Immunology_Janeway

Immunology_Janeway. TCRpre-TCR CD8 CD4 pro-T cell pro-B cell pre-B cell immature B cell B1 B cell natural killer cell B2 B cell MZ B cell pro-NK CLPHSC pre-T cell double-positive T cell CD8 T cell thymus Bone marrow CD4 T cell CD8 T cell CD4 T cell pre-BCR BCR IgD CD3˜, CD3°, CD3˛TAP1, TAP2, tapasin CIITA, RFXANK, RFX5, RFXAP ˝H, ˙5, Igˆ, IgˇBLNK ZAP-70 AIRERAG-1, RAG-2 Artemis, DNA-PKc, DNA ligase IV CD45 BTK IL-7RˆADA Periphery ˇc, Jak3 °c SCID SCID XSCID MHC class I defciency MHC class II defciency B-cell defciency B-cell defciency SCID-like immunodefciency APECEDSCID Omenn syndrome RS-SCID SCID SCID SCID X-linked agammaglobulinemia Fig. 13.2 Defects in T-cell and B-cell development that cause immunodeficiency. the pathways leading to circulating naive t cells and B cells are shown here. Mutations in genes that encode the proteins (indicated in red boxes) are known to cause human immunodeficiency diseases. BCR, B-cell receptor; ClP, common lymphoid progenitor; HSC, hematopoietic stem cell; MZ B cell,


Immunology_Janeway

Immunology_Janeway. that encode the proteins (indicated in red boxes) are known to cause human immunodeficiency diseases. BCR, B-cell receptor; ClP, common lymphoid progenitor; HSC, hematopoietic stem cell; MZ B cell, marginal zone B cell; pre-BCR, pre-B-cell receptor; pre-tCR, pre-t-cell receptor; RS-SCiD, radiation-sensitive SCiD; SCiD, severe combined immunodeficiency; tCR, t-cell receptor; XSCiD, X-linked SCiD. immunodeficiency can also be caused by mutations in genes in the thymic epithelium that impair thymic development, and thus t-cell development.


Immunology_Janeway

Immunology_Janeway. As in all serious Tcell deficiencies, patients with XSCID do not make effective antibody responses to most antigens, although their B cells seem normal. Most, but not all, naive IgMpositive B cells from female carriers of XSCID have inactivated the defective X chromosome rather than the normal one (see Section 133), showing that Bcell development is affected by, but is not wholly dependent on, the γc chain. Mature memory B cells that have undergone class switching have inactivated the defective X chromosome almost without exception. This might reflect the fact that the γc chain is also part of the receptor for IL21, which is important for the maturation of classswitched B cells (see Section 104). 13-4 SCID can also be due to defects in the purine salvage pathway.


Immunology_Janeway

Immunology_Janeway. Variants of autosomal recessive SCID that arise from defects in enzymes of the salvage pathway of purine synthesis include adenosine deaminase (ADA) deficiency (see Fig. 13.2) and purine nucleotide phosphorylase (PNP) deficiency. ADA catalyzes the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively, and its deficiency results in the accumulation of deoxyadenosine and its precursor, Sadenosylhomocysteine, which are toxic to developing T and B cells. PNP catalyzes the conversion of inosine and guanosine to hypoxanthine and guanine, respectively. PNP deficiency, which is a rarer form of SCID, also causes the accumulation of toxic precursors but affects developing T cells more severely than B cells. In both diseases, the development of lymphopenia, or decreased numbers of lymphocytes, is progressive after birth, resulting in profound lymphopenia within the first few years of life. Because both enzymes are housekeeping proteins expressed by many cell types,


Immunology_Janeway

Immunology_Janeway. numbers of lymphocytes, is progressive after birth, resulting in profound lymphopenia within the first few years of life. Because both enzymes are housekeeping proteins expressed by many cell types, the immune deficiency associated with each of these inherited defects is part of a broader clinical syndrome.


Immunology_Janeway

Immunology_Janeway. 13-5 Defects in antigen receptor gene rearrangement can result in SCID.


Immunology_Janeway

Immunology_Janeway. Another group of autosomally inherited defects leading to SCID is caused by failures of DNA rearrangement in developing lymphocytes. Mutations in either the RAG1 or RAG2 gene that result in nonfunctional proteins cause arrest of lymphocyte development at the pro to preTcell and Bcell transitions because of a failure of V(D)J recombination (see Fig. 13.2). Thus, there is a complete lack of both T cells and B cells in these patients. Because the effects of RAG deficiencies are limited to lymphocytes that undergo antigen gene rearrangement, NKcell development is not impaired. There are other children with hypomorphic mutations (which cause reduced, but not absent, function) in either RAG1 or RAG2 who can make a small amount of functional RAG protein, allowing limited V(D)J recombination. This latter group includes patients with a distinctive and severe disease called Omenn syndrome, which, in addition to increased susceptibility to multiple opportunistic infections, has clinical features


Immunology_Janeway

Immunology_Janeway. latter group includes patients with a distinctive and severe disease called Omenn syndrome, which, in addition to increased susceptibility to multiple opportunistic infections, has clinical features very similar to graftversushost disease characterized by rashes, eosinophilia, diarrhea, and enlargement of the lymph nodes (see Section 1536). Normal or increased numbers of activated T cells are found in these children. An explanation for this phenotype is that low levels of RAG activity allow some limited Tcell receptor gene recombination. No B cells are found, however, suggesting that B cells have more stringent requirements for RAG activity. Due to the limited number of Tcell receptors that are successfully rearranged, the repertoire of T cells is highly restricted in patients with Omenn syndrome, and there is activation and clonal expansion of the limited number of specificities present. The clinical features strongly suggest that these peripheral T cells are autoreactive and are


Immunology_Janeway

Immunology_Janeway. syndrome, and there is activation and clonal expansion of the limited number of specificities present. The clinical features strongly suggest that these peripheral T cells are autoreactive and are responsible for the graftversushost phenotype. In addition to Omenn syndrome, which is manifested very early in life, other forms of immunodeficiency have also been associated with reduced but not absent RAG activity, and are often characterized by granulomatous disease that is not evident until late childhood or adolescence.


Immunology_Janeway

Immunology_Janeway. A subset of patients with autosomal recessive SCID are characterized by an abnormal sensitivity to ionizing radiation. They produce very few mature B and T cells because there is a failure of DNA rearrangement in their developing lymphocytes; only rare VJ or VDJ joints are seen, and most of these are abnormal. This type of SCID is due to defects in ubiquitous DNA repair proteins involved in repairing DNA doublestrand breaks, which are generated not only during antigen receptor gene rearrangement (see Section 55) but also by ionizing radiation. Owing to the increased radiosensitivity in these patients, this class of SCID is called radiationsensitive SCID (RSSCID) to distinguish it from SCID due to lymphocytespecific defects. Defects in the genes for Artemis, DNA proteinkinase catalytic subunit (DNAPKcs), and DNA ligase IV cause RSSCID (see Fig. 13.2). Because defects in repair of DNA breaks increase the risk of translocations during cell division that can lead to malignant


Immunology_Janeway

Immunology_Janeway. subunit (DNAPKcs), and DNA ligase IV cause RSSCID (see Fig. 13.2). Because defects in repair of DNA breaks increase the risk of translocations during cell division that can lead to malignant transformation, patients with RSSCID variants are also more likely to develop cancer.


Immunology_Janeway

Immunology_Janeway. 13-6 Defects in signaling from T-cell antigen receptors can cause severe immunodeficiency.


Immunology_Janeway

Immunology_Janeway. Several gene defects have been described that interfere with signaling through the Tcell receptor (TCR) and thus block the activation of T cells early in thymic development. Patients with mutations in the CD3δ, CD3ε, or CD3ζ chains of the CD3 complex have defective preTcell receptor signaling and fail to progress to the doublepositive stage of thymic development (see Fig. 13.2), resulting in SCID. Another lymphocyte signaling defect that leads to severe immunodeficiency is caused by mutations in the tyrosine phosphatase CD45. Humans and mice with CD45 deficiency show a marked reduction in peripheral Tcell numbers and also abnormal Bcell maturation. Severe immunodeficiency also occurs in patients who make a defective form of the cytosolic protein tyrosine kinase ZAP70, which transmits signals from the Tcell receptor (see Section 77). CD4 T cells emerge from the thymus in normal numbers, whereas CD8 T cells are absent. However, the CD4 T cells that mature fail to respond to stimuli that


Immunology_Janeway

Immunology_Janeway. from the Tcell receptor (see Section 77). CD4 T cells emerge from the thymus in normal numbers, whereas CD8 T cells are absent. However, the CD4 T cells that mature fail to respond to stimuli that normally activate the cells through the Tcell receptor.


Immunology_Janeway

Immunology_Janeway. Wiskott–Aldrich syndrome (WAS), which is caused by a defect in the WAS gene on the X chromosome that encodes WAS protein (WASp), has shed new light on the molecular basis of signaling and immune synapse formation between various cells in the immune system. Although the disease also affects platelets and was first described as a bloodclotting disorder, it also causes immunodeficiency that is characterized by reduced Tcell numbers, defective NKcell cytotoxicity, and a failure of antibody responses (see Section 719). WASp is expressed in all hematopoietic cell lineages and is a key regulator of lymphocyte and platelet development and function through its transduction of receptormediated signals that induce reorganization of the cytoskeleton (see Section 925). Several signaling pathways downstream of the Tcell receptor are known to activate WASp (see Section 7.19). Activation of WASp in turn activates the Arp2/3 complex, which is essential for initiating actin polymerization that is


Immunology_Janeway

Immunology_Janeway. downstream of the Tcell receptor are known to activate WASp (see Section 7.19). Activation of WASp in turn activates the Arp2/3 complex, which is essential for initiating actin polymerization that is critical for immune synapse formation and the polarized release of effector molecules by T cells. In patients with WAS, and in mice whose Was gene has been knocked out, T cells fail to respond normally to Tcell receptor crosslinking. It has also recently been suggested that WASp is required for the suppressive function of natural Treg cells, and this may help explain why patients with WASp are susceptible to autoimmune diseases.


Immunology_Janeway

Immunology_Janeway. 13-7 Genetic defects in thymic function that block T-cell development result in severe immunodeficiencies. A disorder of thymic development associated with SCID and a lack of body hair has been known for many years in mice; the mutant strain is descriptively named nude (see Section 810). A small number of children have been described with the same phenotype. In both mice and humans this syndrome is caused by mutations in the gene FOXN1, which encodes a transcription factor selectively expressed in skin and thymus. FOXN1 is necessary for the differentiation of thymic epithelium and the formation of a functional thymus. In patients with a mutation in FOXN1, the lack of thymic function prevents normal Tcell development. Bcell development is normal in individuals with the mutation, yet Bcell responses are deficient because of the lack of T cells, and the response to nearly all pathogens is profoundly impaired.


Immunology_Janeway

Immunology_Janeway. DiGeorge syndrome is another disorder in which the thymic epithelium fails to develop normally, resulting in SCID. The genetic abnormality underlying this complex developmental disorder is a deletion within one copy of chromosome 22. The deletion varies between 1.5 and 5 megabases in size, with the smallest deletion that causes the syndrome containing approximately 24 genes. The relevant gene within this interval is TBX1, which encodes the transcription factor Tbox 1. DiGeorge syndrome is caused by the deletion of a single copy of this gene, such that patients with this disorder are haploinsufficient for TBX1. Without the proper inductive thymic environment, T cells cannot mature, and both cellmediated immunity and Tcelldependent antibody production are impaired. Patients with this syndrome have normal levels of serum immunoglobulin but an absence of, or incomplete development of, the thymus and parathyroid glands, with varying degrees of Tcell immunodeficiency.


Immunology_Janeway

Immunology_Janeway. Defects in the expression of MHC molecules can lead to severe immunodeficiency as a result of effects on the positive selection of T cells in the thymus (see Fig. 13.2). Individuals with bare lymphocyte syndrome lack expression of all MHC class II molecules; the disease is now called MHC class II deficiency. Because the thymus lacks MHC class II molecules, CD4 T cells cannot be positively selected and few develop. The antigenpresenting cells in these individuals also lack MHC class II molecules and so the few CD4 T cells that do develop cannot be stimulated by antigen. MHC class I expression is normal, and CD8 T cells develop normally. However, such people suffer from severe immunodeficiency, illustrating the central importance of CD4 T cells in adaptive immunity to most pathogens.


Immunology_Janeway

Immunology_Janeway. MHC class II deficiency is caused not by mutations in the MHC genes themselves but by mutations in one of several genes encoding generegulatory proteins that are required for the transcriptional activation of MHC class II genes. Four complementing gene defects (known as groups A, B, C, and D) have been defined in patients who fail to express MHC class II molecules, indicating that the products of at least four different genes are required for the normal expression of these proteins. Genes corresponding to each complementation group have been identified: the MHC class II transactivator, or CIITA, is mutated in group A, and the genes RFXANK, RFX5, and RFXAP are mutated in groups B, C, and D, respectively (see Fig. 13.2). These last three encode proteins that are components of a multimeric complex, RFX, which is involved in the control of gene transcription. RFX binds a DNA sequence named an Xbox, which is present in the promoter region of all MHC class II genes.


Immunology_Janeway

Immunology_Janeway. A more limited immunodeficiency, associated with chronic respiratory bacterial infections and skin ulceration with vasculitis, has been observed in a small number of patients who have almost no cellsurface MHC class I molecules—a condition known as MHC class I deficiency. In contrast to those with MHC class II deficiency, affected individuals have normal levels of mRNA encoding MHC class I molecules and normal production of MHC class I proteins, but very few of the proteins reach the cell surface. This condition is due either to mutations in TAP1 or TAP2, which encode the subunits of the peptide transporter responsible for transporting peptides generated in the cytosol into the endoplasmic reticulum, where they are loaded into nascent MHC I molecules, or to mutations in TAPBP, which encodes tapasin, another component of the peptide transporter complex (see Section 64). Although the reduction in MHC class I molecules on the surface of thymic epithelial cells results in reduced numbers


Immunology_Janeway

Immunology_Janeway. tapasin, another component of the peptide transporter complex (see Section 64). Although the reduction in MHC class I molecules on the surface of thymic epithelial cells results in reduced numbers of CD8 T cells (see Fig. 13.2), people with MHC class I deficiency are not abnormally susceptible to viral infections. This is surprising given the key role of MHC class I presentation and of cytotoxic CD8 T cells in combating viral infections. There is, however, evidence for TAPindependent pathways for the presentation of certain peptides by MHC class I molecules, and the clinical phenotype of TAP1and TAP2deficient patients indicates that these pathways can compensate to allow sufficient development and function of CD8 T cells to control viruses.


Immunology_Janeway

Immunology_Janeway. Some defects in thymic cells lead to a phenotype with other effects besides those of immunodeficiency. The gene AIRE encodes a transcription factor that enables thymic epithelial cells to express many self proteins and so to mediate efficient negative selection. Defects in AIRE lead to a complex syndrome called APECED (autoimmune polyendocrinopathycandidiasisectodermal dystrophy), which is characterized by autoimmunity, developmental defects, and immunodeficiency (see Section 823, and Chapter 15). in antibody production that cause an inability to clear extracellular bacteria and some viruses.


Immunology_Janeway

Immunology_Janeway. In addition to inherited defects in proteins that are crucial to both Tcell and Bcell development, such as RAG1 and RAG2, defects that are specific to Bcell development have also been identified (see Fig. 13.2). Patients with these defects are characterized by an inability to cope with extracellular bacteria and some viruses whose efficient clearance requires specific antibodies. Pyogenic bacteria, such as staphylococci and streptococci, have polysaccharide capsules that are not directly recognized by the receptors on macrophages and neutrophils that stimulate phagocytosis. The bacteria escape elimination by the innate immune response and are successful extracellular pathogens, but can be cleared by an adaptive immune response. Opsonization by antibody and complement enables phagocytes to ingest and destroy the bacteria (see Section 1022). The principal effect of deficiencies in antibody production is therefore a failure to control infections by pyogenic bacteria. Susceptibility to


Immunology_Janeway

Immunology_Janeway. to ingest and destroy the bacteria (see Section 1022). The principal effect of deficiencies in antibody production is therefore a failure to control infections by pyogenic bacteria. Susceptibility to some viral infections, notably those caused by enteroviruses, is also increased because of the importance of antibodies in neutralizing viruses that enter the body through the gut.


Immunology_Janeway

Immunology_Janeway. The first description of an immunodeficiency disease was Ogden C. Bruton’s account, in 1952, of the failure of a male child to produce antibody. Because inheritance of this condition is Xlinked and is characterized by the absence of immunoglobulin in the serum (agammaglobulinemia), it was called Bruton’s Xlinked agammaglobulinemia (XLA) (see Fig. 13.2). Since then, autosomal recessive variants of agammaglobulinemia have been described. Infants with these diseases are usually identified as a result of recurrent infections with pyogenic bacteria, such as Streptococcus pneumoniae, and enteroviruses. In this regard, it should be noted that normal infants have a transient deficiency in immunoglobulin production in the first 3–12 months of life. The newborn infant has antibody levels comparable to those of the mother because of the transplacental transport of maternal IgG (see Section 1017). As this IgG is catabolized, antibody levels gradually decrease until the infant begins to produce


Immunology_Janeway

Immunology_Janeway. to those of the mother because of the transplacental transport of maternal IgG (see Section 1017). As this IgG is catabolized, antibody levels gradually decrease until the infant begins to produce significant amounts of its own IgG at about 6 months (Fig. 13.3). Thus, IgG levels are quite low between the ages of 3 months and 1 year. This can lead to a period of heightened susceptibility to infection, especially in premature babies, who begin with lower levels of maternal IgG and also reach immune competence later after birth. Because of the transient protection afforded


Immunology_Janeway

Immunology_Janeway. Fig. 13.3 Immunoglobulin levels in newborn infants fall to low levels at about 6 months of age. Babies are born with high levels of maternal igG, which is actively transported across the placenta from the mother during gestation. after birth, the production of igM starts almost immediately; the production of igG, however, does not begin for about 6 months, during which time the total level of igG falls as the maternally acquired igG is catabolized. thus, igG levels are low from about the age of 3 months to 1 year, which can lead to susceptibility to disease. newborn infants by maternal antibodies, XLA is typically detected several months after birth, when maternal antibody levels in the infant have declined.


Immunology_Janeway

Immunology_Janeway. The defective gene in XLA encodes a protein tyrosine kinase called BTK (Bruton’s tyrosine kinase), which is a member of the Tec family of kinases that transduce signals through the preBcell receptor (preBCR; see Section 720). As discussed in Section 83, the preBcell receptor is composed of successfully rearranged μ heavy chains complexed with the surrogate light chain composed of λ5 and VpreB, and with the signaltransducing subunits Igα and Igβ. Stimulation of the preBcellreceptor recruits cytoplasmic proteins, including BTK, which convey signals required for the proliferation and differentiation of preB cells. In the absence of BTK function, Bcell maturation is largely arrested at the preBcell stage (see Fig. 13.2; see also Section 83), resulting in profound Bcell deficiency and agammaglobulinemia. Some B cells do mature, however, perhaps as a result of compensation by other Tec kinases.


Immunology_Janeway

Immunology_Janeway. During embryonic development, females randomly inactivate one of their two X chromosomes. Because BTK is required for Blymphocyte development, only cells in which the normal allele of BTK is active develop into mature B cells. Thus, in all B cells in female carriers of a mutant BTK gene, the active X chromosome is the normal one and the abnormal X chromosome is inactivated. This fact allowed female carriers of XLA to be identified even before the nature of the BTK protein was known. In contrast, the active X chromosomes in the T cells and macrophages of carriers are an equal mixture of normal and BTK mutant X chromosomes. Nonrandom Xinactivation only in B cells shows conclusively that the BTK gene is required for the development of B cells but not the other cell types, and that BTK must act in the B cells themselves rather than in stromal or other cells required for Bcell development (Fig. 13.4).


Immunology_Janeway

Immunology_Janeway. Autosomal recessive deficiencies in other components of the preBCR also block early Bcell development and cause severe Bcell deficiency and congenital agammaglobulinemia similar to that of XLA. These disorders are much rarer than XLA, and include mutations in the genes that encode the μ heavy chain (IGHM), which is the second most common cause of agammaglobulinemia; λ5 (IGLL1); and Igα (CD79A) and Igβ (CD79B) (see Fig. 13.2). Mutations that cripple the Bcell receptor signaling adaptor, Bcell linker protein (encoded by BLNK), also cause the arrest of early Bcell development that results in selective Bcell deficiency.


Immunology_Janeway

Immunology_Janeway. Patients with pure Bcell defects resist many pathogens other than pyogenic bacteria. Fortunately, the latter can be suppressed with antibiotics and with monthly infusions of human immunoglobulin collected from a large pool of donors. Because there are antibodies against many common pathogens in this pooled immunoglobulin, it serves as a fairly successful shield against infection. T-cell activation and function that lead to abnormal antibody responses.


Immunology_Janeway

Immunology_Janeway. T-cell activation and function that lead to abnormal antibody responses. After their development in the bone marrow or thymus, B and T cells require antigendriven activation and differentiation to mount effective immune responses. Analogous to defects in early Tcell development, defects in Tcell activation and differentiation that occur after thymic selection have an impact on both cellmediated immunity and antibody responses (Fig. 13.5). Defects specific to the activation and differentiation of B cells can impair their ability to undergo class switching to IgG, IgA, and IgE while leaving cellmediated immunity largely intact. Depending on where in the process of T or Bcell differentiation these defects occur, the characteristics of the immune deficiency that results can be either profound or relatively circumscribed.


Immunology_Janeway

Immunology_Janeway. A common feature of patients with defects that affect Bcell class switching is hyperIgM syndrome (see Fig. 13.5). These patients have normal Band Tcell development and normal or high serum levels of IgM, but make very limited antibody responses against antigens that require Tcell help. Thus immunoglobulin isotypes other than IgM and IgD are produced only in trace amounts. This renders these patients highly susceptible to infection with extracellular pathogens. Several causes for hyperIgM syndromes have been distinguished, and these have helped to elucidate the pathways that are essential for normal classswitch recombination and somatic hypermutation in B cells. Defects have been found in both Tcell helper function and in the B cells themselves.


Immunology_Janeway

Immunology_Janeway. in X-linked agammaglobulinemia (Xla), a protein tyrosine kinase of the tec family called BtK, which is encoded on the X chromosome, is defective. in normal individuals, B-cell development proceeds through a stage in which the pre-B-cell receptor, consisting of μλ5:VpreB (see Section 8-3), transduces a signal via BtK, triggering further B-cell development. in males with Xla, no signal can be transduced and, although the pre-B-cell receptor is expressed, the B cells develop no further. in female mammals, including humans, one of the two X chromosomes in each cell is permanently inactivated early in development. Because the choice of which chromosome to inactivate is random, half of the pre-B cells in a carrier female will have inactivated the chromosome with the wild-type BTK gene, meaning that they can express only the defective BTK gene and cannot develop further. therefore, in the carrier, mature B cells always have the nondefective X chromosome active. this is in sharp contrast to


Immunology_Janeway

Immunology_Janeway. that they can express only the defective BTK gene and cannot develop further. therefore, in the carrier, mature B cells always have the nondefective X chromosome active. this is in sharp contrast to all other cell types, which have the nondefective X chromosome active in only half of their cells. nonrandom X-chromosome inactivation in a particular cell lineage is a clear indication that the product of the X-linked gene is required for the development of cells of that lineage. it is also sometimes possible to identify the stage at which the gene product is required, by detecting the point in development at which X-chromosome inactivation develops bias. using this kind of analysis, one can identify carriers of X-linked traits such as Xla without needing to know the nature of the mutant gene.


Immunology_Janeway

Immunology_Janeway. Fig. 13.5 Defects in T-cell and B-cell activation and differentiation cause immunodeficiencies. the pathways leading to activation and differentiation of naive t cells and B cells are shown here. the protein products of genes known to be mutated in the relevant human immunodeficiency diseases are indicated in red boxes. BCR, B-cell receptor; CViDs, common variable immunodeficiencies; tCR, t-cell receptor. note that the defect in cytoskeletal function in Wiskott–aldrich syndrome (WaS) affects immune-cell function at many steps in this schema, and is not included in the figure for the sake of clarity.


Immunology_Janeway

Immunology_Janeway. Fig. 13.6 Patients with CD40 ligand deficiency are unable to activate their B cells fully. lymphoid tissues in patients with CD40 ligand deficiency, which manifests as a hyper-igM syndrome, are devoid of germinal centers (top panel), unlike a normal lymph node (bottom panel). B-cell activation by t cells is required both for isotype switching and for the formation of germinal centers, where extensive B-cell proliferation takes place. Photographs courtesy of R. Geha and a. Perez-atayde. TCRCD4 activated CD4 T cell mature B cell plasma cells AID, UNG, TACI, CD19, ICOS resting macrophage activated macrophage lgA lgE lgG IL-12, intracellular killing CD40L, NEMO CD40 mutated genes not known BCR IgD B-cell intrinsic hyper-IgM syndromes or CVIDs IgA defciency X-linked hyper-IgM syndromes hyper-IgM syndromes


Immunology_Janeway

Immunology_Janeway. The most common form of hyperIgM syndrome is Xlinked hyperIgM syndrome, or CD40 ligand deficiency, which is caused by mutations in the gene encoding CD40 ligand (CD154) (see Fig. 13.5). CD40 ligand is normally expressed on activated T cells, enabling them to engage the CD40 protein on antigenpresenting cells, including B cells, dendritic cells, and macrophages (see Section 104). In males with CD40 ligand deficiency, B cells are normal, but in the absence of engagement of CD40, their B cells do not undergo isotype switching or initiate the formation of germinal centers (Fig. 13.6). These patients therefore have severe reductions in circulating levels of all antibody isotypes except IgM and are highly susceptible to infections by pyogenic extracellular bacteria.


Immunology_Janeway

Immunology_Janeway. Because CD40 signaling is also required for the activation of dendritic cells and macrophages for optimal production of IL12, which is important for the production of IFNγ by TH1 cells and NK cells, patients with CD40 ligand deficiency also have defects in type 1 immunity and thus manifest a form of combined immunodeficiency. Inadequate crosstalk between T cells and dendritic cells via CD40L–CD40 interaction can lead to lower levels of costimulatory molecules on dendritic cells, thus impairing their ability to stimulate naive T cells (see Section 917). These patients are therefore susceptible to infections by extracellular pathogens that require classswitched antibodies, such as pyogenic bacteria, but also have defects in the clearance of intracellular pathogens, such as mycobacteria, and are particularly prone to opportunistic infections by Pneumocystis jirovecii, which is normally killed by activated macrophages.


Immunology_Janeway

Immunology_Janeway. A similar syndrome has been identified in patients with mutations in two other genes. Not unexpectedly, one is the gene encoding CD40, mutations in which have been found in a few patients with an autosomal recessive variant of hyperIgM syndrome (see Fig. 13.5). In another form of Xlinked hyperIgM syndrome, known as NEMO deficiency, mutations occur in the gene encoding the protein NEMO (‘NFκB essential modulator’; also known as IKKγ, a subunit of the kinase IKK), which is an essential component of the intracellular signaling pathway downstream of CD40 that leads to activation of the transcription factor NFκB (see Fig. 3.15). This group of hyperIgM syndromes shows that mutations at different points in the CD40L–CD40 signaling pathway result in a similar combined immunodeficiency syndrome. In view of the role of NFκB signaling in many other pathways, NEMO deficiency results in additional immune dysfunction beyond its impairment of Bcell class switching (see Section 1315), as well as


Immunology_Janeway

Immunology_Janeway. In view of the role of NFκB signaling in many other pathways, NEMO deficiency results in additional immune dysfunction beyond its impairment of Bcell class switching (see Section 1315), as well as nonimmune manifestations, including abnormalities of the skin.


Immunology_Janeway

Immunology_Janeway. Other variants of hyperIgM syndrome are due to intrinsic defects in the process of Bcell classswitch recombination. Patients having these defects are susceptible to severe extracellular bacterial infections, but because Tcell differentiation and function are spared, they do not show increased susceptibility to intracellular pathogens or opportunistic agents such as P. jirovecii. One classswitching defect is due to mutations in the gene for activationinduced cytidine deaminase (AID), which is required for both somatic hypermutation and class switching (see Section 107). Patients with autosomally inherited defects in the AID gene (AICDA) fail to switch antibody isotype and also have greatly reduced somatic hypermutation (see Fig. 13.5). Immature B cells accumulate in abnormal germinal centers, causing enlargement of the lymph nodes and spleen. Another variant of Bcellintrinsic hyperIgM syndrome was identified recently in a small number of patients with an autosomal recessive defect in


Immunology_Janeway

Immunology_Janeway. causing enlargement of the lymph nodes and spleen. Another variant of Bcellintrinsic hyperIgM syndrome was identified recently in a small number of patients with an autosomal recessive defect in the DNA repair enzyme uracilDNA glycosylase (UNG; see Section 1010), which is also involved in class switching; these patients have normal AID function and normal somatic hypermutation, but defective class switching.


Immunology_Janeway

Immunology_Janeway. Other examples of predominantly antibody deficiency include the most common forms of primary immunodeficiency, referred to as common variable immunodeficiencies (CVIDs). CVIDs are a clinically and genetically heterogeneous group of disorders that typically go undiagnosed until late childhood or adulthood, because the immune deficiency is relatively mild. Unlike other causes of immunoglobulin deficiency, patients with CVID can have defects in immunoglobulin production that are limited to one or more isotypes (see Fig. 13.5). IgA deficiency, the most common primary immunodeficiency, exists in both sporadic and familial forms, and both autosomal recessive and autosomal dominant inheritance have been described. The etiology of IgA deficiency in most patients is not understood, and these patients are asymptomatic. In IgAdeficient patients who do develop recurrent infections, an associated defect in one of the IgG subclasses is often found.


Immunology_Janeway

Immunology_Janeway. A small minority of CVID patients have mutations in the transmembrane protein TACI (TNFlike receptor transmembrane activator and CAML interactor), which is encoded by the gene TNFRSF13B. TACI is the receptor for the cytokines BAFF and APRIL, which are produced by T cells, dendritic cells, and macrophages, and which can provide costimulatory and survival signals for Bcell activation and class switching (see Section 103). Other patients with selective deficiencies in IgG subclasses have also been described. Bcell numbers are typically normal in these patients, but serum levels of the affected immunoglobulin isotype are depressed. Although some of these patients have recurrent bacterial infections, as in IgA deficiency, many are asymptomatic. CVID patients with other defects that affect immunoglobulin class switching have been identified. Included in this group are patients with inherited defects in CD19, which is a component of the Bcell coreceptor (see Fig. 13.5). A genetic defect that


Immunology_Janeway

Immunology_Janeway. class switching have been identified. Included in this group are patients with inherited defects in CD19, which is a component of the Bcell coreceptor (see Fig. 13.5). A genetic defect that has been linked to a small percentage of people with CVID is deficiency of the costimulatory molecule ICOS. As described in Section 917, ICOS is upregulated on T cells when they are activated. The effects of ICOS deficiency have confirmed its essential role in Tcell help for the later stages of Bcell differentiation, including class switching and the formation of memory cells.


Immunology_Janeway

Immunology_Janeway. The final immunodeficiency to be considered in this section is hyperIgE syndrome (HIES), also called Job’s syndrome. This disease is characterized by recurrent skin and pulmonary infections caused by pyogenic bacteria, chronic mucocutaneous candidiasis (noninvasive fungal infection of the skin and mucosal surfaces), very high serum concentrations of IgE, and chronic eczematous dermatitis or skin rash. HIES is inherited in an autosomal recessive or dominant pattern, with the latter manifesting skeletal and dental abnormalities not found in the recessive variant. The inherited defect in the autosomal dominant variant of HIES is in the transcription factor STAT3, which is activated downstream of several cytokine receptors, including those for IL6, IL22, and IL23, and which is central to the differentiation of TH17 cells and activation of ILC3 cells. STAT3 signaling activated by IL6 and IL22 is also important for enhanced antimicrobial resistance of epithelial cells of the skin and


Immunology_Janeway

Immunology_Janeway. the differentiation of TH17 cells and activation of ILC3 cells. STAT3 signaling activated by IL6 and IL22 is also important for enhanced antimicrobial resistance of epithelial cells of the skin and mucosal barriers. Because differentiation of TH17 cells is deficient in these patients, the recruitment of neutrophils normally orchestrated by the TH17 response is also defective, as is production of IL22, an important cytokine in activating epithelial cell production of antimicrobial peptides. This is thought to underlie the impaired defense against extracellular bacteria and fungi at barrier epithelia, such as the skin and mucosae. The cause of the elevated IgE is not understood, but it might be due to an abnormal accentuation of skin and mucosal TH2 responses as a result of TH17 deficiency. In an autosomal recessive variant of HIES, the mutation is in the gene that encodes the protein DOCK8 (dedicator of cytokinesis 8), the function of which in immune cells is poorly characterized.


Immunology_Janeway

Immunology_Janeway. In an autosomal recessive variant of HIES, the mutation is in the gene that encodes the protein DOCK8 (dedicator of cytokinesis 8), the function of which in immune cells is poorly characterized. However, because DOCK8 is thought to play a broader role in Tcell function, as well as NKcell function, this variant of HIES is distinguished from that caused by STAT3 defects by the additional occurrence of opportunistic infections and recurrent cutaneous viral infections (for example, herpes simplex), as well as allergic and autoimmune manifestations.


Immunology_Janeway

Immunology_Janeway. agents are pinpointed by genetic deficiencies of cytokine pathways central to type 1/TH1 and type 3/TH17 responses.


Immunology_Janeway

Immunology_Janeway. Inherited defects in cytokines that are involved in the development and function of different effector Tcell subsets have been defined, as have defects in the receptors or the signaling pathways through which they act. In contrast to the Tcell immunodeficiencies considered above, here we consider those deficiencies that do not have major defects in antibody production. A small number of families have been discovered with individuals who suffer from persistent and sometimes fatal attacks by intracellular pathogens normally restrained by type 1 immunity, especially Mycobacterium, Salmonella, and Listeria species. These microbes are specialized for survival within macrophages, and their eradication requires enhanced microbicidal activities induced by IFNγ produced by type 1 cells: NK cells, ILC1 cells, and TH1 cells (see Section 112). Accordingly, susceptibility to these infections is conferred by a variety of inherited mutations that impair or abolish the function of IL12 or IFNγ, key


Immunology_Janeway

Immunology_Janeway. ILC1 cells, and TH1 cells (see Section 112). Accordingly, susceptibility to these infections is conferred by a variety of inherited mutations that impair or abolish the function of IL12 or IFNγ, key cytokines in the development and functions of type 1 cells (Fig. 13.7). Patients with mutations in the genes encoding the p40 subunit of IL12 (IL12B), the IL12 receptor β1 chain (IL12RB1), and the two subunits (R1 and R2) of the IFNγ receptor (IFNGR1 and IFNGR2) have been identified. Although affected individuals have heightened susceptibility to the more virulent M. tuberculosis, they suffer more frequently from the nontuberculous, or atypical, strains of mycobacteria, such as Mycobacterium avium, likely due to the greater prevalence of atypical strains in the environment. They may also develop disseminated infection after vaccination with Mycobacterium bovis bacillus Calmette–Guérin (BCG), the strain of M. bovis that is used as a live vaccine against M. tuberculosis. Because the IL12 p40


Immunology_Janeway

Immunology_Janeway. disseminated infection after vaccination with Mycobacterium bovis bacillus Calmette–Guérin (BCG), the strain of M. bovis that is used as a live vaccine against M. tuberculosis. Because the IL12 p40 subunit is shared by IL12 and IL23, IL12 p40 deficiency results in a broader infectious disease risk due to defective type 1 and type 3 (TH17) functions (see Fig. 13.7).


Immunology_Janeway

Immunology_Janeway. Fig. 13.7 Inherited defects in effector cytokine pathways also, because Stat1 is activated is by the receptors of type ii that impair type 1/TH1 and type 3/TH17 immunity. Shown are interferon (iFn-γ) and type i interferon (iFn-α and iFn-β, not shown), pathways in il-12, il-23, and iFn-γ signaling for which inherited defects in Stat1 result in impaired antibacterial and antiviral immune defects have been described. note that defects in il-12p40 defense, whereas deficiency in either of the iFn-γ receptor subunits (p40) and il-12Rβ1 result in impaired function of both ilC1 cells/ (iFn-γR1 or iFn-γR2) primarily results in impaired defense against nK cells/tH1 cells and ilC3/tH17 cells because these subunits intracellular bacteria. are shared, respectively, by il-12 and il-23 and their receptors. Similarly, deficiency of the IL12Rβ1 chain, which is shared by the IL12 and IL23 receptors, results in broader susceptibilities than the deficiencies of IFNγ or its receptor.


Immunology_Janeway

Immunology_Janeway. Similarly, deficiency of the IL12Rβ1 chain, which is shared by the IL12 and IL23 receptors, results in broader susceptibilities than the deficiencies of IFNγ or its receptor. Autosomal recessive lossoffunction mutations in STAT1 impair IFNγ receptor signaling and are also associated with increased susceptibility to infections by mycobacterial and other intracellular bacteria (see Fig. 13.7). However, due to its shared function in IFNα receptor signaling in response to IFNα and IFNβ (type I interferons), patients with STAT1 defects are also susceptible to viral infections. Interestingly, patients with partial loss of function of STAT1 have been identified who are susceptible to mycobacterial infections, but not viral infections, suggesting a more stringent requirement of STAT1 in protection against the former.


Immunology_Janeway

Immunology_Janeway. In addition to the TH17related defects described above for STAT3deficient HIES (see Section 139), other defects in cytokinemediated functions of this pathway have been identified that lack the hyperIgE component (Fig. 13.8). Whereas heightened susceptibility to intracellular bacteria is a feature common to immunodeficiencies that impair type 1 immunity, heightened susceptibility to infections by Candida spp. and pyogenic bacteria, particularly


Immunology_Janeway

Immunology_Janeway. C. albicans and S. aureus, respectively, is characteristic of these type 3 deficiencies. This reflects the specialized function of TH17 and ILC3 cells in barrier defense against fungi and extracellular bacteria. Inherited deficiencies in IL17F and IL17RA, the shared receptor component for homo and heterodimeric IL17F–IL17A ligands, confer susceptibility to these infectious agents and thus identify a key role for IL17 cytokines in host defense against them. A similar susceptibility to chronic mucocutaneous candidiasis and pyogenic bacteria has been found in patients with autosomal dominant, gainoffunction mutations in STAT1. Because TH17 cell development is impaired by STAT1 signaling downstream of several cytokine receptors (for example, type I and type II IFN receptors), individuals with these mutations have impaired type 3 defenses. Note that this is in contrast to patients with lossoffunction STAT1 mutations, who are predisposed to intracellular bacterial infections due to


Immunology_Janeway

Immunology_Janeway. with these mutations have impaired type 3 defenses. Note that this is in contrast to patients with lossoffunction STAT1 mutations, who are predisposed to intracellular bacterial infections due to defective type 1 immunity.


Immunology_Janeway

Immunology_Janeway. In addition to inherited defects in effector cytokine genes, some forms of immunodeficiency result in the production of neutralizing autoantibodies against these cytokines. This results in infectious risks similar to those caused by primary cytokine deficiencies. Most patients with APECED syndrome (caused by defects in the AIRE gene; see Section 137) develop chronic mucocutaneous candidiasis that is due to the development of autoantibodies against IL17A, IL17F, and/or IL22. Patients with neutralizing autoantibodies against IFNγ who have impaired protection against atypical mycobacteria have also been reported, although the basis for this is unknown. 13-11 Inherited defects in the cytolytic pathway of lymphocytes can cause uncontrolled lymphoproliferation and inflammatory responses to viral infections.


Immunology_Janeway

Immunology_Janeway. Cytolytic granules are formed from components of late endosomes and lysosomes. Once formed, there are multiple steps in the exocytosis of cytolytic granules from cytotoxic cells and their delivery to target cells. The importance of the cytolytic pathway in immune regulation is highlighted by inherited defects that impair key steps in either the formation or the exocytosis of cytolytic granules (Fig. 13.9). These result in a severe and often fatal condition, known as hemophagocytic lymphohistiocytic (HLH) syndrome, which manifests as uncontrolled activation and expansion of CD8 T lymphocytes and macrophages that infiltrate multiple organs, causing tissue necrosis and organ failure. The hyperactive immune response is thought to reflect the inability of cytotoxic cells to destroy infected targets, and possibly themselves, following an initiating viral infection, particularly by a herpes family virus such as Epstein–Barr virus (EBV). In this regard it is notable that despite the impaired


Immunology_Janeway

Immunology_Janeway. and possibly themselves, following an initiating viral infection, particularly by a herpes family virus such as Epstein–Barr virus (EBV). In this regard it is notable that despite the impaired release of cytolytic granules, the release of IFNγ by CTLs and NK cells of patients with this disorder is not typically impaired, which contributes to the heightened activity of macrophages and associated inflammatory disorder caused by an increased release of proinflammatory cytokines such TNF, IL6, and macrophage colonystimulating factor (MCSF). The activated macrophages phagocytose blood cells, including erythrocytes and leukocytes, which gives the syndrome its name.


Immunology_Janeway

Immunology_Janeway. There are multiple autosomal recessive variants of HLH, also referred to as familial hemophagocytic lymphohistiocytosis (FHL), that are distinguished by the protein in the cytolytic pathway that is affected (see Fig. 13.9). Examples include inherited deficiencies of the cytolytic granule protein perforin, which is required for pore formation in the target cell (and when defective is associated with the syndrome FHL2); of the priming protein, Munc134 (FHL3); of syntaxin 11 (FHL4), a member of the SNARE family of proteins that mediate membrane fusion; and of Munc182 (FHL5), a protein involved in the reorganization of SNARE proteins to activate the fusion process. Because components of the biogenesis and exocytosis of cytolytic granules are shared with other secretory vesicles, such as lysosomes, additional immune defects can occur in affected individuals, as can nonimmune defects. In particular, a subset of the immunodeficiencies that affect cytolytic granule function are also


Immunology_Janeway

Immunology_Janeway. as lysosomes, additional immune defects can occur in affected individuals, as can nonimmune defects. In particular, a subset of the immunodeficiencies that affect cytolytic granule function are also characterized by partial loss of skin pigmentation. This is due to defects in vesicular transport proteins that are also required for the formation or exocytosis of melanosomes, organelles that store the skin pigment melanin in melanocytes. Examples of these immunodeficiencies include Chediak–Higashi syndrome, caused by mutations in a protein, CHS1, which regulates lysosomal trafficking, and Griscelli syndrome, caused by mutations in a small GTPase, RAB27a (see Fig. 13.9), which is integral to the tethering of certain vesicles, including cytolytic granules, to cytoskeletal structures to enable their intracellular trafficking.


Immunology_Janeway

Immunology_Janeway. In patients with Chediak–Higashi syndrome, abnormal giant lysosomes and granules accumulate in T lymphocytes, myeloid cells, platelets, and melanocytes. The hair is typically a metallic silver color, vision is poor because of abnormalities in retinal pigment cells, and platelet dysfunction causes increased bleeding. Because the phagocytes of these patients have defective phagolysosomal fusion, the patients experience defective killing of intracellular and extracellular pathogens in addition to defective cytolytic activity of CTLs and NK cells. Affected children therefore suffer early in life from severe, recurrent infections by a range of bacteria and fungi. This is typically followed by development of hemophagocytic lymphohistiocytosis, often triggered by viral infection such as EBV, leading to an accelerated phase of the disease. Three variants of Griscelli syndrome have been identified, each caused by a distinct gene defect: in the type 2 variant (RAB27A mutation), the defect


Immunology_Janeway

Immunology_Janeway. leading to an accelerated phase of the disease. Three variants of Griscelli syndrome have been identified, each caused by a distinct gene defect: in the type 2 variant (RAB27A mutation), the defect results in both immunodeficiency and pigment abnormalities; in types 1 and 3, only the pigment abnormalities are found. Although the immune defects in children


Immunology_Janeway

Immunology_Janeway. Fig. 13.9 Defects in components involved in the exocytosis of cytotoxic granules cause familial hemophagocytic lymphohistiocytosis (FHL) syndromes. Following antigen recognition, there is polarization of perforin-containing cytotoxic granules of the Ctl toward the target cell at the site of immunological synapse formation. Cytotoxic granules are transported along microtubules to the plasma membrane, where they dock through a RaB27a-dependent interaction. Docked vesicles are primed by Munc13-4-mediated triggering of a conformational change in syntaxin 11, which is part of a large SnaRe (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex connecting the docked vesicle with the plasma membrane. through the actions of Munc18-2, a fusion reaction is initiated via the syntaxin 11-containing SnaRe complex that releases the contents of the cytotoxic granules into the synapse-bounded intercellular space, allowing perforin-mediated pore formation in the target-cell


Immunology_Janeway

Immunology_Janeway. syntaxin 11-containing SnaRe complex that releases the contents of the cytotoxic granules into the synapse-bounded intercellular space, allowing perforin-mediated pore formation in the target-cell plasma membrane. the sites in the exocytic pathway that are affected by inherited defects in each of the proteins highlighted in red are indicated, as is the associated familial hemophagocytic lymphohistiocytosis syndrome.


Immunology_Janeway

Immunology_Janeway. with type 2 Griscelli syndrome have much in common with those of Chediak– Higashi syndrome, their myeloid cells lack the giant intracellular granules that are characteristic of the latter. 13-12 X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein–Barr virus and with the development of lymphomas.


Immunology_Janeway

Immunology_Janeway. In some primary immunodeficiencies, there is unique susceptibility to a single pathogen. Such is the case for two rare Xlinked immunodeficiencies with a similar lymphoproliferative defect that results from vulnerability to a herpes family virus, the Epstein–Barr virus (EBV), albeit via independent mechanisms. EBV specifically infects B cells and typically causes a selflimiting infection in normal individuals due to active control of the virus by the actions of NK cells, NKT cells, and cytotoxic T cells with specificity for B cells expressing EBV antigens. Following the development of immunity to EBV, the virus is not completely cleared, but is maintained in a latent state in infected B cells (see Section 1324). In the presence of certain types of immunodeficiency, however, this control can break down, resulting in overwhelming EBV infection (severe infectious mononucleosis) that is accompanied by unrestrained proliferation of EBVinfected B cells and cytotoxic T cells,


Immunology_Janeway

Immunology_Janeway. this control can break down, resulting in overwhelming EBV infection (severe infectious mononucleosis) that is accompanied by unrestrained proliferation of EBVinfected B cells and cytotoxic T cells, hypogammaglobulinemia (low levels of circulating immunoglobulins), and the potential for the development of lethal, nonHodgkin’s Bcell lymphomas. These occur in the rare immunodeficiency Xlinked lymphoproliferative (XLP) syndrome. XLP syndrome results from mutations in one of two Xlinked genes: the SH2 domaincontaining gene 1A (SH2D1A), which encodes SAP [signaling lymphocyte activation molecule (SLAM)associated protein], or the Xlinked inhibitor of apoptosis gene (XIAP).


Immunology_Janeway

Immunology_Janeway. In XLP1, which accounts for approximately 80% of patients with this syndrome, the defect in SAP results in defective coupling of immunecell receptors of the SLAM family with the Srcfamily tyrosine kinase Fyn in T cells, NKT cells, and NK cells (Fig. 13.10). SLAM family members interact through homotypic or heterotypic binding to modulate the outcome of interactions between T cells and antigenpresenting cells and between NK cells and their target cells. In the absence of SAP, ineffective EBVspecific cytotoxic Tcell and NKcell responses are made, and there is severe deficiency of NKT cells, indicating that SAP has a nonredundant role in the control of EBV infection and the development of NKT cells. There is unchecked proliferation of EBVreactive cytotoxic T cells and NK cells that results in systemic macrophage activation, inflammation, and hemophagocytic features similar to those that occur in immunodeficiencies caused by defects in the cytolytic pathway (see


Immunology_Janeway

Immunology_Janeway. Fig.13.10 X-linked lymphoproliferative disease (XLP) is caused by inherited defects in SAP and XIAP, resulting in abnormal SLAM and TNF family receptor signaling, respectively. SlaM is an immune receptor family, members of which are expressed by t cells, B cells, natural killer (nK) cells, dendritic cells, and macrophages. Signaling is initiated via homotypic or heterotypic interactions between family members. SlaM signaling recruits the Src homology 2 (SH2) domain-containing factor SaP, which recognizes tyrosine-based motifs in the cytoplasmic domain of SlaM to activate the Src-related tyrosine kinase Fyn (left upper panel). Fyn then phosphorylates additional tyrosine residues of SlaM to recruit additional signaling components. Mutation in SaP in patients with XlP1 (right upper panel) disrupts activation of Fyn and SlaM signaling, thereby impairing tand nK-cell cytotoxicity, which results in severe epstein–Barr virus (eBV) infections and lymphoma. Defective SlaM signaling also


Immunology_Janeway

Immunology_Janeway. disrupts activation of Fyn and SlaM signaling, thereby impairing tand nK-cell cytotoxicity, which results in severe epstein–Barr virus (eBV) infections and lymphoma. Defective SlaM signaling also impairs upregulation of inducible t-cell co-stimulator (iCOS) expression in tFH cells, which results in impaired antibody responses. activation of apoptosis-inducing caspases by tnF family receptors, such as Fas, is normally inhibited by XiaP (lower panel). XiaP interacts with both initiator caspases (8 and 9) and executioner caspases (3 and 7) through its baculoviral inhibitory repeat (BiR) domain to inhibit their actions. in XlP2 patients, XiaP is defective, resulting in abnormal regulation of caspase activation that leads to the complex clinical phenotype that includes lymphoproliferation and defective control of eBV.


Immunology_Janeway

Immunology_Janeway. Section 1311). Moreover, defective SLAM signaling between TFH cells and B cells of XLP1 patients causes impaired Tdependent antibody responses and hypogammaglobulinemia. Defects in the XIAP protein, which normally binds the TNFreceptorassociated factors TRAF1 and TRAF2 and inhibits the activation of apoptosisinducing caspases (see Section 723), lead to a similar Xlinked syndrome called XLP2 (see Fig. 13.10). XIAP deficiency results in the enhanced apoptosis and turnover of activated T cells and NK cells. Paradoxically, this leads to a lymphoproliferative phenotype similar to XLP1, the basis of which is not well understood. As in XLP1, there is also severe depletion of NKT cells, indicating that, like SAP, XIAP is required for the normal maintenance of these cells. As in XLP1, there is also defective control of EBV infection in XLP2, although this is less prominent. The exact reason for the impaired suppression of EBV latency in these immunodeficiencies remains to be defined.


Immunology_Janeway

Immunology_Janeway. 13-13 Immunodeficiency is caused by inherited defects in the development of dendritic cells. Our understanding of the diversity and function of dendritic cells has been advanced from studies of mice with genetargeted deletion of transcription factors that result in the loss of subsets of these cells, and from the defects in protection against specific pathogens that result as a consequence of the loss of these subsets. In humans, where study of the development and function of dendritic cells is more challenging, the identification of primary immune deficiencies that result from defects in genes that encode the transcription factors GATA2 and IRF8 has begun to provide insights into the relative roles of these cells in different species.


Immunology_Janeway

Immunology_Janeway. An autosomal dominant mutation of GATA2 has been identified in the largest group of patients with an inherited deficiency of dendritic cells. Affected individuals develop a progressive loss of all subsets of dendritic cells (conventional and plasmacytoid) and monocytes, as well as reduced numbers of B and NK lymphoid cells, a condition that has been termed DCML deficiency. Although Tcell numbers are normal in these patients, their function becomes impaired as dendritic cells are lost. The loss of products of several hematopoietic lineages, but not all, suggests redundancy of the function of GATA2 in unaffected lineages. The basis for the progressive decline in products of the affected lineages is unknown, but is thought to reflect a role for GATA2 in maintaining stemcell progenitors that seed these populations. Given the deficiency of all dendritic and monocyte cells, the immune defects in these individuals are diverse, as are pathogen susceptibilities. These patients also have a


Immunology_Janeway

Immunology_Janeway. seed these populations. Given the deficiency of all dendritic and monocyte cells, the immune defects in these individuals are diverse, as are pathogen susceptibilities. These patients also have a substantial risk of hematologic malignancies.


Immunology_Janeway

Immunology_Janeway. Two inherited defects in interferon regulatory factor 8 (IRF8) are the first to be described that are associated with specific defects in the development of dendritic cells. In both variants, the mutation is in the DNAbinding domain of the transcription factor. In an autosomal recessive form, there is loss of monocytes and all types of circulating dendritic cells; all conventional and plasmacytoid dendritic cells are absent. Because dendritic cells are the primary antigenpresenting cells for naive T cells, their deficiency results in impaired development of effector T cells, and patients with these defects are susceptible to a range of severe opportunistic infections early in life, including those caused by intracellular bacteria, viruses, and fungi. They also develop a striking increase in the number of circulating immature granulocytes; this is thought to be due to diversion of myeloid precursors down the granulocytic pathway in the absence of the monocyte–dendritic cell


Immunology_Janeway

Immunology_Janeway. increase in the number of circulating immature granulocytes; this is thought to be due to diversion of myeloid precursors down the granulocytic pathway in the absence of the monocyte–dendritic cell developmental pathway. In contrast, in patients with autosomal dominant inheritance of a dominantnegative mutant allele of IRF8, there is a less severe phenotype, one that is characterized by a more selective deficiency of the CD1cpositive subset of dendritic cells (thought to be the equivalent of the CD11bpositive subset of mouse


Immunology_Janeway

Immunology_Janeway. Fig. 13.11 Defects in complement components are associated with susceptibility to certain infections and the accumulation of immune complexes. Defects in the early components of the alternative pathway and in C3 lead to susceptibility to extracellular pathogens, particularly pyogenic bacteria. Defects in the early components of the classical pathway predominantly affect the processing of immune complexes (see Section 10-20) and the clearance of apoptotic cells, leading to immune-complex disease. Deficiency of mannose-binding lectin (MBl), the recognition molecule of the mannose-binding lectin pathway, is associated with bacterial infections, mainly in early childhood. Defects in the membrane-attack components are associated only with susceptibility to strains of Neisseria species, the causative agents of meningitis and gonorrhea, implying that the effector pathway is important chiefly in defense against these organisms.


Immunology_Janeway

Immunology_Janeway. dendritic cells). This results in heightened susceptibility to intracellular bacteria, particularly atypical Mycobacterium spp., without the myeloproliferative syndrome seen in patients with the autosomal recessive variant. and tissue damage.


Immunology_Janeway

Immunology_Janeway. The diseases discussed so far are mainly due to disturbances of the adaptive immune system. In the next few sections we look at some immunodeficiency diseases that affect cells and molecules of the innate immune system. We start with the complement system, which can be activated by any of three pathways that converge on the cleavage and activation of complement component C3, allowing it to bind covalently to pathogen surfaces, where it acts as an opsonin (discussed in Chapter 2). Not surprisingly, the spectrum of infections associated with complement deficiencies overlaps substantially with that seen in patients with deficiencies in antibody production. In particular, there is increased susceptibility to extracellular bacteria that require opsonization by antibody and/or complement for efficient clearance by phagocytes (Fig. 13.11). Defects in the activation of C3 by any of the three pathways, as well as defects in C3 itself, are associated with increased susceptibility to infection


Immunology_Janeway

Immunology_Janeway. clearance by phagocytes (Fig. 13.11). Defects in the activation of C3 by any of the three pathways, as well as defects in C3 itself, are associated with increased susceptibility to infection by a range of pyogenic bacteria, including S. pneumoniae, emphasizing the role of C3 as a central effector that promotes the phagocytosis and clearance of capsulated bacteria.


Immunology_Janeway

Immunology_Janeway. In contrast, defects in the membraneattack components of complement (C5C9) downstream of C3 activation have more limited effects, and result almost exclusively in susceptibility to Neisseria species. A similar susceptibility to Neisseria species is found in patients with defects in the alternative complement pathway components factor D and properdin, indicating that defense against these bacteria, which can survive intracellularly, is largely mediated via antibodyindependent extracellular lysis by the membraneattack complex. Data from largepopulation studies in Japan, where endemic N. meningitidis infection is rare, show that the risk each year of infection with this organism is approximately 1 in 2,000,000 to a normal person. This compares with a risk of 1 in 200 to a person in the same population with an inherited deficiency of one of the membraneattack complex proteins—a 10,000fold increase in risk.


Immunology_Janeway

Immunology_Janeway. Membrane-attack components C5 C6 C7 C8 C9 Deÿciency leads to infection with Neisseria spp. only C3b deposition C3 Deÿciency leads to infection with pyogenic bacteria and Neisseria spp. Sometimes immune-complex disease C3 convertase Deÿciency leads to immune-complex disease Deÿciency leads to infection with pyogenic bacteria and Neisseria spp. but no immune-complex disease Deÿciency of MBL leads to bacterial infections, mainly in childhood MBL MASP1 MASP2 C2 C4 C1 C2 C4 Factor D Factor P CLASSICAL PATHWAY ALTERNATIVE PATHWAY MBL PATHWAY


Immunology_Janeway

Immunology_Janeway. The early components of the classical complement pathway are particularly important for the elimination of immune complexes (discussed in Section 1020) and apoptotic cells, which can cause significant pathology in autoimmune diseases such as systemic lupus erythematosus. This aspect of inherited complement deficiency is discussed in Chapter 15. Deficiencies in mannosebinding lectin (MBL), which initiates complement activation independently of antibody (see Section 26), are relatively common (found in 5% of the population). MBL deficiency may be associated with a mild immunodeficiency that results in an increased incidence of bacterial infection in early childhood. A similar phenotype is found in patients with defects in the gene that encodes the MBLassociated serine protease2 (MASP2).


Immunology_Janeway

Immunology_Janeway. Another set of complementrelated diseases is caused by defects in complementcontrol proteins (Fig. 13.12). Deficiencies in decayaccelerating factor (DAF) or protectin (CD59), membraneassociated control proteins that protect the surfaces of the body’s cells from complement activation, lead to destruction of red blood cells, resulting in the disease paroxysmal nocturnal hemoglobinuria, as discussed in Section 216. Deficiencies in soluble complementregulatory proteins such as factor I and factor H have various outcomes. Homozygous factor I deficiency is a rare defect that results in uncontrolled activity of the alternative pathway C3 convertase, leading to a de facto C3 deficiency (see Section 216). Deficiencies in MCP, factor I, or factor H can also cause a condition known as atypical hemolytic–uremic syndrome, so called because it leads to lysis of red blood cells (hemolysis) and impaired kidney function (uremia).


Immunology_Janeway

Immunology_Janeway. A striking consequence of the loss of a complementregulatory protein is seen in patients with C1inhibitor defects, which cause the syndrome known as hereditary angioedema (HAE) (see Section 216). Deficiency of C1 inhibitor results in a failure to regulate both the blood clotting and complement activation pathways, leading to excessive production of vasoactive mediators that cause fluid accumulation in the tissues (edema) and local laryngeal swelling that can result in suffocation. 13-15 Defects in phagocytic cells permit widespread bacterial infections. Deficiencies in phagocyte numbers or function can be associated with severe immunodeficiency; indeed, a total absence of neutrophils is incompatible with survival in a normal environment. Phagocyte immunodeficiencies can be grouped into four general types: deficiencies in phagocyte production, phagocyte adhesion, phagocyte activation, and phagocyte killing of microorganisms (Fig. 13.13). We consider each in turn.


Immunology_Janeway

Immunology_Janeway. Inherited deficiencies of neutrophil production (neutropenias) are classified either as severe congenital neutropenia (SCN) or cyclic neutropenia. In severe congenital neutropenia, which can be inherited as a dominant or recessive trait, the neutrophil count is persistently less than 0.5 ×109 per liter of blood (normal numbers are 3 ×109 to 5.5 × 109 per liter). Cyclic neutropenia is characterized by fluctuation in neutrophil numbers from near normal to very low or undetectable with an approximate cycle time of 21 days, resulting in periodicity of infectious risk. The most common causes of SCN are sporadic or autosomal dominant mutations of the gene that encodes neutrophil elastase (ELA2), a component of the azurophilic, or primary, granules involved in the degradation of phagocytosed microbes. Altered targeting of defective elastase 2 to granules causes apoptosis of developing myelocytes and a developmental block at the promyelocyte–myelocyte stage. Some mutations of ELA2 cause


Immunology_Janeway

Immunology_Janeway. Fig. 13.13 Defects in phagocytic cells are associated with persistence of bacterial infection. Defects in neutrophil development caused by congenital neutropenias result in profound defects in antibacterial defense. impairment of the leukocyte integrins with a common β2 subunit (CD18) or defects in the selectin ligand sialyl-lewisX, prevent phagocytic cell adhesion and migration to sites of infection (leukocyte adhesion deficiency). inability to transmit signals through toll-like receptors (tlRs), due to defects in MyD88 or iRaK4, for example, impairs the proximal sensing of many infectious agents by innate immune cells. the respiratory burst is defective in chronic granulomatous disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and myeloperoxidase deficiency. in chronic granulomatous disease, infections persist because macrophage activation is defective, leading to chronic stimulation of CD4 t cells and hence to granulomas. Vesicle fusion in phagocytes is defective in


Immunology_Janeway

Immunology_Janeway. disease, infections persist because macrophage activation is defective, leading to chronic stimulation of CD4 t cells and hence to granulomas. Vesicle fusion in phagocytes is defective in Chediak–Higashi syndrome. these diseases illustrate the critical role of phagocytes in removing and killing pathogenic bacteria.


Immunology_Janeway

Immunology_Janeway. cyclic neutropenia; how the mutant elastase causes a 21day cycle in neutropenia is still a mystery. A rare autosomal dominant form of SCN is caused by mutations in the oncogene GFI1, which encodes a transcriptional repressor that acts on ELA2. This finding arose from the unexpected observation that mice lacking the protein Gfi1 are neutropenic due to overexpression of Ela2.


Immunology_Janeway

Immunology_Janeway. Autosomal recessive forms of SCN have also been identified. Deficiency of the mitochondrial protein HAX1 leads to increased apoptosis in developing myeloid cells, resulting in a severe neutropenia referred to as Kostmann’s disease. The heightened sensitivity of developing neutrophils to apoptosis is highlighted by SCN associated with genetic defects in glucose metabolism. Patients with recessive mutations in the genes encoding the glucose6phosphatase catalytic subunit 3 (G6PC3) or the glucose6phosphate translocase 1 (SLC37A4) also demonstrate increased apoptosis during granulocyte development that results in neutropenia. Acquired neutropenia associated with chemotherapy, malignancy, or aplastic anemia is also associated with a similar spectrum of severe pyogenic bacterial infections. Finally, neutropenia can also be a feature of other primary immunodeficiency diseases, including CD40 ligand deficiency, CVID, XLA, Wiskott–Aldrich syndrome, and GATA2 deficiency. Some patients exhibit


Immunology_Janeway

Immunology_Janeway. neutropenia can also be a feature of other primary immunodeficiency diseases, including CD40 ligand deficiency, CVID, XLA, Wiskott–Aldrich syndrome, and GATA2 deficiency. Some patients exhibit formation of autoantibodies that lead to accelerated destruction of neutrophils.


Immunology_Janeway

Immunology_Janeway. Defects in the migration of phagocytic cells to extravascular sites of infection can cause serious immunodeficiency. Leukocytes reach such sites by emigrating from blood vessels in a tightly regulated process (see Fig. 3.31). Deficiencies in the molecules involved in each stage of this process can prevent neutrophils and macrophages from penetrating infected tissues, and are referred to as leukocyte adhesion deficiencies (LADs). Deficiency in the leukocyte integrin common β2 subunit CD18, which is a component of LFA1, MAC1, and p150:95, prevents the migration of leukocytes into an infected site by abolishing the cells’ ability to adhere tightly to the endothelium. Because it was the first LAD to be characterized, it is now referred to as type 1 LAD, or LAD1, and is the most common LAD variant. Reduced rolling of leukocytes on the endothelium has been described in rare patients who lack the sialylLewisX antigen owing to a deficiency in the GDPfucosespecific transporter that is involved


Immunology_Janeway

Immunology_Janeway. Reduced rolling of leukocytes on the endothelium has been described in rare patients who lack the sialylLewisX antigen owing to a deficiency in the GDPfucosespecific transporter that is involved in the biosynthesis of sialylLewisX and other fucosylated ligands for the selectins. This is referred to as type 2 LAD or LAD2. LAD3 results from deficiency of Kindlin3, a protein involved in the induction of the highaffinity binding state of β integrins required for firm adhesion. Each variant of LAD has an autosomal recessive pattern of inheritance and causes severe, lifethreatening bacterial or fungal infections early in life that are characterized by impaired wound healing and, in pyogenic bacterial infections, the absence of pus formation. The infections that occur in these patients are resistant to antibiotic treatment. LAD3 is also associated with defects in platelet aggregation that cause increased bleeding.


Immunology_Janeway

Immunology_Janeway. A key step in the activation of innate immune cells, including phagocytes, is their recognition of microbeassociated molecular patterns through Tolllike receptors (TLRs; see Section 35). Several primary immunodeficiencies have been identified that are caused by defects in intracellular signaling components of TLRs. Signaling through all TLRs except TLR3 requires the adaptor protein MyD88, which recruits and activates the kinases IRAK4 and IRAK1, which are required for downstream activation of the NFκB and MAP kinase pathways (see Section 37). Autosomal recessive mutations in the genes encoding MyD88 or IRAK4 have a similar phenotype: recurrent, severe peripheral and invasive infections by pyogenic bacteria that elicit little inflammation, a situation known as a ‘cold’ infection. Note that many of the signaling functions of MyD88 and IRAK4 molecules are shared with IL1 family receptors. Thus, at least part of the immune defect in patients with inherited abnormalities in these molecules


Immunology_Janeway

Immunology_Janeway. many of the signaling functions of MyD88 and IRAK4 molecules are shared with IL1 family receptors. Thus, at least part of the immune defect in patients with inherited abnormalities in these molecules may be attributed to aberrant signaling by IL1 family members. Note also that NEMO deficiency, which impairs Bcell class switching (see Section 139), also impairs TLR and IL1 receptor family signaling through its block of normal NFκB activation. Immunodeficiency associated with defects in NEMO therefore affects both adaptive and innate immune function. Interestingly, increased viral infections are not typical in patients with MyD88 mutations, despite this protein’s role in signaling by each of the nucleic acidsensing TLRs except TLR3 (for example, TLR7, TLR8, and TLR9). This indicates that activation of interferon regulating factors (IRFs) that induce interferon responses downstream of these TLRs remains intact despite the defects in MyD88.


Immunology_Janeway

Immunology_Janeway. Remarkably, of the ten TLRs found in humans, defects in only one—TLR3— have been linked to immunodeficiency. While defects in other TLRs have been identified (for example, TLR5), they have not been associated with an overt immunodeficiency phenotype, likely reflecting a substantial level of redundancy. On the other hand, patients with hemizygous (dominant) and homozygous (recessive) mutations in the gene encoding TLR3, which senses doublestranded RNA, typically have recurrent herpes simplex virus1 (HSV1) infections of the central nervous system (herpes simplex encephalitis) due to impaired production of type I interferons by cells of the nervous system. Those with inherited deficiencies in molecules involved in TLR3 signaling (for example, TRIF, TRAF3, or TBK1) are similarly susceptible to HSV1 encephalitis, as are patients with mutations in the TLRtransport protein UNC93B1, which is required for the transport of TLR3 from the endoplasmic reticulum to the endolysosome. Interestingly,


Immunology_Janeway

Immunology_Janeway. HSV1 encephalitis, as are patients with mutations in the TLRtransport protein UNC93B1, which is required for the transport of TLR3 from the endoplasmic reticulum to the endolysosome. Interestingly, leukocytes from these patients have no defect in their response to TLR3 ligands or HSV1, indicating redundancy of TLR3 function in these cells, but not those of the central nervous system. Similarly, these patients show only a limited predisposition to other viral infections, implying the existence of TLR3independent protection against most other types of viral infection.


Immunology_Janeway

Immunology_Janeway. Genetic defects that affect signaling by pattern recognition receptors (PRRs) other than TLRs have been described. CARD9 is an adaptor molecule involved in signaling downstream of Ctype lectin receptors expressed on myeloid cells. Dectin1, Dectin2, and macrophageinducible Ctype lectin (MINCLE) each recognize fungalassociated molecular patterns that signal through CARD9 to induce secretion of proinflammatory cytokines, including IL6 and IL23 (see Section 31). Autosomal recessive CARD9 deficiency results in impaired TH17 cell responses to fungi, with the result that patients with this deficiency, like patients with inborn errors of IL17 immunity (for example, IL17RA deficiency and IL17F deficiency; see Section 1310), suffer chronic mucocutaneous candidiasis. However, in addition, these patients can suffer infections by dermatophytes, which are ubiquitous filamentous fungi that normally cause common superficial skin and nail infections, such as tinea pedis (athlete’s foot).


Immunology_Janeway

Immunology_Janeway. Fig. 13.14 The autoinflammatory diseases.


Immunology_Janeway

Immunology_Janeway. Most of the other known defects in phagocytic cells affect their ability to ingest microbes and destroy them once ingested (see Fig. 13.13). Patients with chronic granulomatous disease (CGD) are highly susceptible to bacterial and fungal infections and form granulomas as a result of an inability to kill bacteria ingested by phagocytes (see Fig. 11.13). The defect in this case is in the production of reactive oxygen species (ROS) such as the superoxide anion (see Section 32). Discovery of the molecular defect in this disease gave weight to the idea that these agents killed bacteria directly; this notion has since been challenged by the finding that the generation of ROS is not itself sufficient to kill target microorganisms. It is now thought that ROS cause an influx of K+ ions into the phagocytic vacuole, increasing the pH to the optimal level for the action of microbicidal peptides and proteins, which are the key agents in killing the invading microorganism.


Immunology_Janeway

Immunology_Janeway. Genetic defects affecting any of the constituent proteins of the NADPH oxidase expressed in neutrophils and monocytes (see Section 32) can cause chronic granulomatous disease. Patients with the disease have chronic bacterial infections, which in some cases lead to the formation of granulomas. Deficiencies in glucose6phosphate dehydrogenase (G6PD) and myeloperoxidase (MPO) also impair intracellular bacterial killing and lead to a similar, although less severe, phenotype. 13-16 Mutations in the molecular regulators of inflammation can ‘autoinflammatory disease.’


Immunology_Janeway

Immunology_Janeway. There are a small number of diseases in which mutations in genes that control the life, death, and activities of inflammatory cells are associated with severe inflammatory disease. Although they do not lead to immunodeficiency, we have included them in this chapter because they are singlegene defects affecting a crucial aspect of innate immunity—the inflammatory response. These conditions represent a failure of the normal mechanisms that limit inflammation, and are known as autoinflammatory diseases: they can lead to inflammation even in the absence of infection (Fig. 13.14). Familial Mediterranean fever (FMF) is characterized by episodic attacks of severe inflammation, which can occur at various sites throughout the body and are associated with fever, an acutephase response (see Section 318), and severe malaise. The pathogenesis of FMF was a mystery until its cause was discovered to be mutations in the gene MEFV, which encodes a protein called pyrin, to reflect its association with


Immunology_Janeway

Immunology_Janeway. 318), and severe malaise. The pathogenesis of FMF was a mystery until its cause was discovered to be mutations in the gene MEFV, which encodes a protein called pyrin, to reflect its association with fever. Pyrin and pyrin domaincontaining proteins are involved in pathways that lead to the apoptosis of inflammatory cells, and in pathways that inhibit the secretion of proinflammatory cytokines such as IL1β. It is proposed that an absence of functional pyrin leads to unregulated cytokine activity and defective apoptosis, resulting in a failure to control inflammation. In mice, an absence of pyrin causes increased sensitivity to lipopolysaccharide and a defect in macrophage apoptosis. A disease with similar clinical manifestations, known as TNFreceptor associated periodic syndrome (TRAPS), is caused by mutations in quite a different gene, that encoding the TNFα receptor TNFRI. Patients with TRAPS have reduced levels of TNFRI, which lead to increased levels of proinflammatory TNFα in the


Immunology_Janeway

Immunology_Janeway. caused by mutations in quite a different gene, that encoding the TNFα receptor TNFRI. Patients with TRAPS have reduced levels of TNFRI, which lead to increased levels of proinflammatory TNFα in the circulation because it is not regulated by binding to this receptor. The disease responds to therapeutic blockade with antiTNF agents such as etanercept, a soluble TNF receptor developed primarily to treat patients with rheumatoid arthritis (see Section 168). Mutations in the gene encoding PSTPIP1 (prolineserinethreonine phosphataseinteracting protein 1), which interacts with pyrin, are associated with another dominantly inherited autoinflammatory syndrome—pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA). The mutations increase binding of pyrin to PSTPIP1, and it has been proposed that the interaction sequesters pyrin and limits its normal regulatory function.


Immunology_Janeway

Immunology_Janeway. The episodic autoinflammatory diseases Muckle–Wells syndrome and familial cold autoinflammatory syndrome (FCAS) are clearly linked to the inappropriate stimulation of inflammation, because they are due to mutations in NLRP3, a component of the ‘inflammasome’ that normally senses cell damage and stress as a result of infection (see Section 39). The mutations lead to the activation of NLRP3 in the absence of such stimuli and the unregulated production of proinflammatory cytokines. Patients with these dominantly inherited syndromes present with episodes of fever—which is induced by exposure to cold in the case of FCAS—as well as urticarial rash, joint pains, and conjunctivitis. Mutations in NLRP3 are also associated with the autoinflammatory disorder chronic infantile neurologic cutaneous and articular syndrome (CINCA), in which short, recurrent fever episodes are common, although severe arthropathic, neurologic, and dermatologic symptoms predominate. Both pyrin and NLRP3 are


Immunology_Janeway

Immunology_Janeway. and articular syndrome (CINCA), in which short, recurrent fever episodes are common, although severe arthropathic, neurologic, and dermatologic symptoms predominate. Both pyrin and NLRP3 are predominantly expressed in leukocytes and in cells that act as innate barriers to pathogens, such as intestinal epithelial cells. The stimuli that modulate pyrin and related molecules include inflammatory cytokines and stressrelated changes in cells. Indeed, Muckle–Wells syndrome responds dramatically to the drug anakinra, an antagonist of the receptor for IL1.


Immunology_Janeway

Immunology_Janeway. 13-17 Hematopoietic stem cell transplantation or gene therapy can be useful to correct genetic defects.


Immunology_Janeway

Immunology_Janeway. It is frequently possible to correct the defects in lymphocyte development that lead to SCID and some other immunodeficiency phenotypes by replacing the defective component, generally by hematopoietic stem cell (HSC) transplantation (see Section 1536). The main difficulties in these therapies result from human leukocyte antigen (HLA) polymorphism. To be useful, the graft must share some HLA alleles with the host. As we learned in Section 821, the HLA alleles expressed by the thymic epithelium determine which T cells can be positively selected. When HSCs are used to restore immune function to individuals with a normal thymic stroma, both the T cells and the antigenpresenting cells are derived from the graft. Therefore, unless the graft shares at least some HLA alleles with the recipient, the T cells that are selected on host thymic epithelium cannot be activated by graftderived antigenpresenting cells (Fig. 13.15).


Immunology_Janeway

Immunology_Janeway. MHCb-restricted T cells can be activated by MHCa×b APC, and recognize infected MHCb cells Donor cells undergo selection on MHCb in the recipient thymus Hematopoietic stem cell transplant. One MHC allele shared MHCa×bmacrophageAPCMHCbTcells Fig. 13.15 The donor and the recipient of a hematopoietic stem cell (HSC) graft must share at least some MHC molecules to restore immune function.


Immunology_Janeway

Immunology_Janeway. an HSC transplant from a genetically different donor is illustrated in which the donor marrow cells share some MHC molecules with the recipient. the shared MHC type is designated ‘b’ and illustrated in blue; the MHC type of the donor HSCs that is not shared is designated ‘a’ and shown in yellow. in the recipient, developing donor lymphocytes are positively selected on MHCb on thymic epithelial cells and negatively selected by the recipient’s stromal epithelial cells and at the corticomedullary junction by encounter with dendritic cells derived from both the donor HSCs and residual recipient dendritic cells. the negatively selected cells are shown as apoptotic cells. the donor-derived antigen-presenting cells (aPCs) in the periphery can activate t cells that recognize MHCb molecules; the activated t cells can then recognize the recipient’s infected MHCbbearing cells. Host-versus-graft response. Graft failure


Immunology_Janeway

Immunology_Janeway. Host-versus-graft response. Graft failure Fig. 13.16 Grafting of bone marrow can be used to correct immunodeficiencies caused by defects in lymphocyte maturation, but two problems can arise. First, if there are mature t cells in the bone marrow, they can attack cells of the host by recognizing their MHC antigens, causing graft-versus-host disease (top panel). this can be prevented by t-cell depletion of the donor bone marrow (center panel). Second, if the recipient has competent t cells, these can attack the bone marrow stem cells (bottom panel). this causes failure of the graft by the usual mechanism of transplant rejection (see Chapter 15).


Immunology_Janeway

Immunology_Janeway. There is also a danger that mature, postthymic T cells that contaminate donor HSCs prepared from the peripheral blood or bone marrow might recognize the host as foreign and attack it, causing graftversushost disease (GVHD) (Fig. 13.16, top panel). This can be overcome by depleting the donor graft of mature T cells. For immunodeficiency diseases other than SCID where there are residual T cells and NK cells in the recipient, some form of myeloablative treatment (destruction of the bone marrow, typically using cytotoxic drugs) is usually carried out before transplantation, both to generate space for engraftment of the transplanted HSCs and to minimize the threat of hostversusgraft disease (HVGD) (see Fig. 13.16, third panel). The intensity of the myeloablative regimen is dependent on the nature of the immunodeficiency. For diseases where persistence of the patient’s cells can be tolerated, engraftment of only a fraction of donor HSCs is sufficient for cure and nonmyeloablative


Immunology_Janeway

Immunology_Janeway. on the nature of the immunodeficiency. For diseases where persistence of the patient’s cells can be tolerated, engraftment of only a fraction of donor HSCs is sufficient for cure and nonmyeloablative chemotherapy may suffice prior to HSC transplantation. In other conditions such as XLP, which require complete elimination of the patient’s blood cells and full engraftment of donor cells, more intensive (myeloablative) chemotherapy may be required.


Immunology_Janeway

Immunology_Janeway. Because many specific gene defects that cause inherited immunodeficiencies have been identified, an alternative therapeutic approach is somatic gene therapy. This strategy involves the isolation of HSCs from the patient’s bone marrow or peripheral blood, introduction of a normal copy of the defective gene with the use of a viral vector, and reinfusion of the corrected stem cells into the patient. Initially, retroviral vectors were used for gene therapy trials, but were ceased due to severe complications in some patients. Although the genetic defect was corrected in patients with Xlinked SCID, CGD, and WAS who received this treatment, some patients developed leukemia due to insertion of the retrovirus within a protooncogene. The inability to control the site in the genome in which retrovirally encoded genes insert and the use of viral vectors with strong promoters that can transactivate neighboring genes is therefore problematic. More recently, the use of selfinactivating retroviral


Immunology_Janeway

Immunology_Janeway. encoded genes insert and the use of viral vectors with strong promoters that can transactivate neighboring genes is therefore problematic. More recently, the use of selfinactivating retroviral and lentiviral vectors for gene correction has shown promise as a means of avoiding this complication. Also, a technique for the generation of induced pluripotent stem cells (iPS cells) from a patient’s own somatic cells has been demonstrated. Forced expression of a set of transcription factors can reprogram somatic cells to become pluripotent progenitors that can give rise to HSCs. This approach offers the promise of ‘repairing’ specific defective genes in patientderived stem cells by gene targeting ex vivo before reinfusion, but is not yet established. Until better methods for introduction of corrected genes into selfrenewing stem cells are identified, allogeneic HSC transplantation will remain the mainstay of treatment for many primary immunodeficiencies.


Immunology_Janeway

Immunology_Janeway. 13-18 Noninherited, secondary immunodeficiencies are major predisposing causes of infection and death.


Immunology_Janeway

Immunology_Janeway. The primary immunodeficiencies have taught us much about the biology of specific proteins of the immune system. Fortunately, these conditions are rare. In contrast, secondary immunodeficiency is relatively common. Malnutrition devastates many populations around the world, and a major feature of malnutrition is secondary immunodeficiency. This particularly affects cellmediated immunity, and death in famines is frequently caused by infection. Measles, which itself causes immunosuppression, is an important cause of death in malnourished children. In the developed world, measles is an unpleasant illness but major complications are uncommon. In contrast, measles in the malnourished has a high mortality. Tuberculosis is another important infection in the malnourished. In mice, protein starvation causes immunodeficiency by affecting antigenpresenting cell function, but in humans it is not clear how malnourishment specifically affects immune responses. Links between the endocrine and immune


Immunology_Janeway

Immunology_Janeway. causes immunodeficiency by affecting antigenpresenting cell function, but in humans it is not clear how malnourishment specifically affects immune responses. Links between the endocrine and immune systems may provide part of the answer.


Immunology_Janeway

Immunology_Janeway. Adipocytes (fat cells) produce the hormone leptin, levels of which are related directly to the amount of fat present in the body; leptin levels therefore fall during starvation when fat is consumed. Both mice and humans with genetic leptin deficiency have reduced Tcell responses, and in mice the thymus atrophies. In both starved mice and those with inherited leptin deficiency, these abnormalities can be reversed by the administration of leptin. Secondary immunodeficiency states are also associated with hematopoietic tumors such as leukemia and lymphomas. Myeloproliferative diseases, such as leukemia, can be associated with deficiencies of neutrophils (neutropenia) or an excess of immature myeloid progenitors that lack functional properties of mature neutrophils, either of which increases susceptibility to bacterial and fungal infections. Destruction or invasion of peripheral lymphoid tissue by lymphomas or metastases from other cancers can promote opportunistic infections.


Immunology_Janeway

Immunology_Janeway. Congenital asplenia (a rare inherited absence of the spleen), surgical removal of the spleen, and destruction of spleen function by certain diseases are associated with a lifelong predisposition to overwhelming infection by S. pneumoniae, graphically illustrating the role of mononuclear phagocytic cells within the spleen in the clearance of this organism from blood. Patients who have lost spleen function should be vaccinated against pneumococcal infection and are often recommended to take prophylactic antibiotics throughout their life.


Immunology_Janeway

Immunology_Janeway. Secondary immunodeficiency is also a complication of certain medical therapies. A major complication of cytotoxic drugs used to treat cancer is immunosuppression and increased susceptibility to infection. Many of these drugs kill all dividing cells, including normal cells of the bone marrow and lymphoid systems. Infection is thus one of the major side effects of cytotoxic drug therapy. Immune suppression to induce host tolerance of solid organ allografts, such as kidney or heart transplants, also carries a substantial increased risk for infection and even for malignancy. The recent introduction of biologic therapies for some forms of autoimmunity has led to an increased risk of infection because of their immunosuppressive effects. For example, administration of antibodies that block TNFα in patients with rheumatoid arthritis or other forms of autoimmunity has been associated with infrequent, but increased, instances of infectious complications. Summary.


Immunology_Janeway

Immunology_Janeway. Genetic defects can occur in almost any molecule involved in the immune response. These defects give rise to characteristic deficiency diseases, which, although rare, provide much information about the development and functioning of the immune system in normal humans. Inherited immunodeficiencies illustrate the vital role of the adaptive immune response and T cells in particular, without which both cellmediated and humoral immunity fail. They have provided information about the separate roles of B lymphocytes in humoral immunity and of T lymphocytes in cellmediated immunity, the importance of phagocytes and complement in humoral and innate immunity, and the specific functions of a growing number of cellsurface or signaling molecules in the adaptive immune response. There are also some inherited immune disorders whose causes we still do not understand. The study of these diseases will undoubtedly teach us more about the normal immune response and its control. Acquired defects in the


Immunology_Janeway

Immunology_Janeway. immune disorders whose causes we still do not understand. The study of these diseases will undoubtedly teach us more about the normal immune response and its control. Acquired defects in the immune system, the secondary immunodeficiencies, are much more common than the primary, inherited immunodeficiencies. In the next sections we briefly consider general mechanisms by which successful pathogens evade or subvert immune defenses and then detail how extreme subversion of the immune system by one pathogen, the human immunodeficiency virus (HIV), has created a major pandemic characterized by the acquired immune deficiency syndrome (AIDS) in affected individuals.


Immunology_Janeway

Immunology_Janeway. Evasion and subversion of immune defenses.