrophilic granulocyte FIGUrE 372e-2 Schematic model of intercellular interactions of adaptive immune system cells.


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InternalMed_Harrison. In this figure, the arrows denote that cells develop from precursor cells or produce cytokines or antibodies; lines ending with bars indicate suppressive intercellular interactions. Stem cells differentiate into either T cells, antigen-presenting dendritic cells, natural killer cells, macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, and peptide fragments of foreign antigen are presented to CD4+ and/or CD8+ T cells. CD8+ T cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells. For antibody production against the same antigen, active antigen is bound to sIg within the B cell receptor complex and drives B cell maturation into plasma cells that secrete Ig. TH1 or TH2 CD4+ T cells producing interleukin (IL) 4, IL-5, or interferon (IFN) γ regulate the Ig class switching and determine the type of antibody produced. TH17 cells secrete IL-17, IL-22,


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InternalMed_Harrison. Ig. TH1 or TH2 CD4+ T cells producing interleukin (IL) 4, IL-5, or interferon (IFN) γ regulate the Ig class switching and determine the type of antibody produced. TH17 cells secrete IL-17, IL-22, IL-26, which contribute to host defense against extracellular bacteria and fungi, particularly at mucosal surfaces. CD4+, CD25+ T regulatory cells produce IL-10 and downregulate T and B cell responses once the microbe has been eliminated. GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF, tumor necrosis factor.


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InternalMed_Harrison. surveillance of HLA class I– negative cells (malignant and virus-infected cells) Introduction to the Immune System which mediator release can be directly affected. Thus, basophils, like most cells of the immune system, can be activated in the service of host defense against pathogens, or they can be activated for mediation release and cause pathogenic responses in allergic and inflammatory diseases. For further discussion of tissue mast cells, see Chap. 376.


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InternalMed_Harrison. The Complement System Thecomplementsystem,animportantsoluble componentoftheinnateimmunesystem,isaseriesofplasmaenzymes, regulatory proteins, and proteins that are activated in a cascading fashion, resulting in cell lysis. There are four pathways of the complement system: the classic activation pathway activated by antigen/antibody immune complexes, the mannose-binding lectin (MBL) (a serum collectin; Table 372e-3) activation pathway activated by microbes with terminal mannose groups, the alternative activation pathway activated by microbes or tumor cells, and the terminal pathway that is common to the first three pathways and leads to the membrane attack complex that lyses cells (Fig. 372e-5). The series of enzymes of the complement system are serine proteases.


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InternalMed_Harrison. Activation of the classic complement pathway via immune complex binding to C1q links the innate and adaptive immune systems via specific antibodyintheimmunecomplex.The alternative complement activation pathway is antibody-independent and is activated by binding of C3 directly to pathogens and “altered self” such as tumor cells. In the renal glomerular inflammatory disease IgA nephropathy, IgA activates the alternative complement pathway and causes glomerular damage and decreased renal function. Activation of the classic complement pathway via C1, C4, and C2 and activation of the alternative pathway via factor D, C3, and factor B both lead to cleavage and activation of C3. C3 activation fragments, when bound to target surfaces such as bacteria and other foreign antigens, are critical for opsonization (coating by antibody and complement) in preparation for phagocytosis. The MBL pathway substitutes MBL-associated serine proteases (MASPs) 1 and 2 for C1q, C1r, and C1s to activate C4. The


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InternalMed_Harrison. (coating by antibody and complement) in preparation for phagocytosis. The MBL pathway substitutes MBL-associated serine proteases (MASPs) 1 and 2 for C1q, C1r, and C1s to activate C4. The MBL activation pathway is activated by mannose on the surface of bacteria and viruses.


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InternalMed_Harrison. The three pathways of complement activation all converge on the final common terminal pathway. C3 cleavage by each pathway results in activation of C5, C6, C7, C8, and C9, resulting in the membrane attack complex that physically inserts into the membranes of target cells or bacteria and lyses them. Thus, complement activation is a critical component of innate immunity for responding to microbial infection. The functional consequences of complement activation by the three initiating pathways and the terminal pathway are shown in Fig. 372e-5. In general the cleavage products of complement components facilitate microbe or damaged cell clearance (C1q, C4, C3), promote activation and enhancement of inflammation (anaphylatoxins, C3a, C5a), and promote microbe or opsonized cell lysis (membrane attack complex).


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InternalMed_Harrison. Cytokinesare soluble proteinsproducedbya wide varietyof cell types (Tables 372e-7 to 372e-9). They are critical for both normal innate and adaptive immune responses, and their expression may be perturbed in most immune, inflammatory, and infectious disease states. IL-1α, β Type I IL-1r, Type II IL-1r IL-2r α, β, common γ IL-3r, common β IL-4r α, common γ IL-5r α, common γ IL-6r, gp130 IL-7r α, common γ CXCR1, CXCR2 IL-9r α, common γ IL-10r IL-11r α, gp130 IL-15r α, common γ, IL2r β CD4 Monocytes/macrophages, B cells, fibroblasts, most epithelial cells including thymic epithelium, endothelial cells T cells, NK cells, mast cells T cells, mast cells, basophils T cells, mast cells, eosinophils Monocytes-macrophages, B cells, fibroblasts, most epithelium including thymic epithelium, endothelial cells Bone marrow, thymic epithelial cells Monocytes-macrophages, T cells, neutrophils, fibroblasts, endothelial cells, epithelial cells


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InternalMed_Harrison. Bone marrow, thymic epithelial cells Monocytes-macrophages, T cells, neutrophils, fibroblasts, endothelial cells, epithelial cells Monocytes-macrophages, T cells, B cells, keratinocytes, mast cells Activated macrophages, dendritic cells, neutrophils Monocytes-macrophages, epithelial cells, fibroblasts Mast cells, eosinophils, CD8+ T cells, respiratory epithelium Keratinocytes, macrophages DC, T cells Macrophages, other cell types All cells T cells, B cells, NK cells, monocytes-macrophages Monocytes-macrophages, mast cells, eosinophils, bone marrow progenitors T cells, B cells, NK cells, monocytes-macrophages, neutrophils, eosinophils, endothelial cells, fibroblasts Eosinophils, basophils, murine B cells T cells, B cells, epithelial cells, hepatocytes, monocytesmacrophages T cells, B cells, bone marrow cells Neutrophils, T cells, monocytes-macrophages, endothelial cells, basophils Bone marrow progenitors, B cells, T cells, mast cells


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InternalMed_Harrison. T cells, B cells, bone marrow cells Neutrophils, T cells, monocytes-macrophages, endothelial cells, basophils Bone marrow progenitors, B cells, T cells, mast cells Monocytes-macrophages, T cells, B cells, NK cells, mast cells Megakaryocytes, B cells, hepatocytes T cells, NK cells Monocytes-macrophages, B cells, endothelial cells, keratinocytes T cells, NK cells CD4+ T cells, monocytesmacrophages, eosinophils Fibroblasts, endothelium, epithelium, macrophages T cells, B cells, NK cells T cells Upregulates adhesion molecule expression, neutrophil and macrophage emigration, mimics shock, fever, upregulates hepatic acute-phase protein production, facilitates hematopoiesis Promotes T cell activation and proliferation, B cell growth, NK cell proliferation and activation, enhanced monocyte/macrophage cytolytic activity


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InternalMed_Harrison. Promotes T cell activation and proliferation, B cell growth, NK cell proliferation and activation, enhanced monocyte/macrophage cytolytic activity Stimulates TH2 helper T cell differentiation and proliferation; stimulates B cell Ig class switch to IgG1 and IgE anti-inflammatory action on T cells, monocytes; produced by T follicular helper cells in B cell germinal centers that stimulate B cell maturation. Induces acute-phase protein production, T and B cell differentiation and growth, myeloma cell growth, and osteoclast growth and activation Differentiates B, T, and NK cell precursors, activates T and NK cells Induces neutrophil, monocyte, and T cell migration, induces neutrophil adherence to endothelial cells and histamine release from basophils, and stimulates angiogenesis; suppresses proliferation of hepatic precursors Induces mast cell proliferation and function, synergizes with IL-4 in IgG and IgE production and T cell growth, activation, and differentiation


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InternalMed_Harrison. Induces mast cell proliferation and function, synergizes with IL-4 in IgG and IgE production and T cell growth, activation, and differentiation Inhibits macrophage proinflammatory cytokine production, downregulates cytokine class II antigen and B7-1 and B7-2 expression, inhibits differentiation of TH1 helper T cells, inhibits NK cell function, stimulates mast cell proliferation and function, B cell activation, and differentiation Induces megakaryocyte colony formation and maturation, enhances antibody responses, stimulates acute-phase protein production Induces TH1 T helper cell formation and lymphokine-activated killer cell formation; increases CD8+ CTL cytolytic activity; ↓IL-17, ↑IFN-γ Upregulates VCAM-1 and C-C chemokine expression on endothelial cells and B cell activation and differentiation, and inhibits macrophage proinflammatory cytokine production Induces B cell proliferation, inhibits antibody secretion, and expands selected B cell subgroups


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InternalMed_Harrison. Induces B cell proliferation, inhibits antibody secretion, and expands selected B cell subgroups Promotes T cell activation and proliferation, angiogenesis, and NK cells Promotes chemoattraction of CD4+ T cells, monocytes, and eosinophils; inhibits HIV replication; inhibits T cell activation through CD3/T cell receptor Upregulates IFN-γ production, enhances NK cell cytotoxicity Downregulates NK cell–activating molecules, NKG2D/DAP10; produced by T follicular helper cells in B cell germinal centers that stimulate B cell maturation. Opposite effects of IL-12 (↑IL-17, ↑IFN-γ) TNFrI, TNFrII TNFrI, TNFrII LTβR G-CSFr; gp130 GM-CSFr, common β Type I, II, III TGF-β receptor CCR1, CCR2 Macrophages, CD4 T cells, mast cells TH1, TH17 T cells, synovial cells T cells, NK cells Monocytes-macrophages, mast cells, basophils, eosinophils, NK cells, B cells, T cells, keratinocytes, fibroblasts, thymic epithelial cells T cells, B cells


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InternalMed_Harrison. T cells, NK cells Monocytes-macrophages, mast cells, basophils, eosinophils, NK cells, B cells, T cells, keratinocytes, fibroblasts, thymic epithelial cells T cells, B cells Monocytes-macrophages, fibroblasts, endothelial cells, thymic epithelial cells, stromal cells T cells, monocytes-macrophages, fibroblasts, endothelial cells, thymic epithelial cells Fibroblasts, endothelial cells, monocytes-macrophages, T cells, B cells, epithelial cells including thymic epithelium Activated T cells, bone marrow stromal cells, thymic epithelium Activated monocytesmacrophages and T cells, bone marrow stromal cells, some breast carcinoma cell lines, myeloma cells NK cells, mast cells, double-negative thymocytes, activated CD8+ T cells Fibroblasts, smooth-muscle cells, activated PBMCs Fibroblasts, activated PBMCs Nonhematopoietic cells such as fibroblasts Fibroblasts, endothelium, epithelium, macrophages Myeloid cells, endothelial cells


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InternalMed_Harrison. Fibroblasts, activated PBMCs Nonhematopoietic cells such as fibroblasts Fibroblasts, endothelium, epithelium, macrophages Myeloid cells, endothelial cells Monocytes-macrophages, neutrophils, eosinophils, fibroblasts, endothelial cells Megakaryocytes, monocytes, hepatocytes, possibly lymphocyte subpopulations Neurons, hepatocytes, monocytes-macrophages, adipocytes, alveolar epithelial cells, embryonic stem cells, melanocytes, endothelial cells, fibroblasts, myeloma cells Embryonic stem cells, myeloid and lymphoid precursors, mast cells T cells, NK cells Monocytes-macrophages, NK cells, memory T cells, basophils Monocytes-macrophages, T cells, eosinophils, basophils, NK cells Promotes wound healing Promotes antiviral activity; stimulates T cell, macrophage, and NK cell activity; direct antitumor effects; upregulates MHC class I antigen expression; used therapeutically in viral and autoimmune conditions


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InternalMed_Harrison. Antiviral activity; stimulates T cell, macrophage, and NK cell activity; direct antitumor effects; upregulates MHC class I antigen expression; used therapeutically in viral and autoimmune conditions Regulates macrophage and NK cell activations; stimulates immunoglobulin secretion by B cells; induction of class II histocompatibility antigens; TH1 T cell differentiation Fever, anorexia, shock, capillary leak syndrome, enhanced leukocyte cytotoxicity, enhanced NK cell function, acute phase protein synthesis, proinflammatory cytokine induction Cell cytotoxicity, lymph node and spleen development Cell cytotoxicity, normal lymph node development Regulates myelopoiesis; enhances survival and function of neutrophils; clinical use in reversing neutropenia after cytotoxic chemotherapy


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InternalMed_Harrison. Regulates myelopoiesis; enhances survival and function of neutrophils; clinical use in reversing neutropenia after cytotoxic chemotherapy Regulates myelopoiesis; enhances macrophage bactericidal and tumoricidal activity; mediator of dendritic cell maturation and function; upregulates NK cell function; clinical use in reversing neutropenia after cytotoxic chemotherapy Induces hepatic acute-phase protein production; stimulates macrophage differentiation; promotes growth of myeloma cells and hematopoietic progenitors; stimulates thrombopoiesis Induces hepatic acute-phase protein production; stimulates macrophage differentiation; promotes growth of myeloma cells and hematopoietic progenitors; stimulates thrombopoiesis; stimulates growth of Kaposi’s sarcoma cells Stimulates hematopoietic progenitor cell growth, mast cell growth; promotes embryonic stem cell migration


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InternalMed_Harrison. Stimulates hematopoietic progenitor cell growth, mast cell growth; promotes embryonic stem cell migration Downregulates T cell, macrophage, and granulocyte responses; stimulates synthesis of matrix proteins; stimulates angiogenesis Chemoattractant for lymphocytes; only known chemokine of C class Chemoattractant for monocytes, activated memory T cells, and NK cells; induces granule release from CD8+ T cells and NK cells; potent histamine-releasing factor for basophils; suppresses proliferation of hematopoietic precursors; regulates monocyte protease production Chemoattractant for monocytes, memory and naïve T cells, eosinophils, ?NK cells; activates basophils and eosinophils; regulates monocyte protease production Introduction to the Immune System MIG SDF-1 CCR1, CCR2 CCR2, CCR3 CCR3 CCR4 CCR4 CCR1, CCR5 CCR5 CCR1, CCR2, CCR5 CXCR3 CXCR4 Fibroblasts, activated PBMCs Lung, colon, small intestinal epithelial cells, activated endothelial cells


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InternalMed_Harrison. CCR2, CCR3 CCR3 CCR4 CCR4 CCR1, CCR5 CCR5 CCR1, CCR2, CCR5 CXCR3 CXCR4 Fibroblasts, activated PBMCs Lung, colon, small intestinal epithelial cells, activated endothelial cells Pulmonary epithelial cells, heart Thymus, dendritic cells, activated T cells Monocytes-macrophages, dendritic cells, thymus Monocytes-macrophages, T cells Monocytes-macrophages, T cells Monocytes-macrophages, T cells, fibroblasts, eosinophils Dendritic cells, fetal liver cells, activated T cells Thymus, lymph node, appendix Thymic epithelial cells, lymph node, appendix, and spleen Dendritic cells, thymus, liver, small intestine Activated granulocytes, monocyte-macrophages, and epithelial cells Monocytes-macrophages, T cells, fibroblasts, endothelial cells, epithelial cells Monocytes-macrophages, T cells, fibroblasts Monocytes-macrophages, T cells, eosinophils, basophils, NK cells, dendritic cells Monocytes-macrophages, T cells, eosinophils, basophils Eosinophils, basophils T cells, NK cells


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InternalMed_Harrison. Monocytes-macrophages, T cells, eosinophils, basophils, NK cells, dendritic cells Monocytes-macrophages, T cells, eosinophils, basophils Eosinophils, basophils T cells, NK cells Monocytes-macrophages, T cells, dendritic cells, NK cells, eosinophils, basophils Monocytes-macrophages, T cells, NK cells, dendritic cells Monocytes-macrophages, T cells, NK cells, dendritic cells, eosinophils, basophils T cells, B cells Monocytes-macrophages, T cells T cells, monocytesmacrophages, dendritic cells Neutrophils, epithelial cells, ?endothelial cells Neutrophils and ?endothelial cells Neutrophils, basophils Activated T cells, tumor-infiltrating lymphocytes, ?endothelial cells, ?NK cells Activated T cells, tumor-infiltrating lymphocytes T cells, dendritic cells, ?basophils, ?endothelial cells Chemoattractant for monocytes, memory and naïve T cells, dendritic cells, eosinophils, ?NK cells; activates basophils and eosinophils; regulates monocyte protease production


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InternalMed_Harrison. Chemoattractant for monocytes, memory and naïve T cells, dendritic cells, eosinophils, ?NK cells; activates basophils and eosinophils; regulates monocyte protease production Chemoattractant for monocytes, T cells, eosinophils, and basophils Potent chemoattractant for eosinophils and basophils; induces allergic airways disease; acts in concert with IL-5 to activate eosinophils; antibodies to eotaxin inhibit airway inflammation Chemoattractant for activated T cells; inhibits infection with T cell tropic HIV Chemoattractant for monocytes, T cells, dendritic cells, and NK cells, and weak chemoattractant for eosinophils and basophils; activates NK cell function; suppresses proliferation of hematopoietic precursors; necessary for myocarditis associated with coxsackievirus infection; inhibits infection with monocytotropic HIV Chemoattractant for monocytes, T cells, and NK cells; activates NK cell function; inhibits infection with monocytotropic HIV


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InternalMed_Harrison. Chemoattractant for monocytes, T cells, and NK cells; activates NK cell function; inhibits infection with monocytotropic HIV Chemoattractant for monocytes-macrophages, CD4+, CD45Ro+ T cells, CD8+ T cells, NK cells, eosinophils, and basophils; induces histamine release from basophils; inhibits infections with monocytotropic HIV May have a role in induction of immune responses Thymic dendritic cell-derived cytokine, possibly involved in T cell development Neutrophil chemoattractant and activator; mitogenic for some melanoma cell lines; suppresses proliferation of hematopoietic precursors; angiogenic activity IFN-γ-inducible protein that is a chemoattractant for T cells; suppresses proliferation of hematopoietic precursors IFN-γ-inducible protein that is a chemoattractant for T cells; suppresses proliferation of hematopoietic precursors


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InternalMed_Harrison. IFN-γ-inducible protein that is a chemoattractant for T cells; suppresses proliferation of hematopoietic precursors Low-potency, high-efficacy T cell chemoattractant; required for B-lymphocyte development; prevents infection of CD4+, CXCR4+ cells by T cell tropic HIV


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InternalMed_Harrison. Abbreviations: B7-1, CD80; B7-2, CD86; CCR, CC-type chemokine receptor; CXCR, CXC-type chemokine receptor; DC-CK, dendritic cell chemokine; EBV, Epstein-Barr virus; ELC, EB11 ligand chemokine (MIP-1b); G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GRP, growth-related peptide; HSV, herpes simplex virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IP-10, IFN-γ-inducible protein-10; LARC, liverand activation-regulated chemokine; LIF, leukemia inhibitory factor; MCP, monocyte chemotactic protein; M-CSF, macrophage colony-stimulating factor; MDC, macrophage-derived chemokine; MGSA, melanoma growth-stimulating activity; MHC, major histocompatibility complex; MIG, monokine induced by IFN-γ; MIP, macrophage inflammatory protein; NAP, neutrophil-activating protein; NK, natural killer; OSM, oncostatin M; PARC, pulmonaryand activation-regulated chemokine; PBMC, peripheral blood mononuclear cells; PF, platelet factor; RANTES,


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InternalMed_Harrison. NAP, neutrophil-activating protein; NK, natural killer; OSM, oncostatin M; PARC, pulmonaryand activation-regulated chemokine; PBMC, peripheral blood mononuclear cells; PF, platelet factor; RANTES, regulated on activation, normally T cell–expressed and –secreted; SCF, stem cell factor; SDF, stromal cell–derived factor; SLC, secondary lymphoid tissue chemokine; TARC, thymusand activation-regulated chemokine; TCA, T cell activation protein; TECK, thymus expressed chemokine; TGF, transforming growth factor; TH1 and TH2, helper T cell subsets; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.


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InternalMed_Harrison. Source: Data from JS Sundy et al: Appendix B, in Inflammation, Basic Principles and Clinical Correlates, 3rd ed, J Gallin and R Snyderman (eds). Philadelphia, Lippincott Williams and Wilkins, 1999. taBle 372e-8 cc, cXc1, cX3, c1, and Xc famIlIeS of chemokIneS and chemokIne receptorS CXCR3-A CXCL9 (MIG), CXCL10 (IP-10), CXCL11 Type 1 helper cells, mast cells, mesangial Inflammatory skin disease, multiple sclerosis, transplant (I-TAC) cells rejection


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InternalMed_Harrison. Abbreviations: BCA-1, B-cell chemoattractant 1; COPD, chronic obstructive pulmonary disease; CTACK, cutaneous T cell–attracting chemokine; ELC, Epstein-Barr I1-ligand chemokine; ENA, epithelial cell–derived neutrophil-activating peptide; GCP, granulocyte chemotactic protein; GRO, growth-regulated oncogene; HCC, hemofiltrate chemokine; IP-10, interferon inducible 10; I-TAC, interferon-inducible T cell alpha chemoattractant; LARC, liverand activation-regulated chemokine; MCP, monocyte chemoattractant protein; MDC, macrophage-derived chemokine; MEC, mammary-enriched chemokine; MIG, monokine induced by interferon-γ; MIP, macrophage inflammatory protein; PF, platelet factor; SDF, stromal cell–derived factor; SLC, secondary lymphoid-tissue chemokine; SR-PSOX, scavenger receptor for phosphatidylserine-containing oxidized lipids; TARC, thymusand activation-regulated chemokine; TECK, thymus-expressed chemokine; TH2, type 2 helper T cells.


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InternalMed_Harrison. Source: From IF Charo, RM Ranshohoff: N Engl J Med 354:610, 2006, with permission. Copyright Massachusetts Medical Society. All rights reserved. Introduction to the Immune System Hematopoietins IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-15, IL-16, IL-17, IL-21, IL-23, EPO, LIF, GM-CSF, G-CSF, OSM, CNTF, GH, and TPO TNF-α, LT-α, LT-β, CD40L, CD30L, CD27L, 4-1BBL, OX40, OPG, and FasL IL-1α, IL-1β, IL-1ra, IL-18, bFGF, aFGF, and ECGF PDGF PDGF A, PDGF B, and M-CSF TGF-β TGF-β and BMPs (1, 2, 4, etc.) C-X-C chemokines IL-8, Gro-α/β/γ, NAP-2, ENA78, GCP-2, PF4, CTAP-3, MIG, and IP-10 C-C chemokines MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β, RANTES


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InternalMed_Harrison. Abbreviations: aFGF, acidic fibroblast growth factor; 4-1BBL, 401 BB ligand; bFGF, basic fibroblast growth factor; BMP, bone marrow morphogenetic proteins; C-C, cysteinecysteine; CD, cluster of differentiation; CNTF, ciliary neurotrophic factor; CTAP, connective tissue–activating peptide; C-X-C, cysteine-x-cysteine; ECGF, endothelial cell growth factor; EPO, erythropoietin; FasL, Fas ligand; GCP-2, granulocyte chemotactic protein 2; G-CSF, granulocyte colony-stimulating factor; GH, growth hormone; GM-CSF, granulocytemacrophage colony-stimulating factor; Gro, growth-related gene products; IFN, interferon; IL, interleukin; IP, interferon-γ inducible protein; LIF, leukemia inhibitory factor; LT, lymphotoxin; MCP, monocyte chemoattractant; M-CSF, macrophage colony-stimulating factor; MIG, monokine induced by interferon-γ; MIP, macrophage inflammatory protein; NAP-2, neutrophil activating protein 2; OPG, osteoprotegerin; OSM, oncostatin M; PDGF, platelet-derived growth factor; PF, platelet


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InternalMed_Harrison. induced by interferon-γ; MIP, macrophage inflammatory protein; NAP-2, neutrophil activating protein 2; OPG, osteoprotegerin; OSM, oncostatin M; PDGF, platelet-derived growth factor; PF, platelet factor; R, receptor; RANTES, regulated on activation, normal T cell–expressed and –secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; TPO, thyroperoxidase.


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InternalMed_Harrison. Cytokines are involved in the regulation of the growth, development, and activation of immune system cells and in the mediation of the inflammatory response. In general, cytokines are characterized by considerable redundancy; different cytokines have similar functions. In addition, many cytokines are pleiotropic in that they are capable of acting on many different cell types. This pleiotropism results from the expression on multiple cell types of receptors for the same cytokine (see below),leadingtothe formation of“cytokine networks.”The action of cytokines may be (1) autocrine when the target cell is the same cell that secretes the cytokine, (2) paracrine when the target cell is nearby, and (3) endocrine when the cytokine is secreted into the circulation and acts distal to the source.


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InternalMed_Harrison. Cytokines have been named based on presumed targets or based on presumed functions. Those cytokines that are thought to primarily target leukocytes have been named interleukins (IL-1, -2, -3, etc.). Many cytokines that were originally described as having a certain function have retained those names (e.g., granulocyte colony-stimulating factor [G-CSF]). Cytokines belong in general to three major structural families: the hematopoietin family; the TNF, IL-1, platelet-derived growth factor (PDGF), and transforming growth factor (TGF) β families; and the CXC and C-C chemokine families (Table 372e-9). Chemokines are cytokines that regulate cell movement and trafficking; they act through G protein-coupled receptors and have a distinctive three-dimensional structure. IL-8istheonlychemokinethatearlyonwasnamedanIL(Table372e-7). Activation of TH1 CD4+ T cells Activation of TH2 CD4+ T cells IL-2, IFN-˜, IL-3


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InternalMed_Harrison. Activation of TH1 CD4+ T cells Activation of TH2 CD4+ T cells IL-2, IFN-˜, IL-3 IL-3, IL-4, IL-5, IL-6, TNF-°, TNF-˛, GM-CSF IL-10, IL-13 Inhibition Inhibition of TH2 of TH1 responses type responses Eosinophil Mast cell B cell IgM, Induce CD8+ B cell IgG Macrophage basophil G, A, and E cytotoxic antibody activation Kill parasites Regulation Direct antibody killing Kill microbe Opsonize Kill opsonized of vascular of microbes and infected cells microbes for microbes permeability; opsonize for microbial phagocytosis allergic responses; phagocytosis protective responses to bacteria, viruses, and parasitic infections


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InternalMed_Harrison. FIGUrE 372e-3 CD4+ helper T1 (TH1) cells and TH2 T cells secrete distinct but overlapping sets of cytokines. TH1 CD4+ cells are frequently activated in immune and inflammatory reactions against intracellular bacteria or viruses, whereas TH2 CD4+ cells are frequently activated for certain types of antibody production against parasites and extracellular encapsulated bacteria; they are also activated in allergic diseases. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor. (Adapted from S Romagnani: CD4 effector cells, in Inflammation: Basic Principles and Clinical Correlates, 3rd ed, J Gallin, R Snyderman [eds]. Philadelphia, Lippincott Williams & Wilkins, 1999, p 177; with permission.) Introduction to the Immune System Spondylarthritides Increased KIR3DL2 expression May contribute to disease pathology


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InternalMed_Harrison. Introduction to the Immune System Spondylarthritides Increased KIR3DL2 expression May contribute to disease pathology Interaction HLA-B27 homodi-May contribute to mers with KIR3DL1/KIR3DL2; disease pathogenesis independent of peptide patients with extraarticular may have different with respect to KIR Behçet’s disease Altered KIR3DL1 expression Associated with severe eye disease Type 1 diabetes KIR2DS2; HLA-C1 and no Increased disease HLA-C2, no HLA-Bw4 progression Preeclampsia KIR2DL1 with fewer KIR2DS Increased disease (mother); HLA-C2 (fetus) progression Abbreviations: HCV, hepatitis C virus; HLA, human leukocyte antigen; HPV, human papillomavirus; IDDM, insulin-dependent diabetes mellitus; KIR, killer cell immunoglobulin-like receptor. Source: Adapted from R Diaz-Pena et al: Adv Exp Med Biol 649:286, 2009.


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InternalMed_Harrison. Source: Adapted from R Diaz-Pena et al: Adv Exp Med Biol 649:286, 2009. In general, cytokines exert their effects by influencing gene activation that results in cellular activation, growth, differentiation, functional cell-surface molecule expression, and cellular effector function. In this regard, cytokines can have dramatic effects on the regulation of immune responses and the pathogenesis of a variety of diseases. Indeed, T cells have been categorized on the basis of the pattern of cytokines that they secrete, which results in either humoral immune response (TH2) or cell-mediated immune response (TH1). A third type of T helper cell is the TH17 cell that contributes to host defense against extracellular bacteria and fungi, particularly at mucosal sites (Fig. 372e-2).


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InternalMed_Harrison. Cytokine receptors can be grouped into five general families based on similarities in their extracellular amino acid sequences and conserved structural domains. The immunoglobulin (Ig) superfamily represents a large number of cell-surface and secreted proteins. The IL-1 receptors (type 1, type 2) are examples of cytokine receptors with extracellular Ig domains. The hallmark of the hematopoietic growth factor (type 1) receptor family is that the extracellular regions of each receptor contain two conserved motifs. One motif, located at the N terminus, is rich in cysteine residues. The other motif is located at the C terminus proximal to the transmembrane region and comprises five amino acid residues, Outcome determined by balance of signals


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InternalMed_Harrison. Outcome determined by balance of signals FIGUrE 372e-4 Encounters between NK cells: potential targets and possible outcomes. The amount of activating and inhibitory receptors on the NK cells and the amount of ligands on the target cell, as well as the qualitative differences in the signals transduced, determine the extent of the NK response. A. When target cells have no HLA class I or activating ligands, NK cells cannot kill target cells.


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InternalMed_Harrison. B. When target cells bear self-HLA, NK cells cannot kill targets. C. When target cells are pathogen infected and have downregulated HLA and express activating ligands, NK cells kill target cells. D. When NK cells encounter targets with both self-HLA and activating receptors, then the level of target killing is determined by the balance of inhibitory and activating signals to the NK cell. HLA, human leukocyte antigen; NK, natural killer. (Adapted from L Lanier: Annu Rev Immunol 23:225, 2005; reproduced with permission from Annual Reviews Inc. Copyright 2011 by Annual Reviews Inc.) Slow reacting substance of anaphylaxis (SRSA) (leukotriene C4, D4, E4) Eosinophil chemotactic factor of anaphylaxis (ECF-A) Neutrophil chemotactic factor (NCF) Leukotactic activity (leukotriene B4) Heparin Basophil kallikrein of anaphylaxis Smooth-muscle contraction, increased vascular permeability Chemotactic attraction of eosinophils


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InternalMed_Harrison. Smooth-muscle contraction, increased vascular permeability Chemotactic attraction of eosinophils Activates platelets to secrete serotonin and other mediators: smooth-muscle contraction; induces vascular permeability Chemotactic attraction of neutrophils Chemotactic attraction of neutrophils Anticoagulant Cleaves kininogen to form bradykinin Clearance of


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InternalMed_Harrison. FIGUrE 372e-5 The four pathways and the effector mechanisms of the complement system. Dashed arrows indicate the functions of pathway components. (After BJ Morley, MJ Walport: The Complement Facts Books. London, Academic Press, 2000, Chap. 2; with permission. Copyright Academic Press, London, 2000.) tryptophan-serine-X-tryptophan-serine (WSXWS). This family can be grouped on the basis of the number of receptor subunits they have and on the utilization of shared subunits. A number of cytokine receptors, i.e., IL-6, IL-11, IL-12, and leukemia inhibitory factor, are paired with gp130. There is also a common 150-kDa subunit shared by IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors. The gamma chain (γc) of the IL-2 receptor is common to the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. Thus, the specific cytokine receptor is responsible for ligand-specific binding, whereas the subunits such as gp130, the 150-kDa subunit, and γcare important in signal


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InternalMed_Harrison. IL-9, and IL-15 receptors. Thus, the specific cytokine receptor is responsible for ligand-specific binding, whereas the subunits such as gp130, the 150-kDa subunit, and γcare important in signal transduction. The γcgene is on the X chromosome, and mutations in the γ cprotein result in the X-linked form of severe combined immune deficiency syndrome (X-SCID) (Chap. 374).


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InternalMed_Harrison. The members of the interferon (type II) receptor family include the receptors for IFN-γ and -β, which share a similar 210-amino-acid binding domain with conserved cysteine pairs at both the amino and carboxy termini. The members of the TNF (type III) receptor family share a common binding domain composed of repeated cysteine-rich regions. Members of this family include the p55 and p75 receptors for TNF (TNF-R1 and TNF-R2, respectively); CD40 antigen, which is an important B cell-surface marker involved in immunoglobulin isotype switching; fas/Apo-1, whose triggering induces apoptosis; CD27 and CD30, which are found on activated T cells and B cells; and nerve growth factor receptor.


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InternalMed_Harrison. The common motif for the seven transmembrane helix family was originally found in receptors linked to GTP-binding proteins. This family includes receptors for chemokines (Table 372e-8), β-adrenergic receptors,and retinalrhodopsin. Itisimportanttonote thattwomembers of the chemokine receptor family, CXC chemokine receptor type 4 (CXCR4) and β chemokine receptor type 5 (CCR5), have been found to serve as the two major co-receptors for binding and entry of HIV into CD4-expressing host cells (Chap. 226).


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InternalMed_Harrison. Significant advances have been made in defining the signaling pathways through which cytokines exert their intracellular effects. The Janus family of protein tyrosine kinases (JAK) is a critical element involved in signaling via the hematopoietin receptors. Four JAK kinases, JAK1, JAK2, JAK3, and Tyk2, preferentially bind different cytokine receptor subunits. Cytokine binding to its receptor brings the cytokine receptor subunits into apposition and allows a pair of JAKs to transphosphorylate and activate one another. The JAKs then phosphorylate the receptor on the tyrosine residues and allow signaling molecules to bind to the receptor, whereby the signaling molecules become phosphorylated. Signaling molecules bind the receptor because they have domains (SH2, or src homology 2 domains) that can bind phosphorylated tyrosine residues. There are a number of these important signaling molecules that bind the receptor, such as the adapter molecule SHC, which can couple the receptor to the


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InternalMed_Harrison. can bind phosphorylated tyrosine residues. There are a number of these important signaling molecules that bind the receptor, such as the adapter molecule SHC, which can couple the receptor to the activation of the mitogen-activated protein kinase pathway. In addition, an important class of substrate of the JAKs is the signal transducers and activators of transcription (STAT) family of transcription factors. STATs have SH2 domains that enable them to bind to phosphorylated receptors, where they are then phosphorylated by the JAKs. It appears that different STATs have specificity for different receptor subunits. The STATs then dissociate from the receptor and translocate to the nucleus, bind to DNA motifs that they recognize, and regulate gene expression. The STATs preferentially bind DNA motifs that are slightly different from one another and thereby control transcription of specific genes. The importance of this pathway is particularly relevant to lymphoid development. Mutations of


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InternalMed_Harrison. motifs that are slightly different from one another and thereby control transcription of specific genes. The importance of this pathway is particularly relevant to lymphoid development. Mutations of JAK3 itself also result in a disorder identical to X-SCID; however, because JAK3 is found on chromosome 19 and not on the X chromosome, JAK3 deficiency occurs in boys and girls (Chap. 374).


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InternalMed_Harrison. Adaptive immunity is characterized by antigen-specific responses to a foreign antigen or pathogen. A key feature of adaptive immunity is that following the initial contact with antigen (immunologic priming), subsequent antigen exposure leads to more rapid and vigorous immune responses (immunologic memory). The adaptive immune system consists of dual limbs of cellular and humoral immunity. The principal effectors of cellular immunity are T lymphocytes, whereas the principal effectors of humoral immunity are B lymphocytes. Both B and T lymphocytes derive from a common stem cell (Fig. 372e-6).


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InternalMed_Harrison. The proportion and distribution of immunocompetent cells in various tissues reflect cell traffic, homing patterns, and functional capabilities. Bone marrow is the major site of maturation of B cells, monocytes-macrophages, DCs, and granulocytes and contains pluripotent stem cells that, under the influenceofvarious colony-stimulating factors, are capable of giving rise to all hematopoietic cell types. T cell precursors also arise from hematopoietic stem cells and home to the thymus for maturation. Mature T lymphocytes, B lymphocytes,monocytes, and DCs enter the circulation and home to peripheral lymphoid organs (lymph nodes, spleen) and mucosal surface-associated lymphoid tissue (gut, genitourinary, and respiratory tracts) as well as the skin and mucous membranes and await activation by foreign antigen.


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InternalMed_Harrison. T Cells The pool of effector T cells is established in the thymus early in life and is maintained throughout life both by new T cell production in the thymus and by antigen-driven expansion of virgin peripheral T cells into “memory” T cells that reside in peripheral lymphoid organs. The thymus exports ~2% of the total number of thymocytes per day throughout life, with the total number of daily thymic emigrants decreasing by ~3% per year during the first four decades of life.


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InternalMed_Harrison. Mature T lymphocytes constitute 70–80% of normal peripheral blood lymphocytes (only 2% of the total-body lymphocytes are containedinperipheralblood),90%ofthoracicductlymphocytes,30–40% of lymph node cells, and 20–30% of spleen lymphoid cells. In lymph nodes, T cells occupy deep paracortical areas around B cell germinal centers, and in the spleen, they are located in periarteriolar areas of whitepulp(Chap. 79).Tcellsaretheprimaryeffectorsofcell-mediated immunity, withsubsetsofT cellsmaturing into CD8+ cytotoxic Tcells capable of lysis of virus-infected or foreign cells (short-lived effector T cells) and CD4+ T cells capable of T cell help for CD8+ T cell and B cell development. Two populations of long-lived memory T cells are triggered by infections: effector memory and central memory T cells. CD7 CD2 cCD3, TCR°˛ CD1 °,˛ Germ line °,˛ Germ line °Germ line ˛-V-DJ Rearranged CD4, CD8 CD7 CD2 cCD3, TCR°˛ CD4 CD7 CD2 cCD3, TCR°˛ CD8 cCD3, TCR˝˙ CD8


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InternalMed_Harrison. CD7 CD2 cCD3, TCR°˛ CD1 °,˛ Germ line °,˛ Germ line °Germ line ˛-V-DJ Rearranged CD4, CD8 CD7 CD2 cCD3, TCR°˛ CD4 CD7 CD2 cCD3, TCR°˛ CD8 cCD3, TCR˝˙ CD8 Surface Ig Absent Absent ˆ H-chain at ˆ H-chain in IgM expressed IgD and IgM surface as cytoplasm on cell surface made from part of pre-˛ and at surface FIGUrE 372e-6 Development stages of T and B cells. Elements of the developing T and B cell receptor for antigen are shown schematically. The classification into the various stages of B cell development is primarily defined by rearrangement of the immunoglobulin (Ig) heavy (H) and light (L) chain genes and by the absence or presence of specific surface markers. The classification of stages of T cell development is primarily defined by cell-surface marker protein expression (sCD3, surface CD3 expression; cCD3, cytoplasmic CD3 expression; TCR, T cell receptor).


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InternalMed_Harrison. (Adapted from CA Janeway et al [eds]: Immunobiology. The Immune Systemic Health and Disease, 4th ed. New York, Garland, 1999; with permission.) Introduction to the Immune System Effector memory T cells reside in nonlymphoid organs and respond rapidly to repeated pathogenic infections with cytokine production and cytotoxic functions to kill virus-infected cells. Central memory T cells home to lymphoid organs where they replenish long-and short-lived and effector memory T cells as needed.


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InternalMed_Harrison. In general, CD4+ T cells are the primary regulatory cells of T and B lymphocyte and monocyte function by the production of cytokines and by direct cell contact (Fig. 372e-2). In addition, T cells regulate erythroid cell maturation in bone marrow and, through cell contact (CD40 ligand), have an important role in activation of B cells and induction of Ig isotype switching. Considerable evidence now exists that colonization of the gut by commensal bacteria (the gut microbiome) is responsible for expansion of the peripheral CD4+ T cell compartment in normal children and adults. Human T cells express cell-surface proteins that mark stages of intrathymic T cell maturation or identify specific functional subpopulations of mature T cells. Many of these molecules mediate or participate in important T cell functions (Table 372e-1, Fig. 372e-6).


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InternalMed_Harrison. The earliest identifiable T cell precursors in bone marrow are CD34+ pro-T cells (i.e., cells in which TCR genes are neither rearranged nor expressed). In the thymus, CD34+ T cell precursors begin cytoplasmic (c) synthesis of components of the CD3 complex of TCR-associated molecules (Fig. 372e-6). Within T cell precursors, TCR for antigen gene rearrangement yields two T cell lineages, expressing either TCR-αβ chains or TCR-γδ chains. T cells expressing the TCR-αβ chains constitute the majority of peripheral T cells in blood, lymph node, and spleen and terminally differentiate into either CD4+ or CD8+ cells. Cells expressing TCR-γδ chains circulate as a minor population in blood; their functions, although not fully understood, have been postulated to be those of immune surveillance at epithelial surfaces and cellular defenses against mycobacterial organisms and other intracellular bacteria through recognition of bacterial lipids.


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InternalMed_Harrison. In the thymus, the recognition of self-peptides on thymic epithelial cells, thymic macrophages, and DCs plays an important role in shaping the T cell repertoire to recognize foreign antigen (positive selection) and in eliminating highly autoreactive T cells (negative selection). As immature cortical thymocytes begin to express surface TCR for antigen, autoreactive thymocytes are destroyed (negative selection), thymocytes with TCRs capable of interacting with foreign antigen peptidesin thecontext of self-MHC antigens are activatedanddevelop to maturity (positive selection), and thymocytes with TCRs that are incapable of binding to self-MHC antigens die of attrition (no selection). Mature thymocytes that are positively selected are either CD4+ helper T cells or MHC class II–restricted cytotoxic (killer) T cells, or they are CD8+ T cells destined to become MHC class I–restricted cytotoxic T cells. MHC class I– or class II–restricted means that T cells recognize antigen peptide fragments


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InternalMed_Harrison. (killer) T cells, or they are CD8+ T cells destined to become MHC class I–restricted cytotoxic T cells. MHC class I– or class II–restricted means that T cells recognize antigen peptide fragments only when they are presented in the antigen-recognition site of a class I or class II MHC molecule, respectively (Chap. 373e).


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InternalMed_Harrison. After thymocyte maturation and selection, CD4 and CD8 thymocytes leave the thymus and migrate to the peripheral immune system. The thymus continues to be a contributor to the peripheral immune system well into adult life, both normally and when the peripheral T cell pool is damaged, such as occurs in AIDS and cancer chemotherapy.