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InternalMed_Harrison. T Cell Primary Immunodeficiencies with Hyper-IgE Several T cell PIDs are associated with elevated serum IgE levels (as in Omenn syndrome). A condition sometimes referred to as autosomal recessive hyper-IgE syndrome is notably characterized by recurrent bacterial infections in the skin and respiratory tract and severe skin and mucosal infections by pox viruses and human papillomaviruses, together with severe allergic manifestations. T and B lymphocyte counts are low. Mutations in the DOCK8 genehavebeenfoundinmostofthesepatients.Thiscondition is an indication for HSCT. A very rare, related condition with autosomal recessive inheritance that causes a similar susceptibility to infection with various microbes (see above), including mycobacteria, reportedly results from a deficiency in Tyk-2, a JAK family kinase involved in the signaling of many different cytokine receptors.


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InternalMed_Harrison. autosomal Dominant Hyper-IgE Syndrome This unique condition, the autosomal dominant hyper-IgE syndrome, is usually diagnosed by the combination of recurrent skin and lung infections that can be complicatedbypneumatoceles.Infectionsarecausedbypyogenicbacteriaand fungi. Several other manifestations characterize hyper-IgE syndrome, including facial dysmorphy, defective loss of primary teeth, hyperextensibility, scoliosis, and osteoporosis. Elevated serum IgE levels are typical of this syndrome. Defective TH17 effector responses have been shown toaccount at leastin part forthe specific patternsof susceptibility to particular microbes. This condition is caused by a heterozygous (dominant) mutation in the gene encoding the transcription factor STAT3 that is required in a number of signaling pathways following binding of cytokine to cytokine receptors (such as that of IL-6 and the IL-6 receptor). It also results in partially defective antibody production because of defective IL-21R


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InternalMed_Harrison. pathways following binding of cytokine to cytokine receptors (such as that of IL-6 and the IL-6 receptor). It also results in partially defective antibody production because of defective IL-21R signaling. Hence, immunoglobulin substitution can be considered as prophylaxis of bacterial infections.


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InternalMed_Harrison. Cartilage Hair Hypoplasia The autosomal recessive cartilage hair hypoplasia (CHH) disease is characterized by short-limb dwarfism, metaphyseal dysostosis, and sparse hair, together with a combined T and B cell PID of extremely variable intensity (ranging from quasi-SCID to no clinically significant immune defects). The condition can predispose to erythroblastopenia, autoimmunity, and tumors. It is caused by mutations in the RMRP gene for a noncoding ribosome-associated RNA.


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InternalMed_Harrison. FIGUrE 374-4 B cell differentiation and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which give rise to pre-B cells. The B cell differentiation pathway goes through the pre–B cell stage (expression of the μ heavy chain and surrogate light chain), the immature B cell stage (expression of surface IgM), and the mature B cell stage (expression of surface IgM and IgD). The main phenotypic characteristics of these cells are indicated. In lymphoid organs, B cells can differentiate into plasma cells and produce IgM or undergo (in germinal centers) Ig class switch recombination (CSR) and somatic mutation of the variable region of V genes (SHM) that enable selection of high-affinity antibodies. These B cells produce antibodies of various isotypes and generate memory B cells. PIDs are indicated in the purple boxes. CVID, common variable immunodeficiency.


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InternalMed_Harrison. CD40 Ligand and CD40 Deficiencies Hyper-IgM syndrome (HIGM) is a glomerulonephritis, skin and visceral vasculitis (including brain well-known PID that is usually classified as a B cell immune deficiency vasculitis), erythema nodosum, and arthritis. Another possible conse(see Fig. 374-4 and below). It results from defective immunoglobulin quence of WAS is lymphoma, which may be virally induced (e.g., by classswitchrecombination(CSR)ingerminalcentersandleadsto EBVorKaposi’ssarcoma–associatedherpesvirus).Thrombocytopenia profound deficiency in production of IgG, IgA, and IgE (although IgM can be severe and compounded by the peripheral destruction of production is maintained). Approximately half of HIGM sufferers are platelets associated with autoimmune disorders. Hypomorphic mutaalso prone to opportunistic infections, e.g., interstitial pneumonitis tions usually lead to milder outcomes that are generally limited to caused by Pneumocystis jiroveci (in young children), protracted


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InternalMed_Harrison. prone to opportunistic infections, e.g., interstitial pneumonitis tions usually lead to milder outcomes that are generally limited to caused by Pneumocystis jiroveci (in young children), protracted diar-thrombocytopenia. It is noteworthy that even patients with “isolated” rhea and cholangitis caused by Cryptosporidium, and infection of the X-linked thrombocytopenia can develop severe autoimmune disease brain with Toxoplasma gondii. or lymphoma later in life. The immunologic workup is not very


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InternalMed_Harrison. In the majority of cases, this condition has an X-linked inheritance informative; there can be a relative CD8+ T cell deficiency, frequently and is caused by a deficiency in CD40 ligand (L). CD40L induces sig-accompanied by low serum IgM levels and decreased antigen-specific naling events in B cells that are necessary for both CSR and adequate antibody responses. A typical feature is reduced-sized platelets on a activation of other CD40-expressing cells that are involved in innate blood smear. Diagnosis is based on intracellular immunofluorescence immune responses against the above-mentioned microorganisms. analysisofWASprotein(WASp)expressioninbloodcells.WASpreg-More rarely, the condition is caused by a deficiency in CD40 itself. The ulates the actin cytoskeleton and thus plays an important role in many poorer prognosis of CD40L and CD40 deficiencies (relative to most lymphocyte functions, including cell adhesion and migration and the other HIGM conditions) implies that (1) thorough


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InternalMed_Harrison. role in many poorer prognosis of CD40L and CD40 deficiencies (relative to most lymphocyte functions, including cell adhesion and migration and the other HIGM conditions) implies that (1) thorough investigations have formation of synapses between antigen-presenting and target cells. tobeperformedinallcasesofHIGMand(2)potentiallycurativeHSCT Predispositiontoautoimmunedisordersisinpartrelatedtodefective should be discussed on a case-by-case basis for this group of patients. regulatory T cells. The treatment of WAS should match the severity of disease expression. Prophylactic antibiotics, immunoglobulin G (IgG) Wiskott-aldrich Syndrome Wiskott-Aldrich syndrome (WAS) is a com-supplementation, and careful topical treatment of eczema are indiplex, recessive, X-linked disease with an incidence of approximately 1 cated. Although splenectomy improves platelet count in a majority of in 200,000 live births. It is caused by mutations in the WASP gene that cases, this intervention is associated


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InternalMed_Harrison. of approximately 1 cated. Although splenectomy improves platelet count in a majority of in 200,000 live births. It is caused by mutations in the WASP gene that cases, this intervention is associated with a significant risk of infection affect not only T lymphocytes but also the other lymphocyte subsets, (both before and after HSCT). Allogeneic HSCT is curative, with fairly dendritic cells, and platelets. WAS is typically characterized by the fol-good results overall. Gene therapy trials are also under way. A similar lowing clinical manifestations: recurrent bacterial infections, eczema, condition has been reported in a girl with a deficiency in the Wiskottand bleeding caused by thrombocytopenia. However, these mani-Aldrich interacting protein (WIP). festations are highly variable—mostly as a consequence of the many A few other complex PIDs are worth mentioning. Sp110 deficiency different WASP mutations that have been observed. Null mutations causes a T cell PID with liver


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InternalMed_Harrison. as a consequence of the many A few other complex PIDs are worth mentioning. Sp110 deficiency different WASP mutations that have been observed. Null mutations causes a T cell PID with liver venoocclusive disease and hypogammapredispose affected individuals to invasive and bronchopulmonary globulinemia.Chronic mucocutaneous candidiasis (CMC)isaheterogeinfections, viral infections, severe eczema, and autoimmune manifes-neous disease, considering the different inheritance patterns that have tations. The latter include autoantibody-mediated blood cytopenia, been observed. In some cases, chronic candidiasis is associated with late-onset bronchopulmonary infections, bronchiectasis, and brain aneurysms. Moderate forms of CMC are related to autoimmunity and AIRE deficiency (see below). In this setting, predisposition to Candida infection is associated with the detection of autoantibodies to TH17 cytokines. Recently, deficiencies in IL-17F and IL-17 receptor A and, above all, gain-of-function


InternalMed_Harrison

InternalMed_Harrison. predisposition to Candida infection is associated with the detection of autoantibodies to TH17 cytokines. Recently, deficiencies in IL-17F and IL-17 receptor A and, above all, gain-of-function mutations in STAT1 have been found to be associated with CMC. In all cases, CMC is related to defective TH17 function. Innate immunodeficiency in CARD9 also predisposes to chronic invasive fungal infection.


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InternalMed_Harrison. B LYMPHOCYTE DEFICIENCIES (TaBLE 374-1, FIG. 374-4)


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InternalMed_Harrison. Deficiencies that predominantly affect B lymphocytes are the most frequent PIDs and account for 60–70% of all cases. B lymphocytes make antibodies. Pentameric IgMs are found in the vascular compartment and are also secreted at mucosal surfaces. IgG antibodies diffuse freely into extravascular spaces, whereas IgA antibodies are produced and secreted predominantly from mucosa-associated lymphoid tissues. Although Ig isotypes have distinct effector functions, including Fc receptor–mediated and (indirectly) C3 receptor– dependent phagocytosis of microorganisms, they share the ability to recognize and neutralize a given pathogen. Defective antibody production therefore allows the establishment of invasive, pyogenic bacterialinfectionsaswellasrecurrentsinusandpulmonaryinfections (mostly caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and, less frequently, gram-negative bacteria). If left untreated, recurrent bronchial infections lead to bronchiectasis and,


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InternalMed_Harrison. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and, less frequently, gram-negative bacteria). If left untreated, recurrent bronchial infections lead to bronchiectasis and, ultimately, cor pulmonale and death. Parasitic infections such as caused by Giardia lamblia and bacterial infections caused by Helicobacter and Campylobacter of the gut are also observed. A complete lack of antibody production (namely agammaglobulinemia) can also predispose affected individuals to severe, chronic, disseminated enteroviral infections causing meningoencephalitis, hepatitis, and a dermatomyositis-like disease.


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InternalMed_Harrison. Even with the most profound of B cell deficiencies, infections rarely occur before the age of 6 months; this is because of transient protection provided by the transplacental passage of immunoglobulins during the last trimester of pregnancy. Conversely, a genetically nonimmunodeficient child born to a mother with hypogammaglobulinemia is, in the absence of maternal Ig substitution, usually prone to severe bacterial infections in utero and for several months after birth.


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InternalMed_Harrison. Diagnosis of B cell PIDs relies on the determination of serum Ig levels (Table 316-2). Determination of antibody production following immunization with tetanus toxoid vaccine or nonconjugated pneumococcal polysaccharide antigens can also help diagnose more subtle deficiencies. Another useful test is B cell phenotype determination in switched μ−δ− CD27+ and nonswitched memory B cells (μ+δ+ CD27+). In agammaglobulinemic patients, examination of bone marrow B cell precursors (Fig. 374-4) can help obtain a precise diagnosis and guide the choice of genetic tests.


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InternalMed_Harrison. agammaglobulinemia Agammaglobulinemia is characterized by a profounddefectinBcelldevelopment(<1%ofthenormalBcellblood count). In most patients, very low residual Ig isotypes can be detected in the serum. In 85% of cases, agammaglobulinemia is caused by a mutation in the BTK gene that is located on the X chromosome. The BTK gene product is a kinase that participates in (pre) B cell receptor signaling. When the kinase is defective, there is a block (albeit a leaky one) at the pre-B to B cell stage (Fig. 374-4). Detection of BTK by intracellular immunofluorescence of monocytes, and lack thereof in patients with X-linked agammaglobulinemia, is a useful diagnostic test. Not all of the mutations in BTK result in agammaglobulinemia, since some patients have a milder form of hypogammaglobulinemia and low but detectable B cell counts. These cases should not be confused with common variable immunodeficiency (CVID, see below). About 10% of agammaglobulinemia cases are caused by alterations in


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InternalMed_Harrison. and low but detectable B cell counts. These cases should not be confused with common variable immunodeficiency (CVID, see below). About 10% of agammaglobulinemia cases are caused by alterations in genes encoding elements of the pre-B cell receptor, i.e., the μ heavy chain, the λ5 surrogate light chain, Igα or Igβ, the scaffold protein BLNK, and the p85 α subunit of phosphatidylinositol 3 phosphate kinase (P13K). In 5% of cases, the defect is unknown. It is noteworthy that agammaglobulinemia can be observed in patients with ICF syndrome, despite the presence of normal peripheral B cell counts. 2111 Lastly, agammaglobulinemia can be a manifestation of a myelodysplastic syndrome (associated or not with neutropenia). Treatment of agammaglobulinemic patients is based on immunoglobulin replacement (see below). Profound hypogammaglobulinemia is also observed in adults, in association with thymoma.


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InternalMed_Harrison. Hyper-IgM (HIGM) Syndromes HIGM is a rare B cell PID characterized by defective Ig CSR. It results in very low serum levels of IgG and IgA and elevated or normal serum IgM levels. The clinical severity is similar to that seen in agammaglobulinemia, although chronic lung disease and sinusitis are less frequent and enteroviral infections are uncommon. As discussed above, a diagnosis of HIGM involves screening for an X-linked CD40L deficiency and an autosomal recessive CD40 deficiency, which affect both B and T cells. In 50% of cases affecting only B cells, these isolated HIGM syndromes result from mutations in the gene encodingactivation-induceddeaminase,theproteinthatinducesCSRin B cell germinal centers. These patients usually have enlarged lymphoid organs. In the other 50% of cases, the etiology is unknown (except for rareUNGandPMS2deficiencies).Furthermore,IgM-mediatedautoimmunity and lymphomas can occur in HIGM syndrome. It is noteworthy that HIGM can result from fetal rubella


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InternalMed_Harrison. the etiology is unknown (except for rareUNGandPMS2deficiencies).Furthermore,IgM-mediatedautoimmunity and lymphomas can occur in HIGM syndrome. It is noteworthy that HIGM can result from fetal rubella syndrome or can be a predominant immunologic feature of other PIDs, such as the immunodeficiency associated with ectodermic anhydrotic hypoplasia X-linked NEMO deficiency and the combined T and B cell PIDs caused by DNA repair defects such as AT and Cernunnos deficiency.


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InternalMed_Harrison. Common Variable Immunodeficiency (CVID) CVID is an ill-defined condi tion characterized by low serum levels of one or more Ig isotypes. Its prevalence is estimated to be 1 in 20,000. The condition is recognized predominantly in adults, although clinical manifestations can occur earlier in life. Hypogammaglobulinemia is associated with at least partially defective antibody production in response to vaccine antigens. B lymphocyte counts are often normal but can be low. Besides infections, CVID patientsmaydevelop lymphoproliferation (splenomegaly),granulomatouslesions,colitis,antibody-mediatedautoimmunedisease,and lymphomas.Afamilyhistoryisfoundin10%ofcases.Aclear-cutdominant inheritance pattern is found in some families, whereas recessive inheritance is observed more rarely. In most cases, no molecular cause canbeidentified.AsmallnumberofpatientsinGermanywerefoundto carry mutations in the ICOS gene encoding a T cell-membrane protein


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InternalMed_Harrison. inheritance is observed more rarely. In most cases, no molecular cause canbeidentified.AsmallnumberofpatientsinGermanywerefoundto carry mutations in the ICOS gene encoding a T cell-membrane protein thatcontributestoBcellactivationandsurvival.In10%ofpatientswith CVID, monoallelic or biallelic mutations of the gene encoding TACI (a member of the tumor necrosis factor [TNF] receptor family that is expressed on B cells) have been found. In fact, heterozygous TACI mutations correspond to a genetic susceptibility factor, since similar heterozygous mutations are found in 1% of controls. The BAFF receptor was found to be defective in a kindred with CVID, although not all individuals carrying the mutation have CVID.


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InternalMed_Harrison. Recently a group of patients with hypogammaglobulinemia and lymphoproliferation were shown to exhibit dominant gain of function mutations in the PIK3CD gene encoding the p110δ form of P13 kinase. A diagnosis of CVID should be made after excluding the presence of hypomorphic mutations associated with agammaglobulinemia or more subtle T cell defects; this is particularly the case in children. It is possible that many cases of CVID result from a constellation of factors, rather than a single genetic defect. Recently, rare cases of hypogammaglobulinemia were found to be associated with CD19 and CD81 deficiencies. These patients have B cells that can be identified by typing for other B cell markers. Hypogammaglobulinemia can be associated with neutropenia and lymphopenia in the warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIM) caused by dominant gain-of-function mutation of CXCR4, resulting in cell retention in the bone marrow.


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InternalMed_Harrison. Selective Ig Isotype Deficiencies IgA deficiency and CVID represent polar ends of a clinical spectrum due to the same underlying gene defect(s) in a large subset of these patients. IgA deficiency is the most common PID; it can be found in 1 in every 600 individuals. It is asymptomatic in most cases; however, individuals may present 2112 with increased numbers of acute and chronic respiratory infections that may lead to bronchiectasis. In addition, over their lifetime, these patients experience an increased susceptibility to drug allergies, atopic disorders, and autoimmune diseases. Symptomatic IgA deficiency is probably related to CVID, since it can be found in relatives of patients with CVID. Furthermore, IgA deficiency may progress to CVID. It is thus important to assess serum Ig levels in IgA-deficient patients (especially when infections occur frequently) in order to detect changes that should prompt the initiation of immunoglobulin replacement. Selective IgG2 (+G4) deficiency


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InternalMed_Harrison. in IgA-deficient patients (especially when infections occur frequently) in order to detect changes that should prompt the initiation of immunoglobulin replacement. Selective IgG2 (+G4) deficiency (which in some cases may be associated with IgA deficiency) can also result in recurrent sinopulmonaryinfectionsandshouldthusbespecificallysoughtinthis clinical setting. These conditions are ill-defined and often transient duringchildhood.Apathophysiologicexplanationhasnotbeenfound.


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InternalMed_Harrison. Selective antibody Deficiency to Polysaccharide antigens Some patients with normal serum Ig levels are prone to S. pneumoniae and H. influenzae infections of the respiratory tract. Defective production of antibodies against polysaccharide antigens (such as those in the S. pneumoniae cell wall) can be observed and is probably causative. This condition may correspond to a defect in marginal zone B cells, a B cell subpopulation involved in T-independent antibody responses.


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InternalMed_Harrison. Immunoglobulin replacement IgG antibodies have a half-life of 21–28 days. Thus, injection of plasma-derived polyclonal IgG containing a myriad of high-affinity antibodies can provide protection against disease-causing microorganisms in patients with defective IgG antibody production. This form of therapy should not be based on laboratory data alone (i.e., IgG and/or antibody deficiency) but should be guided by the occurrence or not of infections; otherwise, patients might be subjected to unjustified IgG infusions. Immunoglobulin replacement can be performed by IV or subcutaneous routes. In the former case, injections have to be repeated every 3–4 weeks, with a residual target level of 800 mg/mL in patients who had very low IgG levels prior to therapy. Subcutaneous injections are typically performed once a week, although the frequency can be adjusted on a case-by-case basis. A trough level of 800 mg/mL is desirable. Whatever the mode of administration, the main goal is to reduce the


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InternalMed_Harrison. performed once a week, although the frequency can be adjusted on a case-by-case basis. A trough level of 800 mg/mL is desirable. Whatever the mode of administration, the main goal is to reduce the frequency of the respiratory tract infections and prevent chronic lung and sinus disease. The two routes appear to be equally safe and efficacious, and so the choice should be left to the preference of the patient.


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InternalMed_Harrison. In patients with chronic lung disease, chest physical therapy with good pulmonary toilet and the cyclic use of antibiotics are also needed. Immunoglobulinreplacementiswelltoleratedbymostpatients,although the selection of the best-tolerated Ig preparation may be necessary in certain cases. Since IgG preparations contain a small proportion of IgAs, caution should be taken in patients with residual antibody production capacity and a complete IgA deficiency, as these subjects may develop anti-IgA antibodies that can trigger anaphylactic shock. These patients should be treated with IgA-free IgG preparations. Immunoglobulin replacement is a lifelong therapy; its rationale and procedures have to be fully understood and mastered by the patient and his or her family in order to guarantee the strict observance required for efficacy.


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InternalMed_Harrison. An increasing number of PIDs have been found to cause homeostatic dysregulation of the immune system, either alone or in association with increased vulnerability to infections. Defects of this type affecting the innate immune system and autoinflammatory syndromes will not be covered in this chapter. However, three specific entities (hemophagocytic lymphohistiocytosis, lymphoproliferation, and autoimmunity) will be described below. Hemophagocytic lymphohistiocytosis (HLH) is characterized by an unremitting activation of CD8+ T lymphocytes and macrophages that leads to organ damage (notably in the liver, bone marrow, and central nervous system). This syndrome results from a broad set of inherited diseases, all of which impair T and NK lymphocyte cytotoxicity. The manifestations of HLH are often induced by a viral infection. EBV is the most frequent trigger. In severe forms of HLH, disease onset may start during the first year of life or even (in rare cases) at birth.


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InternalMed_Harrison. Diagnosis reliesonthe identification of thecharacteristic symptoms ofHLH(fever,hepatosplenomegaly,edema,neurologicdiseases,blood cytopenia, increased liver enzymes, hypofibrinogenemia, high triglyceride levels, elevated markers of T cell activation, and hemophagocytic features in the bone marrow or cerebrospinal fluid). Functional assays of postactivation cytotoxic granule exocytosis (CD107 fluorescence at the cell membrane) can suggest genetically determined HLH. The conditions can be classified into three subsets: 1. Familial HLH with autosomal recessive inheritance, including perforin deficiency (30% of cases) that can be recognized by assessing intracellular perforin expression; Munc13-4 deficiency (30% of cases); syntaxin 11 deficiency (10% of cases); Munc18-2 deficiency (20% of cases); and a few residual cases that lack a known molecular defect. 2.


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InternalMed_Harrison. 2. HLH with partial albinism. Three conditions combine HLH and abnormal pigmentation, where hair examination can help in the diagnosis: Chédiak-Higashi syndrome, Griscelli syndrome, and Hermansky Pudlak syndrome type II. Chédiak-Higashi syndrome is also characterized by the presence of giant lysosomes within leukocytes (Chap. 80), in addition to a primary neurologic disorder with slow progression of symptoms over time. 3.


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InternalMed_Harrison. 3. X-linked proliferative syndrome (XLP) is characterized in most patients by the induction of HLH following EBV infection, while other patients develop progressive hypogammaglobulinemia similar to what is observed in CVID and/or certain lymphomas. XLP is caused by a mutation in the SH2DIA gene that encodes the adaptor protein SAP (associated with a SLAM family receptor). Several immunologic abnormalities have been described, including low 2B4-mediated NK cell cytotoxicity, impaired differentiation of NKT cells, defective antigen-induced T cell death, and defective T cell helper activity for B cells. A related disorder (XLP2) has recently been described. It is also X-linked and induces HLH (frequently after EBV infection), although the clinical manifestation may be less pronounced. The condition is associated with a deficiency of the antiapoptotic molecule XIAP. The pathophysiology of XLP2 and its relationship to XLP1 remain unclear.


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InternalMed_Harrison. HLH is a life-threatening complication. The treatment of this condition requires aggressive immunosuppression with either the cytotoxic agent etoposide or anti–T cell antibodies. Once remission has been achieved, HSCT should be performed, since it provides the only curative form of therapy. Autoimmune lymphoproliferative syndrome (ALPS) is characterized by nonmalignant T and B lymphoproliferation causing splenomegaly and enlargedlymphnodes;70%ofpatientsalsodisplayautoimmunemanifestations such as autoimmune cytopenias, Guillain-Barré syndrome, uveitis, and hepatitis (Chaps. 79 and 372e). A hallmark of ALPS is the presence of CD4–CD8– TCRαβ+ T cells (2–50%) in the blood of affectedindividuals.HypergammaglobulinemiainvolvingIgGandIgA is also frequently observed. The syndrome is caused by a defect in Fas-mediated apoptosis of lymphocytes, which can thus accumulate and mediate autoimmunity. Furthermore, ALPS can lead to malignancies.


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InternalMed_Harrison. MostpatientscarryaheterozygousmutationinthegeneencodingFas that is characterized by dominant inheritance and variable penetrance, depending on the nature of the mutation. A rare and severe form of the disease with early onset can be observed in patients carrying a biallelic mutationofFas,whichprofoundlyimpairstheprotein’sexpressionand/ or function. Fas-ligand, caspase 10, caspase 8, and neuroblastoma RAS viral oncogene homologue (NRAS) mutations have also been reported in a few cases of ALPS. Many cases of ALPS have not been precisely delineated at the molecular level. A B cell–predominant ALPS has recently been found associated with a protein kinase Cδ gene mutation. Treatment ofALPS isessentially basedon the useof proapoptoticdrugs, which need to be carefully administered in order to avoid toxicity. CoLITIS, AUToIMMUNITY, ANd PRIMARY IMMUNodEFICIENCIES


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InternalMed_Harrison. Several PIDs (most of which are T cell–related) can cause severe gut inflammation. The prototypic example is immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), characterized by a widespread inflammatory enteropathy, food intolerance, skin rashes, autoimmune cytopenias, and diabetes. The syndrome is caused by loss-of-function mutations in the gene encoding the transcription factorFOXP3,whichisrequiredfortheacquisitionofeffectorfunction by regulatory T cells. In most cases of IPEX, CD4+CD25+ regulatory T cells are absent from the blood. This condition has a poor prognosis and requires aggressive immunosuppression. The only possible curative approach is allogeneic HSCT. IPEX-like syndromes that lack a FOXP3 mutation have also been described. In some cases, a CD25 deficiency has been found. Defective CD25 expression also impairs regulatory cell expansion/function. This functional T cell deficiency means that CD25-deficient patients are also at increased risk of


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InternalMed_Harrison. has been found. Defective CD25 expression also impairs regulatory cell expansion/function. This functional T cell deficiency means that CD25-deficient patients are also at increased risk of opportunistic infections. It is noteworthy that abnormalities in regulatory T cells have been described in other PID settings, such as in Omenn syndrome, STAT5b deficiency, STIM1 (Ca flux) deficiency, and WAS; these abnormalities mayaccount (at least in part) for theoccurrence of inflammation and autoimmunity. The autoimmune features observed in a small fraction of patients with DiGeorge syndrome may have the same cause. Recently, severe inflammatory gut disease has been described in patients with a deficiency in the IL-10 receptor or IL-10.


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InternalMed_Harrison. A distinct autoimmune entity is observed in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome, which is characterized by autosomal recessive inheritance. It consists of multiple autoimmune manifestations that can affect solid organs in general and endocrine glands in particular. Mild, chronic Candida infection is often associated with this syndrome. The condition is due to mutations in the autoimmune regulator (AIRE) gene and results in impaired thymic expression of self-antigens by medullary epithelial cells and impaired negative selection of self-reactive T cells that leads to autoimmune manifestations. A combination of hypogammaglobulinemia, autoantibody production, cold-induced urticaria or skin granulomas, or autoinflammation hasbeenreported, andhasbeentermedthe PLCβ2-associated antibody deficiency and immune dysregulation (PLAID or APLAID).


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InternalMed_Harrison. The variety and complexity of the clinical manifestations of the many different PIDs strongly indicate that it is important to raise awareness of these diseases. Indeed, early diagnosis is essential for establishing an appropriate therapeutic regimen. Hence, patients with suspected PIDs must always be referred to experienced clinical centers that are able to perform appropriate molecular and genetic tests. A precise molecular 2113 diagnosisis notonlynecessary for initiating the mostsuitabletreatment, but is also important for genetic counseling and prenatal diagnosis.


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InternalMed_Harrison. One pitfall that may hamper diagnosis is the high variability that is associated with many PIDs. Variable disease expression can result from the differing consequences of various mutations associated with a givencondition,asexemplifiedbyWASand,toalesserextent,X-linked agammaglobulinemia (XLA). There can also be effects of modifier genes (as also suspected in XLA) and environmental factors such as EBVinfectionthatcanbethemaintriggerofdiseaseinXLPconditions. Furthermore, it has recently been established that somatic mutations in an affected gene can attenuate the phenotype of a number of T cell PIDs. This has been described for ADA deficiency, X-linked SCID, RAG deficiencies, NF-κB essential modulator (NEMO) deficiency, and, most frequently, WAS. In contrast, somatic mutations can create disease states analogous to PID, as reported for ALPS. Lastly, cytokineneutralizing autoantibodies can mimic a PID, as shown for IFN-γ.


InternalMed_Harrison

InternalMed_Harrison. ManyaspectsofthepathophysiologyofPIDsare still unknown, and thedisease-causinggenemutationshavenotbeenidentifiedinallcases (as illustrated by CVID and IgA deficiency). However, our medical understanding of PIDs has now reached the stage where scientifically based approaches to the diagnosis and treatment of these diseases can be implemented. immunodeficiency (PID) has been described as one facet of a more complex disease setting. It is essential to consider associated diseases when a PID is identified as the primary manifestation and, conversely, not neglect the potentially harmful consequences of a PID that could be masked by other manifestations of a particular syndrome. Below is a short description of these syndromes in which the PID is classified according to the arm of the immune system that is affected. 1. Primary Immunodeficiencies of the Innate Immune System


InternalMed_Harrison

InternalMed_Harrison. Below is a short description of these syndromes in which the PID is classified according to the arm of the immune system that is affected. 1. Primary Immunodeficiencies of the Innate Immune System Several severe congenital neutropenia (SCN) syndromes can be associated with malformations. The recently described SCN disease caused by glucose-6-phosphatase deficiency (G6PC3) can be associated with heart and urogenital malformations. The related glycogenesis Ib disease combines SCN with hypoglycemia and hepatosplenomegaly. Some HAX-1 gene mutations lead to neurocognitive impairments as well as SCN. Barth syndrome combines SCN with cardiomyopathy. Lastly, Shwachman syndrome is a known autosomal recessive entity (caused by mutation of the SBDS gene) in which the defect in granulopoiesis can extend to the other hematopoietic lineages; short stature, bone metaphyseal dysplasia, and exocrine pancreatic insufficiency are known hallmarks of this condition.


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InternalMed_Harrison. Syndromic asplenia combines the risk of infection with heart defects and situs inversus. Leukocyte adhesion deficiency (LAD) type II includes growth retardation and impairment of cognitive development. A few patients with X-linked chronic granulomatous disease present with a contiguous gene deletion syndrome that can include the McLeod phenotype, which is characterized by anemia, acanthocytosis, and a severe risk of immune reaction against donor red cells because the patient’s red cells do not express the Kell antigen. The McLeod phenotype also can result in a neurologic disease. X-linked nuclear factor-κB (NF-κB) essential modulator (NEMO) deficiency provokes not only a variable set of deficiencies of both innate and adaptive immunity but also mild osteopetrosis, lymphedema, and, more frequently, anhydrotic ectodermal dysplasia, dysmorphic facies, and abnormal conical teeth. The last finding is often helpful in the diagnosis of that condition.


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InternalMed_Harrison. 2. Primary Immunodeficiencies of the Adaptive Immune System T cell primary immunodeficiencies. Reticular dysgenesis, a rare severe combined immunodeficiency (SCID) characterized by T lymphopenia and agranulocytosis, can cause sensorineural deafness. Coronin A deficiency is another SCID variant that can be associated with behavioral disorders because the Coronin A gene is located in a genome area known to have been deleted in some patients with this disorder. The lack of enzymes of purine metabolism (adenosine deaminase and purine nucleoside phosphorylase) provokes not only profound T cell lymphocytopenia but also neurologic impairment, including dysautonomia and abnormalities of cognitive development of variable intensity, in many patients. The neurologic impairment can persist after hematopoietic stem cell transplantation (HSCT). Mild chondrodysplasia is a common finding in adenosine deaminase (ADA) deficiency and, indeed, can help the physician arrive at a final diagnosis.


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InternalMed_Harrison. Primary thymic defects. DiGeorge syndrome is a complex embryopathy that is caused by hemizygous interstitial deletion of chromosome 22, leading to multiple developmental defects, including conotruncal defects, hypoparathyroidism, and dys-375e-1 morphic syndrome. Although a profound T cell immunodeficiency is rare in DiGeorge syndrome (∼1% of cases), failure to recognize this feature is likely to have a fatal outcome. Similarly, some forms of the related CHARGE syndrome (mutation of the CHD7 gene) also cause a profound T cell immunodeficiency. c) T cell primary immunodeficiencies related to calcium influx defects. Recently, rare T cell PIDs were found to be caused by defective store-operated entry of calcium ions into T and B lymphocytes after antigen stimulation. These defects (caused by ORA-1 and STIM-1 deficiencies) also lead to anhydrotic ectodermal dysplasia, abnormal teeth, and, above all, a nonprogressive muscle disease characterized by excessive fatigue.


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InternalMed_Harrison. d) DNA repair defects. Several genetic defects impair DNA repair pathways. Many lead to combined T and B lymphocyte PIDs in a syndromal setting of varying complexity. The most common is ataxia-telangiectasia (AT), an autosomal recessive disorder with an incidence of 1 in 40,000 live births; AT causes a B cell immunodeficiency (low IgA, IgG2 deficiency, and low antibody production) that often requires immunoglobulin replacement therapy. AT is associated with a progressive T cell immunodeficiency. As the condition’s name suggests, the hallmark features are telangiectasia and cerebellar ataxia. These manifestations may not be detectable before age 3–4 years, and so AT should be considered in young children with IgA deficiency and problematic infections. Diagnosis is based on a cytogenetic analysis showing excessive chromosomal rearrangements (mostly affecting chromosomes 7 and 14) in lymphocytes. AT is caused by mutation of the gene encoding the ATM protein, a kinase that plays a major


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InternalMed_Harrison. showing excessive chromosomal rearrangements (mostly affecting chromosomes 7 and 14) in lymphocytes. AT is caused by mutation of the gene encoding the ATM protein, a kinase that plays a major role in the detection of DNA lesions and the organization of DNA repair (or cell death if the lesions are too numerous) by triggering several different pathways. Overall, AT is a progressive disease that carries a very high risk of lymphoma, leukemia, and (during adulthood) carcinomas. A variant of AT (AT-like disease) is caused by mutation of the MRE11 gene. Nijmegen breakage syndrome (NBS) is a less common condition that also results from chromosome instability (and the same cytogenetic abnormalities as in AT). It is characterized by a severe T and B cell combined immunodeficiency with autosomal recessive inheritance. Subjects with NBS exhibit microcephaly and a birdlike face but neither ataxia nor telangiectasia. The risk of malignancies is also very high. Nijmegen breakage syndrome results


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InternalMed_Harrison. recessive inheritance. Subjects with NBS exhibit microcephaly and a birdlike face but neither ataxia nor telangiectasia. The risk of malignancies is also very high. Nijmegen breakage syndrome results from a deficiency in Nibrin (NBS1, a protein associated with MRE11 and Rad50 that is involved in checking DNA lesions) caused by hypomorphic mutations. Severe forms of dyskeratosis congenita (also known as Hoyeraal-Hreidersson syndrome) combine a progressive immunodeficiency that can include an absence of B and natural killer cell (NK) lymphocytes, progressive bone marrow failure, microcephaly, in utero growth retardation, and gut disease. The disease can be X-linked or, more rarely, autosomal recessive. It is caused by the mutation of genes encoding telomere maintenance proteins, including dyskerin (DKC1). Bloom syndrome (helicase deficiency) combines a typical dysmorphic syndrome with growth retardation, skin lesions, and a mild immunodeficiency that also can be found in some patients


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InternalMed_Harrison. dyskerin (DKC1). Bloom syndrome (helicase deficiency) combines a typical dysmorphic syndrome with growth retardation, skin lesions, and a mild immunodeficiency that also can be found in some patients with Fanconi’s anemia. Rare forms of combined T and B cell immunodeficiencies with autosomal recessive inheritance are associated in more complex syndromes with microcephaly, failure to grow, and a variable dysmorphic syndrome. These disorders are caused by mutation of the genes that encode DNA ligase 4 and Cernunnos (XLF), both of which are members of the nonhomologous end-joining DNA repair pathway.


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InternalMed_Harrison. The Vici syndrome combines callosal agenesis, cataracts, cardiomyopathy, hyperpigmentation, and a combined immunodeficiency. It is caused by biallelic EPG5 gene mutation that results in defective autophagy. CHAPTER 375e Primary Immunodeficiencies Associated with (or Secondary to) Other Diseases Lastly, immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome is a complex autosomal recessive syndrome that variably combines a mild T cell immunodeficiency and a more severe B cell immunodeficiency with a coarse face, intestinal disease, and mild mental retardation. A cytogenetic diagnostic feature is the presence of multiradial chromosomes (most frequently chromosomes 1, 9, and 16) caused by DNA defective methylation. The syndrome is a result of either DNA methyltransferase DNMT3B deficiency or ZBTB24 deficiency.


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InternalMed_Harrison. Growth hormone insensitivity syndrome (Laron dwarfism) with combined primary immunodeficiency. Mutations in the STAT5b gene, which encodes a transcription factor involved in signaling downstream of the growth hormone receptor and the interleukin 2 (IL-2) receptor, lead to susceptibility to infection because of a partial, functional T cell immunodeficiency associated with autoimmune manifestations. The autoimmune manifestations probably result from defective generation/activation of regulatory T cells.


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InternalMed_Harrison. Hyper-IgE syndrome (autosomal dominant form). Hyper-IgE syndrome is a complex disorder that combines skin infections, inflammation, and susceptibility to bacterial and fungal infections of skin and lungs, often with pneumatoceles, with characteristic syndromic signs such as facial dysmorphy, defective loss of primary teeth, hyperextensibility, scoliosis, and osteoporosis. Elevated serum IgE levels are typical of hyper-IgE syndrome. The recently reported defects in TH17 effector responses account, at least in part, for the vulnerability to specific infections. This condition is caused by heterozygous (dominant) mutation of the gene encoding the transcription factor STAT3, which is required in a number of signaling pathways downstream of cytokine/cytokine receptor interactions (notably for IL-6 and IL21).


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InternalMed_Harrison. Primary immunodeficiencies with bone disease. The autosomal recessive cartilage hair hypoplasia (CHH) disease is characterized by short-limb dwarfism, metaphyseal dysostosis, and sparse hair, together with a combined T and B cell PID of variable intensity, ranging from quasi-SCID to an absence of clinically significant immunodeficiency. The condition can predispose to erythroblastopenia, autoimmunity, and tumors. It is caused by mutations in the RMRP gene for a noncoding ribosome-associated RNA. Schimke immunoosseous dysplasia is a rare autosomal recessive condition characterized by severe T and B cell immunodeficiency with spondyloepiphyseal dysplasia, growth retardation, and kidney and vascular diseases. It is the consequence of mutations in the SMARCAL1 gene. The function of the gene product may be related to DNA repair.


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InternalMed_Harrison. Venoocclusive disease with immunodeficiency (VODI syndrome) is a rare autosomal recessive condition predominantly found in populations originating from Lebanon. It combines severe hepatic venoocclusive disease with usually mild T cell immunodeficiency and panhypogammaglobulinemia. It is caused by a deficiency in a nuclear protein, Sp110. 3.


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InternalMed_Harrison. 3. B Cell Primary Immunodeficiencies Hypogammaglobulinemia can be associated with chromosomal defects such as trisomy 18 and Jacobsen syndrome (hemizygous deletion of part of the long arm of chromosome 11). A rare biallelic deficiency of the mismatch repair protein PMS2 leads to a partial deficiency in Ig class switch recombination in patients at a very high risk of cancer in general and colon carcinomas and lymphomas in particular. Transcobalamin deficiency disturbs vitamin B12 transport and therefore impairs hematopoiesis. Hypogammaglobulinemia is easily corrected by vitamin B12 administration and can be a characteristic of this very rare disorder. 4.


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InternalMed_Harrison. 4. Primary Immunodeficiencies Affecting Regulatory Pathways Several inherited disorders that lead to hemophagocytic lymphohistiocytosis (HLH) also have features that are important in terms of both diagnosis and prognosis. Three of these disorders—Griscelli syndrome, Chédiak-Higashi syndrome, and the Hermansky-Pudlak type II syndrome—are characterized by partial albinism and silvery hair appearance that can facilitate diagnosis. Hermansky-Pudlak type II also can be a bleeding disorder if platelet aggregation is defective. Chédiak-Higashi syndrome also is characterized by an early-onset progressive neurologic disorder with impaired cognitive development and motor and sensory deficiencies, culminating in a generalized encephalopathy. The encephalopathy is not prevented or arrested by allogeneic HSCT even when the HLH risk is controlled. 5. Primary Immunodeficiencies Associated with Other Conditions


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InternalMed_Harrison. 5. Primary Immunodeficiencies Associated with Other Conditions Predisposition to infection, notably severe disseminated opportunistic infections including nontuberculous mycobacterial infections, can be associated with autoantibodies against interferon γ as observed in Asia. A number of conditions can cause PIDs indirectly. For example, hypercatabolism in patients with Steinert’s disease may cause hypogammaglobulinemia. Intestinal lymphangiectasia that includes both immunoglobulin and naive T cell loss and can expose the patient to a significant infectious risk. Urinary IgG loss may result from severe nephritic syndromes. A number of drugs, including antimalarials, captopril, penicillamine, phenytoin, and sulfasalazine, can induce predominantly IgA hypogammaglobulinemia in (probably predisposed) adults.


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InternalMed_Harrison. One also should also consider (1) diseases that are not thought to be PIDs but include the occurrence of recurrent infections and (2) genetic defects of the immune system that lead to other clinical manifestations. A very good example of the first group is cystic fibrosis (CF). Despite having a functionally normal immune system, patients with CF develop protracted bacterial respiratory tract infections, notably Pseudomonas aeruginosa colonization. This bacterium can incapacitate innate immune responses and cause unremitting inflammation that further facilitates infection. An example of the second group is primary alveolar proteinosis, which is caused by a defect in surfactant clearance by alveolar macrophages. The condition results from mutation of the gene encoding the granulocyte-macrophage colony-stimulating factor receptor α. Allergies, Anaphylaxis, and Systemic Mastocytosis allergies, anaphylaxis, and 376 Systemic Mastocytosis Joshua A. Boyce, K. Frank Austen


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InternalMed_Harrison. Allergies, Anaphylaxis, and Systemic Mastocytosis allergies, anaphylaxis, and 376 Systemic Mastocytosis Joshua A. Boyce, K. Frank Austen The term atopy implies a tendency to manifest asthma, rhinitis, urticaria, and atopic dermatitis alone or in combination, in association with the presence of allergen-specific IgE. However, individuals without an atopic background may also develop hypersensitivity reactions, particularly urticaria and anaphylaxis, associated with the presence of IgE. Inasmuch as the mast cell is a key effector cell in allergic rhinitis and asthma, and the dominant effector in urticaria, anaphylaxis, and systemic mastocytosis, its developmental biology, activation pathway, product profile, and target tissues will be considered in the introduction to these clinical disorders.


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InternalMed_Harrison. The binding of IgE to human mast cells and basophils, a process termed sensitization, prepares these cells for subsequent antigen-specific activation. The high-affinity Fc receptor for IgE, designated FcεRI, is composed of one α, one β, and two disulfide-linked γ chains, which together cross the plasma membrane seven times. The α chain is responsible for IgE binding, and the β and γ chains provide for signal transduction that follows the aggregation of the sensitized tetrameric receptors by polymeric antigen. The binding of IgE stabilizes the α chain at the plasma membrane, thus increasing the density of FcεRI receptors at the cell surface while sensitizing the cell for effector responses. This accounts for the correlation between serum IgE levels and the numbers of FcεRI receptors detected on circulating basophils.


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InternalMed_Harrison. 2114 Signal transduction is initiated through the action of a Src family– related tyrosine kinase termed Lyn that is constitutively associated with the β chain. Lyn transphosphorylates the canonical immunoreceptor tyrosine-based activation motifs (ITAMs) of the β and γ chains of the receptor, resulting in recruitment of more active Lyn to the β chain and of Syk tyrosine kinase. The phosphorylated tyrosines in the ITAMs function as binding sites for the tandem src homology two (SH2) domains within Syk. Syk activates not only phospholipase Cγ, which associates with the linker of activated T cells at the plasma membrane, but also phosphatidylinositol 3-kinase to provide phosphatidylinositol-3,4,5-trisphosphate, which allows membrane targeting of the Tec family kinase Btk and its activation by Lyn. In addition, the Src family tyrosine kinase Fyn becomes activated after aggregation of IgE receptors and phosphorylates the adapter protein Gab2 that enhances activation of phosphatidylinositol


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InternalMed_Harrison. Lyn. In addition, the Src family tyrosine kinase Fyn becomes activated after aggregation of IgE receptors and phosphorylates the adapter protein Gab2 that enhances activation of phosphatidylinositol 3-kinase. Indeed, this additional input is essential for mast cell activation, but it can be partially inhibited by Lyn, indicating that the extent of mast cell activation is in part regulated by the interplay between these Src family kinases. Activated phospholipase Cγ cleaves phospholipid membrane substrates to provide inositol-1,4,5-trisphosphate (IP3) and 1,2-diacylglycerols (1,2-DAGs) so as to mobilize intracellular calcium and activate protein kinase C, respectively. The subsequent opening of calcium-regulated activated channels provides the sustained elevations of intracellular calcium required to recruit the mitogen-activated protein kinases, ERK, JNK, and p38 (serine/threonine kinases), which provide cascades to augment arachidonic acid release and to mediate nuclear translocation


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InternalMed_Harrison. to recruit the mitogen-activated protein kinases, ERK, JNK, and p38 (serine/threonine kinases), which provide cascades to augment arachidonic acid release and to mediate nuclear translocation of transcription factors for various cytokines. The calcium ion–dependent activation of phospholipases cleaves membrane phospholipids to generate lysophospholipids, which, like 1,2-DAG, may facilitate the fusion of the secretory granule perigranular membrane with the cell membrane, a step that releases the membrane-free granules containing the preformed mediators of mast cell effects. The secretory granule of the human mas t cell has a crystalline structure, unlike mast cells of lower species. IgE-dependent cell activation results in solubilization and swelling of the granule contents within the first minute of receptor perturbation; this reaction is followed by the ordering of intermediate filaments about the swollen granule, movement of the granule toward the cell surface, and fusion of the


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InternalMed_Harrison. minute of receptor perturbation; this reaction is followed by the ordering of intermediate filaments about the swollen granule, movement of the granule toward the cell surface, and fusion of the perigranular membrane with that of other granules and with the plasmalemma to form extracellular channels for mediator release while maintaining cell viability. In addition to exocytosis, aggregation of FcεRI initiates two other pathways for generation of bioactiveproducts, namely, lipid mediators and cytokines. The biochemical steps involved in expression of such cytokines as tumor necrosis factor α (TNF-α), interleukin (IL) 1, IL-6, IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and others, including an array of chemokines, have not been specifically defined for mast cells. Inhibition studies of cytokine production (IL-1β, TNF-α, and IL-6) in mouse mast cells with cyclosporine or FK506 reveal binding to the ligand-specific immunophilin and attenuation of the


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InternalMed_Harrison. mast cells. Inhibition studies of cytokine production (IL-1β, TNF-α, and IL-6) in mouse mast cells with cyclosporine or FK506 reveal binding to the ligand-specific immunophilin and attenuation of the calcium ion-and calmodulin-dependent serine/ threonine phosphatase, calcineurin. Lipid mediator generation (Fig. 376-1) involves translocation of calcium ion–dependent cytosolic phospholipase A2 to the outer nuclear membrane, with subsequent release of arachidonic acid for metabolic processing by the distinct prostanoid and leukotriene pathways. The constitutiveprostaglandinendoperoxide synthase-1(PGHS-1/cyclooxygenase-1)andthedenovoinduciblePGHS-2(cyclooxygenase-2)convert releasedarachidonicacidtothesequentialintermediates,prostaglandins G2 and H2. The glutathione-dependent hematopoietic prostaglandin D2 (PGD2) synthase then converts PGH2 to PGD2, the predominant mast cell prostanoid. The PGD2 receptor DP1 is expressed by platelets and epithelial cells, whereas DP2 is expressed by TH2


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InternalMed_Harrison. D2 (PGD2) synthase then converts PGH2 to PGD2, the predominant mast cell prostanoid. The PGD2 receptor DP1 is expressed by platelets and epithelial cells, whereas DP2 is expressed by TH2 lymphocytes, eosinophils, and basophils. Mast cells also generate thromboxane A2 (TXA2), a short lived but powerful mediator that induces bronchoconstriction and platelet activation through the T prostanoid (TP) receptor. For leukotriene biosynthesis, the released arachidonic acid is metabolized by 5-lipoxygenase (5-LO) in the presence of an integral nuclear membrane protein, 5-LO activating protein (FLAP). The calcium


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InternalMed_Harrison. LTC,4 LTD4 FIGUrE 376-1 Pathways for biosynthesis and release of membrane-derived lipid mediators from mast cells. In the 5-lipoxygenase pathway, leukotriene A4 (LTA4) is the intermediate from which the terminal-pathway enzymes generate the distinct final products, leukotriene C (LTC ) and leukotriene B (LTB ), which leave the cell by separate saturable transport systems. Gamma glutamyl transpeptidase and a dipeptidase then cleave glutamic acid and glycine from LTC to form LTD and LTE , respectively. The major mast cell product of the cyclooxygenase system is PGD2.


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InternalMed_Harrison. ion–dependent translocation of 5-LO to the nuclear membrane converts the arachidonic acid to the sequential intermediates, 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and leukotriene (LT) A4. LTA4 is conjugated with reduced glutathione by LTC4 synthase, an integral nuclear membrane protein homologous to FLAP. Intracellular LTC4 is released by a carrier-specific export step for extracellular metabolism to the additional cysteinyl leukotrienes, LTD4 and LTE4, by the sequential removal of glutamic acid and glycine. Alternatively, cytosolic LTA4 hydrolase converts some LTA4 to the dihydroxy leukotriene LTB4, whichalsoundergoesspecificexport.TworeceptorsforLTB4,BLT1and BLT2, mediate chemotaxis of human neutrophils. Two receptors for the cysteinyl leukotrienes, CysLT1 and CysLT2, are present on smooth muscle of the airways and the microvasculature and on hematopoietic cells such as macrophages, eosinophils, and mast cells. Whereas the CysLT1 receptor has a preference for LTD4 and is


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InternalMed_Harrison. on smooth muscle of the airways and the microvasculature and on hematopoietic cells such as macrophages, eosinophils, and mast cells. Whereas the CysLT1 receptor has a preference for LTD4 and is blocked by the receptor antagonists in clinical use, the CysLT2 receptor is equally responsive to LTD4 and LTC4, is unaffected by these antagonists, and is a negative regulatorofthefunctionoftheCysLT1receptor.LTD4,actingatCysLT1 receptors, is the most potent known bronchoconstrictor, whereas LTE4 induces a vascular leak and mediates the recruitment of eosinophils to the bronchial mucosa. Studies in gene-deleted mice indicate the existence of additional receptors for LTE4. The lysophospholipid formed during the release of arachidonic acid from 1-O-alkyl-2-acyl-snglyceryl-3-phosphorylcholine can be acetylated in the second position to form platelet-activating factor (PAF). Serum levels of PAF correlated positively with the severity of anaphylaxis to peanut in a recent study, whereas the levels


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InternalMed_Harrison. acetylated in the second position to form platelet-activating factor (PAF). Serum levels of PAF correlated positively with the severity of anaphylaxis to peanut in a recent study, whereas the levels of PAF acetyl hydrolase (a PAF-degrading enzyme) were inversely related to the same outcome.


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InternalMed_Harrison. Unlike most other cells of bone marrow origin, mast cells circulate as committed progenitors lacking their characteristic secretory granules. These committed progenitors express c-kit, the receptor for stem cell factor (SCF). Unlike most other lineages, they retain and increase c-kit expression with maturation. The SCF interaction with c-kit is an absolute requirement for the development of constitutive tissue mast cells residing in skin and connective tissue sites and for the accumulation of mast cells at mucosal surfaces during TH2-type immune responses. Several T cell-derived cytokines (IL-3, IL-4, IL-5, and IL-9) can potentiate SCF-dependent mast cell proliferation and/ or survival in vitro in mice and humans. Indeed, mast cells are absent from the intestinal mucosa in clinical T cell deficiencies, but are present in the submucosa. Based on the immunodetection of secretory granuleneutralproteases, mastcells inthelungparenchymaandintestinal mucosa selectively express tryptase, and


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InternalMed_Harrison. deficiencies, but are present in the submucosa. Based on the immunodetection of secretory granuleneutralproteases, mastcells inthelungparenchymaandintestinal mucosa selectively express tryptase, and those in the intestinal and airway submucosa, perivascular spaces, skin, lymph nodes, and breast parenchyma express tryptase, chymase, and carboxypeptidase A (CPA). In the mucosal epithelium of severe asthmatics, mast cells can express tryptase and CPA without chymase. The secretory granules of mast cells selectively positive for tryptase exhibit closed scrolls with a periodicitysuggestiveofacrystalline structureby electronmicroscopy, whereasthesecretorygranulesofmastcellswithmultipleproteasesare scroll-poor, with an amorphous or lattice-like appearance.


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InternalMed_Harrison. Mast cells are distributed at cutaneous and mucosal surfaces and in submucosal tissues about venules and could influence the entry of foreign substances by their rapid response capability (Fig. 376-2). Upon stimulus-specific activation and secretory granule exocytosis, histamineandacid hydrolasesaresolubilized,whereastheneutral proteases, which are cationic, remain largely bound to the anionic proteoglycans, heparin and chondroitin sulfate E, with which they function as a complex. Histamine and the various lipid mediators (PGD2, LTC4/ D4/E4, PAF) alter venular permeability, thereby allowing influx of plasma proteins such as complement and immunoglobulins, whereas LTB4 mediates leukocyte–endothelial cell adhesion and subsequent directed migration (chemotaxis). The accumulation of leukocytes and plasma opsonins facilitates defense of the microenvironment. The inflammatory response can also be detrimental, as in asthma, where the smooth-muscle constrictor activity of the cysteinyl


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InternalMed_Harrison. and plasma opsonins facilitates defense of the microenvironment. The inflammatory response can also be detrimental, as in asthma, where the smooth-muscle constrictor activity of the cysteinyl leukotrienes is evident and much more potent than that of histamine.


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InternalMed_Harrison. The cellular component of the mast cell–mediated inflammatory response is augmented and sustained by cytokines and chemokines. IgE-dependent activation of human skin mast cells in situ elicits TNF-α production and release, which in turn induces endothelial cell responses favoring leukocyte adhesion. Similarly, activation of purified human lung mast cells or cord blood–derived cultured mast cells in vitro results in substantial production of proinflammatory (TNF-α) and immunomodulatory cytokines (IL-4, IL-5, IL-13) and Allergies, Anaphylaxis, and Systemic Mastocytosis Leukocyte responses tion and on the cytokine microenvironment pro- • Adherence vided by the antigen-presenting dendritic cells, LTC4 with IL-4 directing a TH2 subset, interferon (IFN) • Mast cell proliferation γ a TH1 profile, and IL-6 with transforming • Eosinophil activation growth factor β (TGF-β) a TH17 subset. Allergens


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InternalMed_Harrison. Proteoglycans • Globopentaosylceramide production that facilitate the immune response by direct initiation of cytokine generation from innate cell types such as basophils, mast cells, eosinophils, • Activation of matrix and others. The TH2 response is associated with activation of specific B cells that can also pres • Activation of coagulation cascade • GM-CSF • Augmented venular permeability for antibody production. Synthesis and release Activated mast cell • IL-13 • Leukocyte adherence into the plasma of allergen-specific IgE results in sensitization of FcεR1-bearing cells such as mast • TNF–° cells and basophils, which become activated on exposure to the specific allergen. In certain dis-FIGUrE 376-2 Bioactive mediators of three categories generated by IgE-dependent eases, including those associated with atopy, the activation of murine mast cells can elicit common but sequential target cell effects lead-monocyte and eosinophil populations can express ing to acute and sustained


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InternalMed_Harrison. those associated with atopy, the activation of murine mast cells can elicit common but sequential target cell effects lead-monocyte and eosinophil populations can express ing to acute and sustained inflammatory responses. GM-CSF, granulocyte-macrophage a trimeric FcεR1, which lacks the β chain, and yet colony-stimulating factor; IL, interleukin; IFN, interferon; LT, leukotriene; PAF, platelet-respond to its aggregation. An additional recently activating factor; PGD2, prostaglandin D2; TNF, tumor necrosis factor. recognized class of c-kit-expressing innate cells chemokines. Bronchial biopsy specimens from patients with asthma 2115 reveal that mast cells are immunohistochemically positive for IL-4 and IL-5, but that the predominant localization of IL-4, IL-5, and GM-CSF is to T cells, defined as TH2 by this profile. IL-4 modulates the T cell phenotype to the TH2 subtype, determines the isotype switch to IgE (as does IL-13), and upregulates FcεRI-mediated expression of cytokines by mast


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InternalMed_Harrison. as TH2 by this profile. IL-4 modulates the T cell phenotype to the TH2 subtype, determines the isotype switch to IgE (as does IL-13), and upregulates FcεRI-mediated expression of cytokines by mast cells based on in vitro studies.


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InternalMed_Harrison. An immediateandlate cellular phase ofallergicinflammation can be induced in the skin, nose, or lung of some allergic humans with local allergen challenge. The immediate phase in the nose involves pruritus and waterydischarge; in the lung, it involves bronchospasm and mucus secretion; and in the skin, it involves a wheal-and-flare response with pruritus. The reduced nasal patency, reduced pulmonary function, or erythema with swelling at the skin site in a late-phase response at 6–8 h is associated with biopsy findings of infiltrating and activated TH2 cells, eosinophils, basophils, and some neutrophils. The progression from early mast cell activation to late cellular infiltration has been used as an experimentalsurrogateofrhinitisorasthma.However,inasthma,there is an intrinsic hyperreactivity of the airways independent of the associated inflammation. Moreover, early-and late-phase responses (at least in the lung) are far more sensitive to blockade of IgE-dependent mast cell activation


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InternalMed_Harrison. of the airways independent of the associated inflammation. Moreover, early-and late-phase responses (at least in the lung) are far more sensitive to blockade of IgE-dependent mast cell activation (or actions of histamine and cysteinyl leukotrienes) than are spontaneous or virally induced asthma exacerbations.


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InternalMed_Harrison. Consideration of the mechanism of immediate-type hypersensitivity diseases in the human has focused largely on the IgE-dependent recognition of otherwise innocuous substances. A region of chromosome 5 (5q23-31) contains genes implicated in the control of IgE levels including IL-4 and IL-13, as well as IL-3 and IL-9, which are involved in mucosal mast cell hyperplasia, and IL-5 and GM-CSF, which are central to eosinophil development and their enhanced tissue viability. Genes with linkage to the specific IgE response to particular allergens include those encoding the major histocompatibility complex (MHC) and certain chains of the T cell receptor (TCR-αδ). The complexity of atopy and the associated diseases includes susceptibility, severity, and therapeutic responses, each of which is among the separate variables modulated by both innate and adaptive immune stimuli.


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InternalMed_Harrison. The induction of allergic disease requires sensitization of a predisposed individual to a specific allergen. The greatest propensity for the development of atopic allergy occurs in childhood and early adolescence. The allergen is processed by antigen-presenting cells of the monocytic lineage (particularly dendritic cells) located throughout the body at surfaces that contact the outside environment, such as the nose, lungs, eyes, skin, and intestine. These antigen-presenting cells presentthe epitope-bearing peptidesvia their MHC to T helper cells and their subsets. The T cell response depends both on cognate recogni- 2116 (termed nuocytes, natural helper cells, or group 2 innate lymphoid cells) can generate large quantities of IL-5 and IL-13 during antihelminth responses, are prominent in nasal polyps from humans, and could well contribute to inflammation in allergic diseases.


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InternalMed_Harrison. Life-threatening anaphylactic responses of sensitized humans occur within minutes after systemic exposure to specific antigen. They are manifested by respiratory distress due to laryngeal edema and/or intensebronchospasm,oftenfollowedbyvascularcollapse,orbyshock without antecedent respiratory difficulty. Cutaneous manifestations exemplified by pruritus and urticaria with or without angioedema are characteristic of such systemic anaphylactic reactions. Gastrointestinal manifestations include nausea, vomiting, crampy abdominal pain, and diarrhea.


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InternalMed_Harrison. There is no convincingevidence that age,sex, race,orgeographiclocation predisposes a human to anaphylaxis except through exposure to specific immunogens. According to most studies, atopy does not predispose individualsto anaphylaxisfrom penicillin therapy orvenomof a stinging insect but is a risk factor for allergens in food or latex. Risk factors for a poor outcome, however, include older age, use of beta blockers, and the presence of preexisting asthma. Severe hymenoptera anaphylaxis (generally with prominent hypotension) can be a presenting feature of underlying systemic mastocytosis. Additionally, some individuals suffering from recurrent episodes of idiopathic anaphylaxispossess morphologically aberrant mast cellsintheir bone marrow that express a mutant, constitutively active form of c-kit, even without evidence of frank mastocytosis.


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InternalMed_Harrison. The materials capable of eliciting the systemic anaphylactic reaction in humans include the following: heterologous proteins in the form of hormones (insulin, vasopressin, parathormone); enzymes (trypsin, chymotrypsin, penicillinase, streptokinase); pollen extracts (ragweed, grass, trees); nonpollen allergen extracts (dust mites, dander of cats, dogs, horses, and laboratory animals); food (peanuts, milk, eggs, seafood, nuts, grains, beans, gelatin in capsules); monoclonal antibodies; occupation-related products (latex rubber products); Hymenoptera venom (yellow jacket, yellow and white-faced hornets, paper wasp, honey bee, imported fire ants); polysaccharides such as dextran and thiomersal as a vaccine preservative; drugs such as protamine; antibiotics (penicillins, cephalosporins, amphotericin B, nitrofurantoin, quinolones); chemotherapy agents (carboplatin, paclitaxel, doxorubicin); local anesthetics (procaine, lidocaine); muscle relaxants (suxamethonium, gallamine, pancuronium);


InternalMed_Harrison

InternalMed_Harrison. B, nitrofurantoin, quinolones); chemotherapy agents (carboplatin, paclitaxel, doxorubicin); local anesthetics (procaine, lidocaine); muscle relaxants (suxamethonium, gallamine, pancuronium); vitamins (thiamine, folic acid); diagnostic agents (sodium dehydrocholate, sulfobromophthalein); biologics (omalizumab, rituximab, etanercept); and occupation-related chemicals (ethylene oxide). Drugs function as haptens that form immunogenic conjugates with host proteins. The conjugating hapten may be the parent compound, a nonenzymatically derived storage product, or a metabolite formed in the host. Recombinant biologics can also induce the formation of IgE against the proteins or against glycosylated structures that serve as immunogens. Most recently, outbreaks of anaphylaxis to the anti-epidermal growth factor antibody cetuximab were reported in association with elevated titers of serum IgE to alpha-1,3-galactose, an oligosaccharide found on certain nonprimate proteins. Alpha-galactose


InternalMed_Harrison

InternalMed_Harrison. growth factor antibody cetuximab were reported in association with elevated titers of serum IgE to alpha-1,3-galactose, an oligosaccharide found on certain nonprimate proteins. Alpha-galactose antibodies also account for some episodes of delayed anaphylaxis to beef, lamb, and pork.


InternalMed_Harrison

InternalMed_Harrison. Individuals differ in the time of appearance of symptoms and signs, butthehallmarkoftheanaphylacticreactionistheonsetofsomemanifestation within seconds to minutes after introduction of the antigen (with the exception of alpha-galactose allergy), generally by injection or less commonly by ingestion. There may be upper or lower airway obstruction or both. Laryngeal edema may be experienced as a “lump” in the throat, hoarseness, or stridor, whereas bronchial obstruction is associated with a feeling of tightness in the chest and/or audible wheezing. Patients with asthma are predisposed to severe involvement of the lower airways and increased mortality. Flushing with diffuse erythema and a feeling of warmth may occur. A characteristic feature is the eruption of well-circumscribed, discrete cutaneous wheals with erythematous,raised, serpiginous borders and blanched centers. These urticarial eruptions are intensely pruritic and may be localized or disseminated. They may coalesce to form


InternalMed_Harrison

InternalMed_Harrison. cutaneous wheals with erythematous,raised, serpiginous borders and blanched centers. These urticarial eruptions are intensely pruritic and may be localized or disseminated. They may coalesce to form giant hives, and they seldom persistbeyond48h.Alocalized,nonpitting,deeperedematouscutaneousprocess, angioedema,may also bepresent. It maybeasymptomatic or cause a burning or stinging sensation. Angioedema of the bowel wall may cause sufficient intravascular volume depletion to precipitate cardiovascular collapse.


InternalMed_Harrison

InternalMed_Harrison. In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination. The microscopic findings in the bronchi, however, are limited to luminal secretions, peribronchial congestion, submucosal edema, and eosinophilic infiltration,andthe acute emphysema isattributedtointractable bronchospasm that subsides with death. The angioedema resulting in death by mechanical obstruction occurs in the epiglottis and larynx, but the process also is evident in the hypopharynx and to some extent in the trachea. On microscopic examination, there is wide separation of the collagen fibers and the glandular elements; vascular congestion andeosinophilicinfiltrationalsoarepresent.Patientsdyingofvascular collapse without antecedent hypoxia from respiratory insufficiency have visceral congestion with a presumptive loss of intravascular fluid volume. The associated electrocardiographic abnormalities, with or without infarction, in some patients may


InternalMed_Harrison

InternalMed_Harrison. insufficiency have visceral congestion with a presumptive loss of intravascular fluid volume. The associated electrocardiographic abnormalities, with or without infarction, in some patients may reflect a primary cardiac event mediated by mast cells (which are prominent near the coronary vessels) or may be secondary to a critical reduction in blood volume.


InternalMed_Harrison

InternalMed_Harrison. The angioedematous and urticarial manifestations of anaphylaxis have been attributed to the release of endogenous histamine. A role for the cysteinyl leukotrienes in causing marked bronchiolar constriction seems likely. Vascular collapse without respiratory distress in response to experimental challenge with the sting of a hymenopteran was associated with marked and prolonged elevations in blood histamine and intravascular coagulation and kinin generation. The finding that patients with systemic mastocytosis and episodic vascular collapse excrete large amounts of PGD2 metabolites in addition to histamine suggests that PGD2 is also of importance in the hypotensive anaphylactic reactions. As noted, serum PAF levels correlate with severity of anaphylaxis and are inversely proportional to the constitutive level of the acetylhydrolase involved in PAF inactivation. The actions of the array of mast cell–derived mediators are likely additive or synergistic at the target tissues.


InternalMed_Harrison

InternalMed_Harrison. Thediagnosisofananaphylacticreactiondependsonahistoryrevealing the onset of symptoms and signs within minutes after the responsible material is encountered. It is appropriate to rule out a complement-mediated immune complex reaction, an idiosyncratic response to a nonsteroidal anti-inflammatory drug (NSAID), or the direct effect of certain drugs or diagnostic agents on mast cells. Intravenous administration of a chemical mast cell–degranulating agent, including opiate derivatives and radiographic contrast media, may elicit generalized urticaria, angioedema, and a sensation of retrosternal oppression with or without clinically detectable bronchoconstriction or hypotension. In the transfusion anaphylactic reaction that occurs in patients with IgA deficiency, the responsible specificity resides in IgG or IgE anti-IgA; the mechanism of the reaction mediated by IgG anti-IgA is presumed to be complement activation with secondary mast cell participation.


InternalMed_Harrison

InternalMed_Harrison. The presence of specific IgE in the blood of patients with systemic anaphylaxis was demonstrated historically by passive transfer of the serum intradermally into a normal recipient, followed 24 h later by antigen challenge into the same site, with subsequent development of a wheal and flare (the Prausnitz-Küstner reaction). In current clinical practice, immunoassays using purified or recombinant antigens can demonstrate the presence of specific IgE in the serum of patients with anaphylactic reactions, and skin testing may be performed after the patient has recovered to elicit a local wheal and flare in response to the putative antigen. Elevations of tryptase levels in serum implicate mast cell activation in a systemic reaction and are particularly informative for anaphylaxis with episodes of hypotension during general anesthesia or when there has been a fatal outcome. However, because of the short half-life of tryptase, elevated levels are best detected within 4 h of a systemic


InternalMed_Harrison

InternalMed_Harrison. of hypotension during general anesthesia or when there has been a fatal outcome. However, because of the short half-life of tryptase, elevated levels are best detected within 4 h of a systemic reaction. Moreover, anaphylactic reactions to foods characteristically are not associated with elevations in serum tryptase.


InternalMed_Harrison

InternalMed_Harrison. Early recognition of an anaphylactic reaction is mandatory, since death can occur within minutes to hours after the first symptoms. Mild symptoms such as pruritus and urticaria can be controlled by administration of 0.3–0.5 mL of 1:1000 (1 mg/mL) epinephrine SC or IM, with repeated doses as required at 5to 20-min intervals for a severe reaction. The failure to use epinephrine within the first 20 min of symptoms is a risk factor for poor outcome in studies of anaphylaxis to food. If the antigenic material was injected into an extremity, the rate of absorption may be reduced by prompt application of a tourniquet proximal to the reaction site, administration of 0.2 mL of 1:1000 epinephrine into the site, and removal without compression of an insect stinger, if present. An IV infusion should be initiated to provide a route for administration of 2.5 mL epinephrine, diluted 1:10,000, at 5to 10-min intervals, volume expanders such as normal saline, and vasopressor agents such as dopamine if


InternalMed_Harrison

InternalMed_Harrison. be initiated to provide a route for administration of 2.5 mL epinephrine, diluted 1:10,000, at 5to 10-min intervals, volume expanders such as normal saline, and vasopressor agents such as dopamine if intractable hypotension occurs. Replacement of intravascular volume due to postcapillary venular leakage may require several liters of saline. Epinephrine provides both αand β-adrenergic effects, resulting in vasoconstriction, bronchial smooth-muscle relaxation, and attenuation of enhanced venular permeability. Oxygen alone via a nasal catheter or with nebulized albuterol may be helpful, but either endotracheal intubation or a tracheostomy is mandatory for oxygen delivery if progressive hypoxia develops. Ancillary agents such as the antihistamine diphenhydramine, 50–100 mg IM or IV, and aminophylline, 0.25–0.5 g IV, are appropriate for urticaria-angioedema and bronchospasm, respectively. Intravenous glucocorticoids, 0.5–1 mg/kg of methylprednisolone, are not effective for the acute event


InternalMed_Harrison

InternalMed_Harrison. 0.25–0.5 g IV, are appropriate for urticaria-angioedema and bronchospasm, respectively. Intravenous glucocorticoids, 0.5–1 mg/kg of methylprednisolone, are not effective for the acute event but may alleviate later recurrence of bronchospasm, hypotension, or urticaria.


InternalMed_Harrison

InternalMed_Harrison. Prevention of anaphylaxis must take into account the sensitivity of the individual, the dose and character of the diagnostic or therapeutic agent, and the effect of the route of administration on the rate of absorption. Beta blockers are relatively contraindicated in persons at risk for anaphylactic reactions, especially those sensitive to Hymenoptera venom or those undergoing immunotherapy for respiratory system allergy. Ifthereis a definitehistory of a past anaphylactic reaction to a medication, it is advisable to select a structurally unrelated agent. A knowledge of cross-reactivity among agents is critical since, for example, cephalosporins have a cross-reactive ring structure with the penicillins. When skin testing, a prick or scratch skin test should precede an intradermal test, since the latter has a higher risk of causing anaphylaxis. These tests should be performed before the administration of certain materials that are likely to elicit anaphylactic reactions, such as


InternalMed_Harrison

InternalMed_Harrison. since the latter has a higher risk of causing anaphylaxis. These tests should be performed before the administration of certain materials that are likely to elicit anaphylactic reactions, such as allergenic extracts. Skin testing for antibiotics or chemotherapeutic agents should be performed only on patients with a positive clinical history consistent with an IgE-mediated reaction and in imminent need of the antibiotic in question; skin testing is of no value for non-IgE-mediated eruptions. With regard to penicillin, two-thirds ofpatientswithapositivereactionhistory and positiveskintests to benzylpenicilloyl-polylysine (BPL) and/or the minor determinant mixture (MDM) of benzylpenicillin products experience allergic reactions with treatment, and these reactions are almost uniformly of the anaphylactic type in those patients with minor determinant reactivity. Even patients without a history of previous clinical reactions have a 2–6% incidence of positive skin tests to the two test


InternalMed_Harrison

InternalMed_Harrison. the anaphylactic type in those patients with minor determinant reactivity. Even patients without a history of previous clinical reactions have a 2–6% incidence of positive skin tests to the two test materials, and about 3 per 1000 with a negative history experience anaphylaxis with 2117 therapy, with a mortality of about 1 per 100,000.


InternalMed_Harrison

InternalMed_Harrison. If an agent carrying a risk of eliciting an anaphylactic response is required because a non-cross-reactive alternative is not available, desensitization can be performed with most antibiotics and other classes of therapeutic agents by the IV, SC, or PO route. Typically, graded quantities of the drug are given by the selected route starting below the threshold dose for an adverse reaction and then doubling each dose until a therapeutic dosage is achieved. Due to the risk of systemic anaphylaxis during the course of desensitization, such a procedure should be performed under the supervision of a specialist and in a setting in which resuscitation equipment is at hand and an IV line is in place. Once a desensitized state is achieved, it is critical to continue administration of the therapeutic agent at regular intervals throughout the treatment period to prevent the reestablishment of a significant pool of sensitized cells.


InternalMed_Harrison

InternalMed_Harrison. A different form of protection involves the development of blocking antibody of the IgG class, which protects against Hymenoptera venom– induced anaphylaxis by interacting with antigen so that less reaches the sensitized tissue mast cells. The maximal risk for systemic anaphylactic reactions in persons with Hymenoptera sensitivity occurs in association withacurrentlypositiveskintest.Althoughthereislittlecross-reactivity between honey bee and yellow jacket venoms, there is a high degree of cross-reactivity between yellow jacket venom and the rest of the vespid venoms (yellow or white-faced hornets and wasps). Prevention involves modification of outdoor activities to exclude bare feet, wearing perfumed toiletries, eating in areas attractive to insects, clipping hedges or grass, and hauling away trash or fallen fruit. As with each anaphylactic sensitivity, the individual should wear an informational bracelet and have immediate access to an unexpired autoinjectable epinephrine kit. Venom


InternalMed_Harrison

InternalMed_Harrison. away trash or fallen fruit. As with each anaphylactic sensitivity, the individual should wear an informational bracelet and have immediate access to an unexpired autoinjectable epinephrine kit. Venom immunotherapy for 5 years can induce a state of resistance to sting reactions that is independent of serum levels of specific IgG or IgE. Forchildren under the ageof 10 with a systemic reaction limitedto skin, the likelihood of progression to more serious respiratory or vascular manifestations is low, and thus immunotherapy is not recommended.


InternalMed_Harrison

InternalMed_Harrison. Urticaria and angioedema may appear separately or together as cutaneous manifestations of localized nonpitting edema; a similar process may occur at mucosal surfaces of the upper respiratory or gastrointestinal tract. Urticaria involves only the superficial portion of the dermis, presenting as well-circumscribed wheals with erythematous raised serpiginous borders and blanched centers that may coalesce to become giant wheals. Angioedema is a well-demarcated localized edema involving the deeper layers of the skin, including the subcutaneous tissue, and can also involve the bowel wall. Recurrent episodes of urticaria and/or angioedema of less than 6 weeks’ duration are considered acute, whereas attacks persisting beyond this period are designated chronic.


InternalMed_Harrison

InternalMed_Harrison. Urticaria and angioedema probably occur more frequently than reported because of the evanescent, self-limited nature of such eruptions,whichseldomrequiremedicalattentionwhenlimitedtotheskin. Although persons in any age group may experience acute or chronic urticaria and/or angioedema, these lesions increase in frequency after adolescence, with the highest incidence occurring in persons in the third decade of life; indeed, one survey of college students indicated that 15–20% had experienced a pruritic wheal reaction.


InternalMed_Harrison

InternalMed_Harrison. Theclassification ofurticaria-angioedema presentedin Table 376-1 focuses on the different mechanisms for eliciting clinical disease and can be useful for differential diagnosis; nonetheless, most cases of chronic urticaria are idiopathic. Urticaria and/or angioedema occurring during the appropriate season in patients with seasonal respiratory allergy or as a result of exposure to animals or molds is attributed to inhalation or physical contact with pollens, animal dander, and mold spores, respectively. However, urticaria and angioedema secondary to inhalation are relatively uncommon compared to urticaria and


InternalMed_Harrison

InternalMed_Harrison. Allergies, Anaphylaxis, and Systemic Mastocytosis 1. IgE-dependent a. Specific antigen sensitivity (pollens, foods, drugs, fungi, molds, Hymenoptera venom, helminths) b. Physical: dermographism, cold, solar, pressure, cholinergic c. Autoimmune 2. Bradykinin-mediated a. Hereditary angioedema: C1 inhibitor deficiency: null (type 1) and dysfunctional (type 2); mutated factor XII (type 3) b. Acquired angioedema: C1 inhibitor deficiency: anti-idiotype and anti-C1 inhibitor c. Angiotensin-converting enzyme inhibitors 3. Complement-mediated a. Necrotizing vasculitis b. Serum sickness c. Reactions to blood products 4. Nonimmunologic a. Direct mast cell–releasing agents (opiates, antibiotics, curare, D-tubocurarine, radiocontrast media) b. Agents that alter arachidonic acid metabolism (aspirin and nonsteroidal anti-inflammatory agents, azo dyes, and benzoates) 5. Idiopathic angioedema elicited by ingestion of fresh fruits, shellfish, fish, milk products, chocolate, legumes including peanuts,


InternalMed_Harrison

InternalMed_Harrison. anti-inflammatory agents, azo dyes, and benzoates) 5. Idiopathic angioedema elicited by ingestion of fresh fruits, shellfish, fish, milk products, chocolate, legumes including peanuts, and various drugs that may elicit not only the anaphylactic syndrome with prominent gastrointestinal complaints but also urticaria alone.


InternalMed_Harrison

InternalMed_Harrison. Additional etiologies include physical stimuli such as cold, heat, solar rays, exercise, and mechanical irritation. The physical urticarias can be distinguished by the precipitating event and other aspects of the clinical presentation. Dermographism, which occurs in 1–4% of the population, is defined by the appearance of a linear wheal at the site of a brisk stroke with a firm object or by any configuration appropriate to the eliciting event (Fig. 376-3). Dermographism has a prevalence that peaks in the second to third decades. It is not influenced by atopy and has a duration generally of <5 years. Pressure urticaria, which often accompanies chronic idiopathic urticaria, presents in response to a sustained stimulus such as a shoulder strap or belt, running (feet), or manual labor (hands). Cholinergic urticaria is distinctive in that the pruritic wheals are of small size (1–2 mm) and are surrounded by a large area of erythema; attacks are precipitated by fever, a hot bath or shower, or


InternalMed_Harrison

InternalMed_Harrison. Cholinergic urticaria is distinctive in that the pruritic wheals are of small size (1–2 mm) and are surrounded by a large area of erythema; attacks are precipitated by fever, a hot bath or shower, or exercise and are presumptively attributed to a rise in core


InternalMed_Harrison

InternalMed_Harrison. FIGUrE 376-3 Dermographic urticarial lesion inducedbystrokingtheforearmlightlywiththeedgeofatongueblade.Thephotograph,takenafter2minutes,demonstratesaprominentwheal-and-flarereactionintheshapeofanX.(From LA Goldsmith et al [eds]: Fitzpatrick’s Dermatology in General Medicine, 8th ed. New York, McGraw-Hill, 2012. Photograph pro-vided by Allen P. Kaplan, MD, Medical University of South Carolina.) body temperature. Exercise-induced anaphylaxis can be precipitated by exertion alone or can be dependent on prior food ingestion. There is an association with the presence of IgE specific for α-5 gliadin, a component of wheat. The clinical presentation can be limited to flushing, erythema, and pruritic urticaria but may progress to angioedema of the face, oropharynx, larynx, or intestine or to vascular collapse; it is distinguished from cholinergic urticaria by presenting with wheals of conventional size and by not occurring with fever or a hot bath. Cold urticaria is local at body areas


InternalMed_Harrison

InternalMed_Harrison. vascular collapse; it is distinguished from cholinergic urticaria by presenting with wheals of conventional size and by not occurring with fever or a hot bath. Cold urticaria is local at body areas exposed to low ambient temperature or cold objects but can progress to vascular collapse with immersion in cold water (swimming). Solar urticaria is subdivided into six groups by the response to specific portions of the light spectrum. Vibratory angioedema may occur after years of occupational exposure or can be idiopathic; it may be accompanied by cholinergic urticaria. Other rare formsofphysicalallergy,alwaysdefinedbystimulus-specificelicitation, include local heat urticaria, aquagenic urticaria fromcontactwithwater of anytemperature (sometimesassociatedwithpolycythemiavera),and contact urticaria from direct interaction with some chemical substance.


InternalMed_Harrison

InternalMed_Harrison. Angioedema without urticaria due to the generation of bradykinin occurs with C1 inhibitor (C1INH) deficiency that may be inborn as an autosomal dominant characteristic or may be acquired through the appearance of an autoantibody. The angiotensin-converting enzyme (ACE) inhibitors can provoke a similar clinical presentation in 0.1– 0.5% of hypertensive patients due to attenuated degradation of bradykinin. The urticaria and angioedema associated with classic serum sickness or with hypocomplementemic cutaneous necrotizing angiitis are believed to be immune-complex diseases. The drug reactions to mast cell granule–releasing agents and to NSAIDs may be systemic, resembling anaphylaxis, or limited to cutaneous sites.


InternalMed_Harrison

InternalMed_Harrison. Urticarial eruptions are distinctly pruritic, may involve any area of the body from the scalp to the soles of the feet, and appear in crops of 12-to 36-h duration, with old lesions fading as new ones appear. Most of the physical urticarias (cold, cholinergic, dermatographism) are an exception, with individual lesions lasting less than 2 h. The most common sites for urticaria are the extremities and face, with angioedema often being periorbital and in the lips. Although self-limited in duration, angioedemaoftheupper respiratorytractmaybe life-threateningdueto laryngealobstruction,whereasgastrointestinalinvolvementmaypresent with abdominal colic, with or without nausea and vomiting, and may result in unnecessary surgical intervention. No residual discoloration occurs with either urticaria or angioedema unless there is an underlying vasculiticprocessleadingtosuperimposedextravasationoferythrocytes.


InternalMed_Harrison

InternalMed_Harrison. The pathology is characterized by edema of the superficial dermis in urticaria and of the subcutaneous tissue and deep dermis in angioedema. Collagen bundles in affected areas are widely separated, and the venules are sometimes dilated. Any perivenular infiltrate consists of lymphocytes,monocytes,eosinophils, and neutrophils that are present in varying combination and numbers.


InternalMed_Harrison

InternalMed_Harrison. Perhaps the best-studied example of IgE-and mast cell–mediated urticaria and angioedema is cold urticaria. Cryoglobulins or cold agglutinins are present in up to 5% of these patients. Immersion of an extremity in an ice bath precipitates angioedema of the distal portion with urticaria at the air interface within minutes of the challenge. Histologic studies reveal marked mast cell degranulation with associatededema of the dermis and subcutaneous tissues. Thehistamine level in the plasma of venous effluent of the cold-challenged and angioedematous extremity is markedly increased, but no such increase appears in the plasma of effluent of the contralateral normal extremity. Elevated levels of histamine have been found in the plasma of venous effluent and in the fluid of suction blisters at experimentally induced lesional sites in patients with dermographism, pressure urticaria, vibratory angioedema, light urticaria, and heat urticaria. By ultrastructural analysis, the pattern of mast cell


InternalMed_Harrison

InternalMed_Harrison. induced lesional sites in patients with dermographism, pressure urticaria, vibratory angioedema, light urticaria, and heat urticaria. By ultrastructural analysis, the pattern of mast cell degranulation in cold urticaria resembles an IgE-mediated response with solubilization of granule contents, fusion of the perigranular and cell membranes, and discharge of granule contents, whereas in a dermographic lesion, there is additional superimposed zonal (piecemeal) degranulation. There are several reports of resolution of cold urticaria by treatment with monoclonal anti-human IgE (omalizumab). Elevations of plasma histamine levels with biopsy-proven mast cell degranulation have also been demonstrated with generalized attacks of cholinergic urticaria and exercise-related anaphylaxis precipitated experimentally in subjects exercising on a treadmill while wearing a wet suit; however, only subjects with cholinergic urticaria have a concomitant decrease in pulmonary function.


InternalMed_Harrison

InternalMed_Harrison. Up to 40% of patients with chronic urticaria have an autoimmune cause for their disease including autoantibodies to IgE (5–10%) or, more commonly, to the α chain of FcεRI (35–45%). In these patients, autologous serum injected into their own skin can induce a wheal-and-flare reaction involving mast cell activation. The presence of these antibodies can alsoberecognized by their capacityto releasehistamine or induce activation markers such as CD63 or CD203 on basophils. An association with antibodies to microsomal peroxidase and/or thyroglobulin has been observed often with clinically significant Hashimoto’s thyroiditis. In vitro studies reveal that these autoantibodies can mediate basophil degranulation with enhancement by serum as a source of the anaphylatoxic fragment, C5a.