Immunology_Janeway

Immunology_Janeway. pro-inflammatory cytokines, and autoantibodies responsible for inflammation and tissue injury. A few autoimmune diseases are caused by antibodies that bind to cell-surface receptors, causing either excess activity or inhibition of receptor function. In some diseases, transplacental passage of IgG autoantibodies can cause disease in the fetus and neonate. T cells can be involved directly in inflammation or cellular destruction, and they are typically required to initiate and sustain an autoantibody response. Similarly, B cells are important antigen-presenting cells for sustaining autoantigen-specific T-cell responses and causing epitope spreading. In spite of our knowledge of the mechanisms of tissue damage and the therapeutic approaches that this information has engendered, it remains to be determined how autoimmune responses are induced.


Immunology_Janeway

Immunology_Janeway. The genetic and environmental basis of autoimmunity. Given the complex mechanisms that exist to prevent autoimmunity, it is not surprising that autoimmune diseases are the result of multiple factors, both genetic and environmental. We first discuss the genetic basis of autoimmunity, attempting to understand how genetic defects perturb various tolerance mechanisms. Genetic defects alone are not, however, always sufficient to cause autoimmune disease. Environmental factors also play a part, although these factors are poorly understood. As we shall see, genetic and environmental factors together can overcome tolerance mechanisms and result in disease. 15-18 Autoimmune diseases have a strong genetic component.


Immunology_Janeway

Immunology_Janeway. 15-18 Autoimmune diseases have a strong genetic component. It is increasingly clear that some individuals are genetically predisposed to autoimmunity. Perhaps the clearest demonstration of this is found in inbred mouse strains that are prone to various types of autoimmune diseases. Mice of the NOD strain are very likely to get diabetes, with female mice becoming diabetic faster than males (Fig. 15.31). For reasons that are still unclear, many autoimmune diseases are more common in females than in males (see Fig. 15.37 below), with some disorders (SLE and MS) showing a high degree of sexual dimorphism. Autoimmune diseases in humans also have a genetic component. Some autoimmune diseases, including type 1 diabetes, run in families, suggesting a role for genetic susceptibility. Most convincingly, if one identical (monozygotic) twin is affected, the other twin is quite likely to be affected as well, whereas concordance of disease is much less in nonidentical (dizygotic) twins.


Immunology_Janeway

Immunology_Janeway. Environmental influences are also clearly involved. For example, although most members of a colony of NOD mice develop diabetes, they do so at different ages. Moreover, disease onset often differs from one animal colony to the next, even though all the mice are genetically identical. Thus, environmental variables must be, in part, determining the rate of diabetes development in genetically susceptible individuals. Particularly striking is the importance of the intestinal microbiota in the development of IBD in mice that Fig. 15.30 The enzyme peptidyl arginine deiminase converts the arginine residues of tissue proteins to citrulline. In tissues stressed by wounds or infection, peptidyl arginine deiminase (PAD) activity is induced. By converting arginine residues to citrulline, PAD destabilizes proteins and makes them more susceptible to degradation. It also introduces novel B‑cell and T‑cell epitopes into tissue proteins that can stimulate an autoimmune response.


Immunology_Janeway

Immunology_Janeway. Fig. 15.31 Sex differences in the incidence of autoimmune disease. Many autoimmune diseases are more common in females than males, as illustrated here by the cumulative incidence of diabetes in a population of diabetes‑prone NOD mice. Females (red line) get diabetes at a much younger age than do males, indicating their greater predisposition. Data kindly provided by S. Wong. Fig. 15.32 Defects in cytokine production or signaling that can lead to autoimmunity. Some of the signaling pathways involved in autoimmunity have been identified by genetic analysis, mainly in animal models. The effects of overexpression or underexpression of some of the cytokines and intracellular signaling molecules involved are listed here (see the text for further discussion).


Immunology_Janeway

Immunology_Janeway. Incidence of diabetes in NOD mice (%) are genetically predisposed to develop intestinal inflammation. Treatment with broad-spectrum antibiotics that reduce or eliminate many components of the commensal flora can delay or eliminate disease onset, and raising susceptible mice under germ-free conditions (i.e., without a microbiota) eliminates disease. Conversely, certain intestinal microbes—such as segmented filamentous bacteria (SFB)—present in some mouse colonies promote intestinal TH17 responses that have been linked to intestinal inflammation. Although analogous organisms in humans have not been clearly identified, human studies suggest that components of the microbiota may predispose genetically susceptible individuals to autoimmune disease. For instance, although Crohn’s disease incidence in susceptible monozygotic twins is much higher than in dizygotic twins, the concordance rate is not 100%. The explanation for incomplete concordance could lie in variability in the intestinal


Immunology_Janeway

Immunology_Janeway. in susceptible monozygotic twins is much higher than in dizygotic twins, the concordance rate is not 100%. The explanation for incomplete concordance could lie in variability in the intestinal microbiota, epigenetic differences, or factors yet to be defined.


Immunology_Janeway

Immunology_Janeway. 15-19 Genomics-based approaches are providing new insight into the immunogenetic basis of autoimmunity.


Immunology_Janeway

Immunology_Janeway. Since the advent of gene knockout technology in mice (see Appendix I, Section A-35), many genes encoding immune system proteins have been experimentally disrupted. Several strains of mice that have been generated show signs of autoimmunity, including autoantibodies and infiltration of organs by T cells. The study of these mice has expanded our knowledge of the pathways that contribute to autoimmunity, and therefore their induced mutations might be candidates for identifying naturally occurring mutations. These mutations likely affect genes that encode cytokines, co-receptors, molecules involved in antigen-signaling cascades, co-stimulatory molecules, proteins involved in apoptosis, and proteins that clear antigen or antigen:antibody complexes. A number of cytokines and signaling proteins implicated in autoimmune disease are listed in Fig. 15.32. Other targeted or mutant genes with autoimmune phenotypes in mice are listed in Fig. 15.33, as are their corresponding human counterparts,


Immunology_Janeway

Immunology_Janeway. implicated in autoimmune disease are listed in Fig. 15.32. Other targeted or mutant genes with autoimmune phenotypes in mice are listed in Fig. 15.33, as are their corresponding human counterparts, where known.


Immunology_Janeway

Immunology_Janeway. Cytokine, receptor, or intracellular signal ResultDefect Defects in cytokine production or signaling that can lead to autoimmunity TNF-˜TNF-˜In˜ammatory bowel disease, arthritis, vasculitis IL-2, IL-7, IL-2R In˜ammatory bowel disease STAT4 In˜ammatory bowel disease IL-23R In˜ammatory bowel disease, psoriasis IL-10, IL-10R, STAT3 In˜ammatory bowel disease TGF-°Ubiquitous underexpression leads to in˜ammatory bowel disease. Underexpression speciÿcally in T cells leads to SLE IL-3 Demyelinating syndrome IFN-˛Overexpression in skin leads to SLE SLE IL-1 receptor agonist Arthritis Overexpression Underexpression Fig. 15.33 Categories of genetic defects that lead to autoimmune syndromes.


Immunology_Janeway

Immunology_Janeway. Fig. 15.33 Categories of genetic defects that lead to autoimmune syndromes. Many genes have been identified in which mutations predispose to autoimmunity in humans and animal models. These are best understood by the type of process affected by the genetic defect. A list of such genes (or the related protein product) is given here, organized by process (see the text for further discussion). In some cases, the same gene has been identified in mice and humans. In other cases, different genes affecting the same mechanism are implicated in mice and humans. The smaller number of human genes identified so far undoubtedly reflects the difficulty of identifying the genes responsible in outbred human populations.


Immunology_Janeway

Immunology_Janeway. In humans, genetic susceptibility to autoimmune disorders has been recently assessed by large-scale genome-wide association studies (GWASs), which look for a correlation between disease frequency and genetic variants (typically single-nucleotide polymorphisms, or SNPs). Such studies typically involve thousands of patients with a given autoimmune disease diagnosis and Fig. 15.34 Manhattan plot depicting risk alleles from genome-wide association studies (GWASs) of Crohn’s disease. The plot highlights selected gene loci identified by analyses of single nuclear polymorphisms (SNPs) with highly significant disease associations in patients with Crohn’s disease compared with healthy controls (see also Section 15‑23). The height of the peaks reflects the statistical significance of the association. The dotted line indicates the threshold for significant associations (5 × 10–08). Figure courtesy of John Rioux and Ben Weaver.


Immunology_Janeway

Immunology_Janeway. healthy controls in order to identify highly significant associations. Example results from GWASs that identify candidate genes linked to Crohn's disease are shown in the ‘Manhattan’ plot in Fig. 15.34. These plots are so named because they resemble a profile view of skyscrapers in the Manhattan skyline. Here, genomic coordinates are located on the x-axis, with the negative logarithm of the P-value of the association being given on the y-axis, and each assayed SNP is represented by a dot. Thus, the variants with the greatest disease association are the ‘tallest skyscrapers’ on the plot. Using this approach, hundreds of significant variants have been identified for multiple autoimmune diseases, suggesting that genetic susceptibility to autoimmune disease in humans may be due to a combination of susceptibility alleles at multiple loci.


Immunology_Janeway

Immunology_Janeway. Analyses of GWASs from multiple autoimmune diseases indicate that certain immune pathways—most notably those involved in T-cell activation and function—are common to multiple different forms of autoimmunity. For example, type 1 diabetes, Graves’ disease, Hashimoto’s thyroiditis, rheumatoid arthritis, and multiple sclerosis all show genetic association with the CTLA4 locus on chromosome 2. The cell-surface protein CTLA-4 is produced by activated T cells and is an inhibitory receptor for B7 co-stimulatory molecules (see Section 9-17). Similarly, many of the most common autoimmune disorders have been linked to central factors involved in the development and function of the TH17 and TH1 immune pathways (Fig. 15.35).


Immunology_Janeway

Immunology_Janeway. Despite confirming much of our knowledge from experimental immunology, these studies have also revealed our ignorance of gene-regulatory mechanisms that predispose to human disease. For instance, the vast majority of risk alleles identified to date (>80%) are not contained within exons (the protein-coding regions of genes), and many variants reside kilobases away from immunologically relevant genes. Understanding how genetic variation at these noncoding sequences in the genome can contribute to disease is a very active area of research. Recent evidence using computational algorithms, coupled to transcriptional and epigenetic profiling of human immune-cell populations,


Immunology_Janeway

Immunology_Janeway. TH1 cell TH17 cell IL-12 production IL-23 production IFN-˜production IFN-˜IL-17 and IL-22 production IL-17, IL-22 IL-12R°2IL-12R°1 IL-12 IL-12p40IL-12p35 IL-23R CCR6 IL-12R°1 IL-23 IL-12p19IL-12p40 Ankylosing spondylitis Infammatory bowel disease Psoriasis Multiple sclerosis Type 1 diabetes Rheumatoid arthritis JAK2TYK2 STAT4 JAK2TYK2 STAT3 1 2 3 4 5 Systemic lupus erythematosus Ulcerative colitis 7 8 6 Dendritic cell NF˛B Dectin-1 CARD9 PTGER4 °-glucan 1, 2 3 2 22 1, 2, 3 1, 2, 3, 4 1, 2, 3, 44, 7, 8 1, 2, 3, 4, 5, 6, 7 2, 6, 7, 8 2, 3, 4 1, 2, 3, 4, 5, 6, 7 4, 7, 8 1, 2, 4 Fig. 15.35 Associations of components of the IL-12R and IL-23R response pathways with autoimmune diseases.


Immunology_Janeway

Immunology_Janeway. Fig. 15.35 Associations of components of the IL-12R and IL-23R response pathways with autoimmune diseases. Multiple components of the interleukin‑12 (IL‑12R) and ‑23 (IL‑23R) receptor response pathways show significant genome‑wide associations with a broad range of immune‑mediated diseases; that is, these components map within genomic intervals that are associated with the respective disease in genome‑wide association studies. Although this figure shows these components in the conventional context of T helper 1 (TH1) and TH17 lymphocytes, it is now recognized that they are widely expressed in innate lymphoid cells and the specific cell type may vary from phenotype to phenotype. Adapted from Parkes M. et al.: Nat. Rev. Genetics 2013, 14:661. With permission from Macmillan Publishers Ltd.


Immunology_Janeway

Immunology_Janeway. suggests that many of the causal variants are located within critical gene-regulatory elements that control gene expression in immune cells (for example enhancers). Many of these gene-regulatory elements are utilized by effector or regulatory T cells following their activation, further confirming T-cell activation as a key event in the etiology of autoimmune disorders. Ultimately, a deeper understanding of how these variants contribute to disease will require new techniques to experimentally mimic and manipulate risk alleles, either singly or in combination, in order to fully elucidate how they affect the biology of immune-cell populations relevant to disease.


Immunology_Janeway

Immunology_Janeway. Despite our current ignorance of how most common genetic variants predispose to (or protect from) autoimmune disorders, several other approaches have begun to shed light on the genetic mechanisms of disease. These include the study of mutations that cause overt alterations in molecules regulating tolerance or the innate immune system; the study of patients with rare, monogenic defects of immune tolerance; and investigations into how certain HLA alleles predispose to disease by their ability to present certain self antigens. We will briefly explore each of these in the following sections. 15-20 Many genes that predispose to autoimmunity fall into categories that affect one or more tolerance mechanisms.


Immunology_Janeway

Immunology_Janeway. 15-20 Many genes that predispose to autoimmunity fall into categories that affect one or more tolerance mechanisms. Many of the genes identified as predisposing to autoimmunity can be classified as affecting autoantigen availability and clearance; apoptosis; signaling thresholds; cytokine expression or signaling; co-stimulatory molecules or their receptors; or regulatory T cells (see Figs. 15.32 and 15.33).


Immunology_Janeway

Immunology_Janeway. Genes that control antigen availability and clearance are important both centrally, in the thymus, and in the periphery. In the thymus, genes that control expression of self proteins influence tolerance in developing lymphocytes. In the periphery, hereditary deficiency of some proteins can predispose to autoimmunity—for example, deficiency of early components of the complement cascade is associated with the development of SLE (see Section 15-16). Genes that control apoptosis, such as FAS, are important in regulating the duration and vigor of immune responses. Failure to regulate immune responses properly causes excessive destruction of self tissues, releasing autoantigens. In addition, because clonal deletion and anergy are not absolute, immune responses can include some self-reactive cells. As long as their numbers are limited by apoptotic mechanisms, they may not necessarily cause autoimmune disease, but they could cause a problem if apoptosis is not properly regulated.


Immunology_Janeway

Immunology_Janeway. One of the largest categories of mutations associated with autoimmunity pertains to signals that control lymphocyte activation. These include mutations in co-stimulatory molecules, inhibitory Fc receptors, and inhibitory receptors containing ITIMs, such as PD-1 and CTLA-4 (see Section 15-19). Another subset contains mutations in proteins involved in signal transduction through the antigen receptor itself. Mutations that affect signaling intensity in either direction—making signaling more or less sensitive—can result in autoimmunity. A decrease in sensitivity in the thymus, for example, can lead to a failure of negative selection and thereby to autoreactivity in the periphery. In contrast, increasing receptor sensitivity in the periphery can lead to greater and prolonged activation, resulting in an exaggerated immune response with the side effect of autoimmunity. Additionally, mutations that affect the expression or signaling of cytokines and co-stimulatory molecules have been linked


Immunology_Janeway

Immunology_Janeway. in an exaggerated immune response with the side effect of autoimmunity. Additionally, mutations that affect the expression or signaling of cytokines and co-stimulatory molecules have been linked to autoimmunity. A final subset comprises mutations effecting Treg-cell development or function, such as FoxP3 mutations (see Section 15-21).


Immunology_Janeway

Immunology_Janeway. 15-21 Monogenic defects of immune tolerance. Predisposition to most of the common autoimmune diseases is due to the combined effects of multiple genes, but there are some monogenic autoimmune diseases (Fig. 15.36). Here, the mutant allele confers a very high risk of disease to the individual, but the overall impact on the population is minimal because these variants are rare. The existence of monogenic autoimmune disease was first observed in mutant mice in which the inheritance of an autoimmune syndrome followed a pattern consistent with a single-gene defect. Such alleles are usually recessive or X-linked. For example, the disease APECED is a recessive autoimmune disease caused by a defect in the gene AIRE (see Section 15-3).


Immunology_Janeway

Immunology_Janeway. Two monogenic autoimmune syndromes have been linked to defects in regulatory T cells. The X-linked recessive autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) is typically caused by missense mutations in the gene encoding the transcription factor FoxP3, which is key in the differentiation and function of some types of Treg cells (see Section 9-21). This disease is characterized by severe allergic inflammation, autoimmune polyendocrinopathy, secretory diarrhea, hemolytic anemia, and thrombocytopenia, and usually leads to early death. Despite mutation of the FOXP3 gene, the number of FoxP3+ Treg cells in the blood of individuals with IPEX is comparable to the number in healthy individuals; however, the


Immunology_Janeway

Immunology_Janeway. Human disease Mouse mutant or knockoutGene Single-gene traits associated with autoimmunity APECED (APS-1) Knockout Mechanism of autoimmunity Decreased expression of self antigens in the thymus, resulting in defective negative selection of self-reactive T cells AIRE IPEX Knockout and mutation (scurfy) Decreased function of CD4 CD25 regulatory T cells FOXP3 ALPS lpr/lpr; gld/gld mutants Failure of apoptotic death of self-reactive B and T cells FAS SLE Knockout Defective clearance of immune complexes and apoptotic cellsC1q IBD Hypomorph Defective autophagy/clearance of bacteria by innate cells in intestines ATG16L1 IBD Knockout Defective IL-10 signaling; impaired anti-infammatory responseIL10RA, IL10RB Type 1 diabetes None Decreased expression of insulin in thymus; impaired negative selectionINS Association with Graves’ disease, type 1 diabetes, and others Knockout Failure of T-cell anergy and reduced activation threshold of self-reactive T cells CTLA4


Immunology_Janeway

Immunology_Janeway. Fig. 15.36 Single-gene traits associated with autoimmunity. APS‑1, autoimmune polyglandular syndrome 1; IPEX, immune Listed are examples of monogenic disorders that cause dysregulation, polyendocrinopathy, enteropathy, X‑linked syndrome; autoimmunity in humans. Mice with targeted deletions (knockout) ALPS, autoimmune lymphoproliferative syndrome. The lpr mutation or spontaneous mutations (for example, lpr/lpr) in homologous in mice affects the gene for Fas, whereas the gld mutation affects genes have similar disease characteristics and are useful models the gene for FasL. Adapted from J.D. Rioux and A.K. Abbas: Nature for the study of the pathogenic basis for these disorders. APECED, 435:584–589. With permission from Macmillan Publishers Ltd. autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; suppressive function normally displayed by these cells is impaired. A spontaneous frameshift mutation in the mouse Foxp3 gene (the scurfy mutation) that results in loss of the


Immunology_Janeway

Immunology_Janeway. dystrophy; suppressive function normally displayed by these cells is impaired. A spontaneous frameshift mutation in the mouse Foxp3 gene (the scurfy mutation) that results in loss of the DNA-binding domain of FoxP3 or complete knockout of Foxp3 leads to an analogous systemic autoimmune disease, in this case associated with the absence of FoxP3+ Treg cells.


Immunology_Janeway

Immunology_Janeway. Autoimmunity caused by defective development and survival of Treg cells also results from mutation of CD25, the high-affinity chain of the IL-2 receptor complex that is constitutively expressed by Treg cells (see Section 9-16). Because deficiency of CD25 affects the development and function of effector T cells as well, in addition to autoimmunity, patients affected by this mutation suffer multiple immunological deficiencies and susceptibility to infections. These findings further confirm the importance of Treg cells in the regulation of the immune system.


Immunology_Janeway

Immunology_Janeway. An interesting case of a monogenic autoimmune disease is autoimmune lymphoproliferative syndrome (ALPS), a systemic autoimmune syndrome caused by mutations in the gene encoding Fas. Fas is normally present on the surface of activated T and B cells, and when ligated by Fas ligand, it signals the Fas-bearing cell to undergo apoptosis (see Section 11-16). In this way it functions to limit the extent of immune responses. Mutations that eliminate or inactivate Fas lead to a massive accumulation of lymphocytes, especially T cells, and in mice, to the production of large quantities of pathogenic autoantibodies and a disease that resembles SLE. A mutation leading to this autoimmune syndrome was first observed in the MRL mouse strain and named lpr, for lymphoproliferation; it was subsequently identified as a mutation in Fas. The study of human patients with the rare autoimmune lymphoproliferative syndrome, which is similar to the syndrome in the MRL/lpr mice, led to the identification of FAS


Immunology_Janeway

Immunology_Janeway. as a mutation in Fas. The study of human patients with the rare autoimmune lymphoproliferative syndrome, which is similar to the syndrome in the MRL/lpr mice, led to the identification of FAS as the mutant gene responsible for most of these cases (see Fig. 15.36).


Immunology_Janeway

Immunology_Janeway. Fig. 15.37 Associations of HLA and sex with susceptibility to autoimmune disease. The ‘relative risk’ for an HLA allele in an autoimmune disease is calculated by comparing the observed number of patients carrying the HLA allele with the number that would be expected, given the prevalence of the HLA allele in the general population. For type 1 insulin‑dependent diabetes mellitus, the association is in fact with the HLA‑DQ gene, which is tightly linked to the DR genes but is not detectable by serotyping. Some diseases show a significant bias in the sex ratio; this is taken to imply that sex hormones are involved in pathogenesis. Consistent with this, the difference in the sex ratio in these diseases is greatest between menarche and menopause, when levels of such hormones are highest. Healthy controls Diabetes DR3/x (24%) DR4/x (17.5%) DR2/x (30.3%) DR3/4 (2.5%) (25.7%) DR4/x (27%) (4%) DR3/4 (39%) DR3/x (30%) DRx/x DRx/x


Immunology_Janeway

Immunology_Janeway. Healthy controls Diabetes DR3/x (24%) DR4/x (17.5%) DR2/x (30.3%) DR3/4 (2.5%) (25.7%) DR4/x (27%) (4%) DR3/4 (39%) DR3/x (30%) DRx/x DRx/x Autoimmune diseases caused by single genes are rare, but are of great interest, as the mutations causing them identify important pathways that normally prevent the development of autoimmune responses. 15-22 MHC genes have an important role in controlling susceptibility to autoimmune disease. Among genetic loci that contribute to autoimmunity, susceptibility to autoimmune disease has so far been most consistently associated with MHC genotype (Fig. 15.37), particularly MHC class II alleles, thus implicating CD4 T cells in their etiology. The development of experimental diabetes or arthritis in transgenic mice expressing specific human HLA antigens strongly suggests that particular MHC alleles confer disease susceptibility.


Immunology_Janeway

Immunology_Janeway. As in genome-wide association studies (GWASs), association of MHC with disease is identified by comparing the frequencies of MHC alleles in patients with the disease with the frequencies in the normal population. For type 1 diabetes, this approach demonstrated an association with the HLA-DR3 and HLA-DR4 alleles, identified by serotyping (Fig. 15.38). Such studies also showed that the MHC class II allele HLA-DR2 has a dominant protective


Immunology_Janeway

Immunology_Janeway. Fig. 15.38 Population studies show association of susceptibility to type 1 diabetes with HLA genotype. The HLA genotypes (determined by serotyping) of patients with diabetes (lower panel) are not representative of those found in the general population (upper panel). Almost all patients with diabetes express HLA‑DR3 and/or HLA‑DR4, and HLA‑DR3/DR4 heterozygosity is greatly overrepresented in diabetics compared with controls. These alleles are linked tightly to HLA‑DQ alleles that confer susceptibility to type 1 diabetes. By contrast, HLA‑DR2 protects against the development of diabetes and is found only extremely rarely in patients with diabetes. The small letter x represents any allele other than DR2, DR3, or DR4. Family studies of HLA haplotypes in type 1 diabetes


Immunology_Janeway

Immunology_Janeway. Family studies of HLA haplotypes in type 1 diabetes Fig. 15.39 Family studies show strong linkage of susceptibility to type 1 diabetes with HLA genotype. In families in which two or more siblings have type 1 diabetes, it is possible to compare the HLA genotypes of affected siblings. Affected siblings share two HLA haplotypes much more frequently than would be expected if the HLA genotype did not influence disease susceptibility.


Immunology_Janeway

Immunology_Janeway. effect: individuals carrying HLA-DR2, even in association with one of the susceptibility alleles, rarely develop diabetes. It has also been shown that two siblings affected with the same autoimmune disease are far more likely than expected to share the same MHC haplotypes (Fig. 15.39). As HLA genotyping has become more exact through DNA sequencing, disease associations originally discovered by serotyping have been defined more precisely. For example, the association between type 1 diabetes and the DR3 and DR4 alleles is now known to be due to their tight genetic linkage to DQβ alleles that confer susceptibility to the disease. Indeed, susceptibility is most closely associated with polymorphisms at a particular position in the DQβ amino acid sequence that affect the peptide-binding cleft of MHC class II (Fig. 15.40). The diabetes-prone NOD strain of mice also has a serine residue polymorphism at that same position in the homologous mouse MHC class II molecule, known as I-Ag7.


Immunology_Janeway

Immunology_Janeway. The association of MHC genotype with autoimmune disease is not surprising; associations can be explained by a simple model in which susceptibility to an autoimmune disease is determined by differences in the ability of different allelic variants of MHC molecules to present autoantigenic peptides to autoreactive T cells. This would be consistent with what we know of T-cell involvement in particular diseases. In diabetes, for example, there are associations with both MHC class I and MHC class II alleles, consistent with the finding that both CD8 and CD4 T cells mediate the autoimmune response. An alternative hypothesis emphasizes the role of MHC alleles in shaping the T-cell receptor repertoire (see Chapter 8). This hypothesis proposes that self peptides associated with certain MHC molecules may drive the positive selection of developing thymocytes that are specific for particular autoantigens. Such


Immunology_Janeway

Immunology_Janeway. Fig. 15.40 Amino acid changes in the sequence of an MHC class II protein correlate with susceptibility to and protection from diabetes. The HLA‑DQβ1 chain contains an aspartic acid (Asp) residue at position 57 in most people; in Caucasoid populations, patients with type 1 diabetes (T1DM) more often have valine, serine, or alanine at this position instead, as well as other differences. Asp 57, shown in red on the backbone structure of the DQβ chain in the top panel, forms a salt bridge (shown in green in the center panel) to an arginine residue (shown in pink) in the adjacent α chain (gray). The change to an uncharged residue (for example, alanine, shown in yellow in the bottom panel) disrupts this salt bridge, altering the stability of the DQ molecule. The non‑obese diabetic (NOD) strain of mice, which develops spontaneous diabetes, shows a similar substitution of serine for aspartic acid at position 57 of the homologous I‑Aβ chain, and NOD mice transgenic for β chains with Asp 57


Immunology_Janeway

Immunology_Janeway. of mice, which develops spontaneous diabetes, shows a similar substitution of serine for aspartic acid at position 57 of the homologous I‑Aβ chain, and NOD mice transgenic for β chains with Asp 57 have a marked reduction in diabetes incidence. Courtesy of C. Thorpe.


Immunology_Janeway

Immunology_Janeway. Fig. 15.41 Crohn’s disease results from a breakdown of the normal homeostatic mechanisms that limit inflammatory responses to the gut microbiota. The innate and adaptive immune systems normally cooperate to limit inflammatory responses to intestinal bacteria through a combination of mechanisms: a mucus layer produced by goblet cells; tight junctions between the intestinal epithelial cells; antimicrobial peptides released from epithelial cells and Paneth cells; and induction of Treg cells that inhibit effector CD4 T‑cell development and promote the production of IgA antibodies that are transported into the intestinal lumen, where they inhibit translocation of intestinal bacteria (not shown). In individuals with impaired homeostatic mechanisms, dysregulated TH1‑and TH17‑cell responses to the intestinal microbiota can result, generating disease‑causing chronic inflammation. Crohn’s disease susceptibility genes of innate immunity include NOD2 and the autophagy genes ATG16L1 and IRGM. A


Immunology_Janeway

Immunology_Janeway. the intestinal microbiota can result, generating disease‑causing chronic inflammation. Crohn’s disease susceptibility genes of innate immunity include NOD2 and the autophagy genes ATG16L1 and IRGM. A major susceptibility gene that affects adaptive immune cells is IL23R, which is expressed by TH17 cells (see also Fig. 15.34).


Immunology_Janeway

Immunology_Janeway. autoantigenic peptides might be expressed at too low a level or bind too poorly to MHC molecules to drive thymic negative selection, but might be present at a sufficient level or bind strongly enough to drive positive selection. This hypothesis is supported by observations that I-Ag7, the MHC class II molecule in NOD mice, binds many peptides very poorly and may therefore be less effective in driving thymic negative selection. 15-23 Genetic variants that impair innate immune responses can predispose to T-cell-mediated chronic inflammatory disease.


Immunology_Janeway

Immunology_Janeway. As noted earlier in this chapter, Crohn’s disease (CD) is one of the two major types of inflammatory bowel disease. CD is thought to result from abnormal hyperresponsiveness of CD4 T cells to antigens of the commensal gut microbiota, rather than to true self antigens. Dysregulation of TH17 and TH1 cells is thought to be pathogenic. Disease can result from a failure of mucosal innate immune mechanisms to sequester luminal bacteria from the adaptive immune system, from T-cell-intrinsic defects that cause heightened effector responses, or from failure of Treg cells to suppress microbiota-reactive TH17 and TH1 cells (Fig. 15.41). Patients with CD have episodes of severe inflammation that commonly affect the terminal ileum, with or without involvement of the colon—hence the alternative name ‘regional ileitis’ for this disease—but any part of the gastrointestinal tract can be involved. The disease is characterized by chronic inflammation and granulomatous lesions in the mucosa and


Immunology_Janeway

Immunology_Janeway. name ‘regional ileitis’ for this disease—but any part of the gastrointestinal tract can be involved. The disease is characterized by chronic inflammation and granulomatous lesions in the mucosa and sub-mucosa of the intestine. Genetic analysis of patients with CD and their families has identified a growing list of disease-susceptibility genes (see Fig. 15.34). One of the earliest to be identified was NOD2 (also known as CARD15), which is expressed predominantly in monocytes, dendritic cells, and the Paneth cells of the small intestine, and is involved in recognition of microbial antigens as part of the innate immune response (see Section 3-8). Mutations and rare polymorphic variants in NOD2 are strongly associated with CD. Mutations in the same gene are also the cause of a dominantly inherited granulomatous disease named Blau syndrome, in which granulomas typically develop in the skin, eyes, and joints. Whereas CD results from a loss of function of NOD2, it is thought that Blau


Immunology_Janeway

Immunology_Janeway. inherited granulomatous disease named Blau syndrome, in which granulomas typically develop in the skin, eyes, and joints. Whereas CD results from a loss of function of NOD2, it is thought that Blau syndrome results from a gain of function.


Immunology_Janeway

Immunology_Janeway. goblet cell intestinal epithelial cells homeostatic dendritic cell TregTH17TH1 anti-infammatory activated phagocytic cell macrophage auto-phagosome (ATG16L1 IRGM) Paneth cell antimicrobial peptides NOD2 bacteriaintestinal lumen mucus layer intestinal lamina propria pro-infammatory IL-6, TGF-˜IL-1˜, IL-23 TGF-˜RAIL-12


Immunology_Janeway

Immunology_Janeway. NOD2 is an intracellular receptor for the muramyl dipeptide derived from bacterial peptidoglycan, and its stimulation activates the transcription factor NFκB and the expression of genes encoding pro-inflammatory cytokines and chemokines (see Section 3-8 and Fig. 12.15). In Paneth cells—specialized intestinal epithelial cells in the base of the small intestinal crypts—activation of NOD2 stimulates the release of granules containing antimicrobial peptides that help sequester commensal bacteria to the intestinal lumen, away from the adaptive immune system. Mutant forms of NOD2 that have lost this function limit this innate antibacterial response, thereby predisposing the individual to heightened effector CD4 T-cell responses to the commensal microbiota and consequent chronic intestinal inflammation (see Section 12-22).


Immunology_Janeway

Immunology_Janeway. In addition to NOD2, other deficiencies in innate immunity have been identified in patients with CD, including defective CXCL8 production and neutrophil accumulation, which can synergize with NOD2 defects to promote intestinal inflammation. Thus, compound defects in innate immunity and the regulation of inflammation may act synergistically to promote immunopathology in CD. GWASs have identified other susceptibility genes for CD that may be linked to impaired innate immune functions (see Fig. 15.34). Defects in two genes (ATG16L1 and IRGM) that contribute to autophagy have been linked to CD, suggesting that other mechanisms that impair clearance of commensal bacteria might predispose to chronic intestinal inflammation. Autophagy, or the digestion of a cell’s cytoplasm by its own lysosomes, is important in the turnover of damaged cellular organelles and proteins; autophagy also has a role in antigen processing and presentation (see Section 6-9), and contributes to the clearance of some


Immunology_Janeway

Immunology_Janeway. is important in the turnover of damaged cellular organelles and proteins; autophagy also has a role in antigen processing and presentation (see Section 6-9), and contributes to the clearance of some phagocytosed bacteria.


Immunology_Janeway

Immunology_Janeway. While defects in important pathways of the innate immune system contribute to CD, genes that regulate the adaptive immune response have also been associated with susceptibility. Most notably, there are variants of the gene for the IL-23 receptor (IL23R) that predispose to disease, consistent with heightened TH17 responses in diseased tissues. Collectively, the growing number of susceptibility genes that confer increased risk for CD point to abnormal regulation of homeostatic innate and adaptive immune responses to the intestinal microbiota as a common factor. 15-24 External events can initiate autoimmunity.


Immunology_Janeway

Immunology_Janeway. The geographic distribution of autoimmune diseases reveals a heterogeneous distribution among different continents, countries, and ethnic groups. For example, the incidence of disease in the Northern Hemisphere seems to decrease from north to south. This gradient is particularly prominent for diseases such as multiple sclerosis and type 1 diabetes in Europe, where the incidence is greater in the northern countries than in Mediterranean regions. Numerous epidemiologic and genetic associations suggest that this may be partly related to levels of vitamin D. The active form of vitamin D is formed in the skin in response to sunlight—which is less intense and less available in northern latitudes—and has numerous immunoregulatory functions that affect cells of the innate and adaptive immune systems, including suppression of TH17 cell development. Studies have also shown an increased incidence of autoimmunity in more developed countries, the basis of which is unknown.


Immunology_Janeway

Immunology_Janeway. Besides vitamin D levels, there are numerous other nongenetic factors contributing to these geographic variations, including socioeconomic status and diet. The contribution of nongenetic factors to disease is exemplified in genetically identical mice, which develop autoimmunity at different rates and severity. There is an emerging appreciation for the diversity of the commensal microbiota having a role in contributing to autoimmune disease—including extraintestinal disease—reflecting the importance of the interplay of the microbiome with the innate and adaptive immune systems in shaping the


Immunology_Janeway

Immunology_Janeway. Fig. 15.42 Infectious agents could break self-tolerance in several different ways. Left panels: because some antigens are sequestered from the circulation, either behind a tissue barrier or within the cell, an infection that breaks cell and tissue barriers might expose hidden antigens. Right panels: molecular mimicry might result in infectious agents inducing either T‑ or B‑cell responses that can cross‑react with self antigens.


Immunology_Janeway

Immunology_Janeway. systemic immune response. Finally, exposure to infections and environmental toxins may be factors that help trigger autoimmunity. However, it should be noted that epidemiological and clinical studies over the past century have also shown a negative correlation between exposure to some types of infections in early life and the development of allergy and autoimmune diseases. This ‘hygiene hypothesis’ proposes that a lack of infection during childhood may affect the regulation of the immune system in later life, leading to a greater likelihood of allergic and autoimmune responses (see Section 14-4). 15-25 Infection can lead to autoimmune disease by providing an environment that promotes lymphocyte activation.


Immunology_Janeway

Immunology_Janeway. 15-25 Infection can lead to autoimmune disease by providing an environment that promotes lymphocyte activation. How might pathogens contribute to autoimmunity? While an infection is in progress, inflammatory mediators released from activated antigen-presenting cells and lymphocytes and the increased expression of co-stimulatory molecules can affect so-called bystander cells—lymphocytes that are not themselves specific for the antigens of the infectious agent. Self-reactive lymphocytes can become activated in these circumstances, particularly if tissue destruction by the infection leads to an increase in the availability of the self antigen (Fig. 15.42, left panels). Furthermore, pro-inflammatory cytokines, such as IL-1 and IL-6, impair the suppressive activity of regulatory T cells, allowing self-reactive naive T cells to become activated to differentiate into effector T cells that can initiate an autoimmune response.


Immunology_Janeway

Immunology_Janeway. The perpetuation or exacerbation of autoimmune disease by viral or bacterial infections has been shown in experimental animal models. For example, the severity of type 1 diabetes in NOD mice is exacerbated by Coxsackie virus B4 infection, which leads to inflammation, tissue damage, the release of sequestered islet antigens, and the generation of autoreactive T cells.


Immunology_Janeway

Immunology_Janeway. We discussed earlier the ability of self ligands such as unmethylated CpG DNA and RNA to directly activate autoreactive B cells via their TLRs and thus break self-tolerance (see Section 15-4 and Fig. 15.25). Microbial ligands for TLRs may also promote autoimmunity by stimulating dendritic cells and macrophages to produce large quantities of cytokines that cause local inflammation and help stimulate already activated autoreactive T and B cells. This mechanism might be relevant to the flare-ups of inflammation that follow infection in patients with autoimmune vasculitis associated with anti-neutrophil cytoplasmic antibodies.


Immunology_Janeway

Immunology_Janeway. One example of how TLR ligands can induce local inflammation derives from an animal model of arthritis in which injection of bacterial CpG DNA, which is recognized by TLR-9, into the joints of mice induces an arthritis characterized by macrophage infiltration. These macrophages express chemokine receptors on their surface and produce large amounts of CC chemokines, which promote leukocyte recruitment to the site of injection. and self molecules can lead to antiself responses and autoimmune disease.


Immunology_Janeway

Immunology_Janeway. and self molecules can lead to antiself responses and autoimmune disease. Infection with certain pathogens is associated with autoimmune sequelae. Some pathogens express antigens that resemble host molecules, a phenomenon called molecular mimicry. In such cases, antibodies produced against a pathogen epitope may cross-react with a self molecule (see Fig. 15.42, right panels). Such structures do not necessarily have to be identical: it is sufficient that they be similar enough to be recognized by the same antibody. Molecular mimicry may also activate autoreactive T cells and result in an attack on self tissues if a processed peptide from a pathogen antigen is similar to a host peptide. A model system to demonstrate molecular mimicry has been generated by using transgenic mice expressing a viral antigen in the pancreas.


Immunology_Janeway

Immunology_Janeway. Inject LCMV into mouse. NP-speciÿc CD8 T cells are activated by LCMV infection Activated CD8 T cells inÿltrate islets and kill ˜ cells expressing NP; this results in diabetes Make transgenic mice that express NP only in the pancreatic ˜ cells pancreas NP is expressed only in ˜ cells and provokes no T-cell response Normally, there is no response to this virus-derived ‘self’ antigen, but upon infection with the virus that was the source of the transgenic antigen, mice develop diabetes, because the virus activates T cells that are cross-reactive with the ‘self’ viral antigen (Fig.15.43).


Immunology_Janeway

Immunology_Janeway. One might wonder why these self-reactive lymphocytes have not been deleted or inactivated by the usual mechanisms of self-tolerance. One reason is that lower-affinity self-reactive B and T cells are not removed efficiently and are present in the naive lymphocyte repertoire as ignorant lymphocytes (see Section 15-4). Pathogens may provide substantially higher local doses of the eliciting antigen in an immunogenic form, whereas normally it would be relatively unavailable to lymphocytes. Some examples of autoimmune syndromes thought to involve molecular mimicry are the rheumatic fever that sometimes follows streptococcal infection, and the reactive arthritis that can occur after enteric infection.


Immunology_Janeway

Immunology_Janeway. Once self-reactive lymphocytes have been activated by such a mechanism, their effector functions can destroy tissues. Autoimmunity of this type is sometimes transient, and remits when the inciting pathogen is eliminated. This is the case in the autoimmune hemolytic anemia that follows mycoplasma infection. The anemia ensues when antibodies against the pathogen cross-react with an antigen on red blood cells, leading to hemolysis (see Section 15-13). The autoantibodies disappear when the patient recovers from the infection. Sometimes, however, the autoimmunity persists well beyond the initial infection. This is true in some cases of rheumatic fever (Fig. 15.44), which occasionally follows a sore throat, scarlet fever, or local skin infections (impetigo) Streptococcal cell wall stimulates antibody response Some antibodies cross-react with heart valve tissue, causing rheumatic fever plasma cell heart antibodies in blood bacteria


Immunology_Janeway

Immunology_Janeway. Streptococcal cell wall stimulates antibody response Some antibodies cross-react with heart valve tissue, causing rheumatic fever plasma cell heart antibodies in blood bacteria Fig. 15.43 Virus infection can break tolerance to a transgenic viral protein expressed in pancreatic β cells. Mice made transgenic for the lymphocytic choriomeningitis virus (LCMV) nucleoprotein under the control of the rat insulin promoter express the nucleoprotein in their pancreatic β cells but do not respond to this protein and therefore do not develop an autoimmune diabetes. However, if the transgenic mice are infected with LCMV, a potent antiviral cytotoxic T‑cell response is elicited, and this kills the β cells, leading to diabetes. It is thought that infectious agents can sometimes elicit T‑cell responses that cross‑react with self peptides (a process known as molecular mimicry) and that this could cause autoimmune disease in a similar way.


Immunology_Janeway

Immunology_Janeway. Fig. 15.44 Antibodies against streptococcal cell-wall antigens cross-react with antigens on heart tissue. The immune response to the bacteria produces antibodies against various epitopes of the bacterial cell surface. Some of these antibodies (yellow) cross‑react with the heart valves, whereas others (blue) do not. An epitope in the heart (orange) is structurally similar, but not identical, to a bacterial epitope (red).


Immunology_Janeway

Immunology_Janeway. caused by Streptococcus pyogenes. The similarity of epitopes on streptococcal antigens to self epitopes leads to antibody-mediated, and possibly T-cellmediated, damage to a variety of tissues, including heart valves and the kidney. Although the tissue injury is typically transient, especially with antibiotic treatment, it can become chronic. Similarly, Lyme disease, an infection with the spirochete Borrelia burgdorferi, can be followed by late-developing autoimmunity (Lyme arthritis). In this case, the mechanism is not entirely clear, but it is likely to involve cross-reactivity of pathogen and host components, leading to autoimmunity. 15-27 Drugs and toxins can cause autoimmune syndromes.


Immunology_Janeway

Immunology_Janeway. Perhaps the clearest evidence of external causative agents in human autoimmunity comes from the effects of certain drugs, which elicit autoimmune reactions in a small proportion of patients. Procainamide, a drug used to treat heart arrhythmias, is notable for inducing autoantibodies similar to those in SLE, although these are rarely pathogenic. Several drugs are associated with the development of autoimmune hemolytic anemia, in which autoantibodies against surface components of red blood cells attack and destroy these cells (see Section 15-13). Toxins in the environment can also cause autoimmunity. When heavy metals, such as gold or mercury, are administered to susceptible strains of mice, a predictable autoimmune syndrome, including the production of autoantibodies, ensues. The extent to which heavy metals promote autoimmunity in humans is debatable, but the animal models show that environmental factors such as toxins could have roles in certain syndromes.


Immunology_Janeway

Immunology_Janeway. The mechanisms by which drugs and toxins cause autoimmunity are uncertain. For some drugs it is thought that they react chemically with self proteins and form derivatives that the immune system recognizes as foreign. The immune response to these haptenated self proteins can lead to inflammation, complement deposition, destruction of tissue, and finally immune responses to the original self proteins. 15-28 Random events may be required for the initiation of autoimmunity.


Immunology_Janeway

Immunology_Janeway. 15-28 Random events may be required for the initiation of autoimmunity. Although scientists and physicians would like to attribute the onset of ‘spontaneous’ diseases to some specific cause, this may not always be possible. There might not be one virus or bacterium, or even any understandable pattern of events that precedes the onset of autoimmune disease. The chance encounter in the peripheral lymphoid tissues of a few autoreactive B and T cells that can interact with each other, at just the moment when an infection is providing pro-inflammatory signals, may be all that is needed. This could be a rare event, but in a susceptible individual such events could be more frequent and/or more difficult to control.


Immunology_Janeway

Immunology_Janeway. Thus, the onset or incidence of autoimmunity can seem to be random. Genetic predisposition represents, in part, an increased chance of occurrence of this random event. This view, in turn, could explain why many autoimmune diseases appear in early adulthood or later, after enough time has elapsed to permit low-frequency events to occur. It may also explain why, after certain kinds of aggressive therapies, the disease eventually recurs after a long interval of remission. Summary.


Immunology_Janeway

Immunology_Janeway. The specific causes of most autoimmune diseases are not known. Genetic risk factors, including particular alleles of MHC class II molecules and polymorphisms or mutations of other genes, have been identified, but many individuals with genetic variants that predispose to a particular autoimmune disease do not get the disease. Epidemiological studies of genetically identical populations of animals have highlighted the role of environmental factors in the initiation of autoimmunity, but although environmental factors have a strong influence on disease, they are not well understood. Some toxins and drugs are known to cause autoimmunity, but their role in the common autoimmune diseases is unclear. Similarly, some autoimmune syndromes can follow viral or bacterial infections. Pathogens can promote autoimmunity by causing nonspecific inflammation and tissue damage, and can sometimes elicit responses to self proteins if they express molecules resembling self, a phenomenon known as molecular


Immunology_Janeway

Immunology_Janeway. autoimmunity by causing nonspecific inflammation and tissue damage, and can sometimes elicit responses to self proteins if they express molecules resembling self, a phenomenon known as molecular mimicry. More research is needed to define specific contributions of environmental factors to autoimmune diseases. It may prove that for most diseases no single environmental trigger that induces disease will be found, but rather a combination of triggers, or even stochastic, or chance, events, will have important roles.


Immunology_Janeway

Immunology_Janeway. Responses to alloantigens and transplant rejection.


Immunology_Janeway

Immunology_Janeway. Although transplantation of tissues to replace diseased organs has emerged as an important medical therapy, adaptive immune responses to the grafted tissues are a major impediment. Rejection is caused by immune responses to alloantigens on the graft, which are proteins that vary from individual to individual within a species and are therefore perceived as foreign by the recipient. When tissues containing nucleated cells are transplanted, T-cell responses to the highly polymorphic MHC molecules almost always trigger a response against the grafted organ. Matching the MHC type of the donor and the recipient increases the success rate of grafts, but perfect matching is possible only when donor and recipient are related, and even in these cases, genetic differences at other loci can still trigger rejection, although less severely. Nevertheless, advances in immunosuppression and transplantation medicine now mean that the precise matching of tissues for transplantation is no longer the major


Immunology_Janeway

Immunology_Janeway. rejection, although less severely. Nevertheless, advances in immunosuppression and transplantation medicine now mean that the precise matching of tissues for transplantation is no longer the major factor in graft survival. In blood transfusion, the earliest and most common tissue transplant, MHC matching is not necessary for routine transfusions, because red blood cells and platelets express small amounts of MHC class I molecules and do not express MHC class II molecules; thus, they are not usually T-cell targets. However, antibodies made against platelet MHC class I molecules can be a problem when repeated transfusions of platelets are required. Blood must be matched for ABO and Rh blood group antigens to avoid the rapid destruction of mismatched red blood cells by antibodies in the recipient (see Appendix I, Sections A-5 and A-7), but because there are only four major ABO types and two Rh types, this is a relatively easy form of tissue matching.


Immunology_Janeway

Immunology_Janeway. In this part of the chapter we examine the immune response to tissue grafts and also ask why such responses do not reject the one foreign tissue graft that is tolerated routinely—the mammalian fetus. 15-29 Graft rejection is an immunological response mediated primarily by T cells. The basic rules of tissue grafting were first elucidated by skin transplantation between inbred strains of mice. Skin can be grafted with 100% success between different sites on the same animal or person (an autograft), or between genetically identical animals or people (a syngeneic graft). However, when skin is grafted between unrelated or allogeneic individuals (an allograft), the graft initially survives but is then rejected about 10–13 days after grafting


Immunology_Janeway

Immunology_Janeway. Fig. 15.45 Skin graft rejection is the result of a T-cell-mediated a second‑set rejection, and the accelerated response is MHC‑anti-graft response. Grafts that are syngeneic are permanently specific; skin from a second donor of the same MHC type is rejected accepted (first panels), but grafts differing at the MHC are rejected equally fast, whereas skin from an MHC‑different donor is rejected about 10–13 days after grafting (first‑set rejection, second panels). in a first‑set pattern (not shown). Naive mice that are given T cells When a mouse is grafted for a second time with skin from the same from a sensitized donor behave as if they had already been grafted donor, it rejects the second graft faster (third panels). This is called (final panels).


Immunology_Janeway

Immunology_Janeway. (Fig. 15.45). This response is called an acute rejection, and it depends on a T-cell response, because skin grafted onto nude mice, which lack T cells, is not rejected. The ability to reject skin can be restored to nude mice by the adoptive transfer of normal T cells. When a recipient that has previously rejected a graft is regrafted with skin from the same donor, the second graft is rejected more rapidly (6–8 days) in an accelerated rejection (see Fig. 15.45). Skin from a third-party donor grafted onto the same recipient at the same time does not show this faster response but follows a first-set rejection course. The rapid course of second-set rejection can also be transferred to new recipients by T cells from the initial recipient, showing that second-set rejection is caused by a memory-type response (see Chapter 11) from clonally expanded and primed T cells specific for the donor skin.


Immunology_Janeway

Immunology_Janeway. Immune responses are the major barrier to effective tissue transplantation, destroying grafted tissue by an adaptive immune response to its foreign proteins. These responses can be mediated by either CD8 or CD4 T cells, or both. Antibodies can also contribute to second-set rejection of tissue grafts. 15-30 Transplant rejection is caused primarily by the strong immune response to nonself MHC molecules.


Immunology_Janeway

Immunology_Janeway. 15-30 Transplant rejection is caused primarily by the strong immune response to nonself MHC molecules. Antigens that differ between members of the same species are known as alloantigens, and an immune response against such antigens is known as an alloreactive response. When donor and recipient differ at the MHC, an alloreactive immune response is directed at the nonself allogeneic MHC molecule or molecules on the graft. In most tissues these are predominantly MHC class I antigens. Once a recipient has rejected a graft of a particular MHC type, any further graft bearing the same nonself MHC will be rapidly rejected in a second response. The frequency of T cells specific for any nonself MHC molecule is relatively high, making differences at MHC loci the most potent trigger of initial graft rejections (see Section 6-13); indeed, the MHC was originally so named because of its central role in graft rejection.


Immunology_Janeway

Immunology_Janeway. Once it became clear that recognition of nonself MHC molecules was a major determinant of graft rejection, a considerable amount of effort was put into MHC matching of recipient and donor. Today, with advances in immunosuppression, MHC matching has become largely irrelevant for most allografts, although it remains important for bone marrow transplantation, for reasons that are discussed in Section 15-36. Even a perfect match at the MHC locus, known as the HLA locus in humans, does not prevent rejection reactions. Grafts between HLA-identical siblings will invariably incite a rejection reaction, albeit more slowly than an unmatched graft, unless donor and recipient are identical twins. This reaction is the result of differences between antigens from non-MHC proteins that also vary between individuals.


Immunology_Janeway

Immunology_Janeway. Thus, unless donor and recipient are identical twins, all graft recipients must be given immunosuppressive drugs chronically to prevent rejection. Indeed, the current success of clinical transplantation of solid organs is more the result of advances in immunosuppressive therapy (see Chapter 16) than of improved tissue matching. The limited supply of cadaveric organs, coupled with the urgency of identifying a recipient once a donor organ becomes available, means that accurate matching of tissue types is achieved only rarely, with the notable exception of matched-sibling donation of kidneys. 15-31 In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules.


Immunology_Janeway

Immunology_Janeway. 15-31 In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules. When donor and recipient are identical at the MHC but differ at other genetic loci, graft rejection is not as rapid, but left unchecked it will still destroy the graft (Fig. 15.46). This is the reason that grafts between HLA-identical siblings would be rejected without immunosuppressive treatment. MHC class I and II molecules bind and present a large selection of peptides derived from self proteins made in the cell, and if these proteins are polymorphic, then different peptides will be produced from them in different members of a species. Such proteins can also be recognized as minor histocompatibility antigens


Immunology_Janeway

Immunology_Janeway. Fig. 15.46 Even complete matching at the MHC does not ensure graft survival. Although syngeneic grafts are not rejected (left panels), MHC‑identical grafts from donors that differ at other loci (minor H antigen loci) are rejected (right panels), albeit more slowly than MHC‑disparate grafts (center panels). Percentage 100 of grafts surviving


Immunology_Janeway

Immunology_Janeway. Percentage 100 of grafts surviving Fig. 15.47 Minor H antigens are peptides derived from polymorphic cellular proteins bound to MHC class I molecules. Self proteins are routinely digested by proteasomes within the cell’s cytosol, and peptides derived from them are delivered to the endoplasmic reticulum, where they can bind to MHC class I molecules and be delivered to the cell surface. If a polymorphic protein differs between the graft donor (shown in red on the left) and the recipient (shown in blue on the right), it can give rise to an antigenic peptide (red on the donor cell) that can be recognized by the recipient’s T cells as nonself and elicit an immune response. Such antigens are the minor H antigens.


Immunology_Janeway

Immunology_Janeway. (Fig. 15.47). One set of proteins that induce minor histocompatibility responses are encoded on the male Y chromosome. Responses induced by these proteins are known collectively as H-Y. As Y chromosome-specific genes are not expressed in females, female anti-male responses occur; however, male anti-female responses do not occur, because both sexes express X-chromosome genes. One H-Y antigen has been identified in mice and humans as peptides from a protein encoded by the gene Smcy. An X-chromosome homolog of Smcy (or Kdm5d), called Smcx (or Kdm5c), does not contain these peptide sequences, which are therefore expressed uniquely in males. Most minor histocompatibility antigens are encoded by autosomal genes and their identity is largely unknown, although an increasing number have now been identified at the genetic level.


Immunology_Janeway

Immunology_Janeway. The response to minor histocompatibility antigens is in many ways analogous to the response to viral infection. However, whereas an antiviral response eliminates only infected cells, a large fraction of cells in the graft express minor histocompatibility antigens, and thus the graft is destroyed in the response against these antigens. Given the virtual certainty of mismatches in minor histocompatibility antigens between two individuals, and the potency of the reactions they incite, it is understandable that successful transplantation requires the use of powerful immunosuppressive drugs. 15-32 There are two ways of presenting alloantigens on the transplanted donor organ to the recipient’s T lymphocytes.


Immunology_Janeway

Immunology_Janeway. 15-32 There are two ways of presenting alloantigens on the transplanted donor organ to the recipient’s T lymphocytes. Before naive alloreactive T cells can develop into effector T cells that cause rejection, they must be activated by antigen-presenting cells that express both the allogeneic MHC and co-stimulatory molecules. Organ grafts carry with them antigen-presenting cells of donor origin, sometimes called passenger leukocytes, and these are an important stimulus to alloreactivity. This route for sensitization of the recipient to a graft seems to involve donor antigen-presenting cells leaving the graft and migrating to secondary lymphoid tissues of the recipient, including the spleen and lymph nodes, where they can activate those host T cells that bear the corresponding T-cell receptors. Because the lymphatic drainage of solid organ allografts is interrupted by transplantation, migration of donor antigen-presenting cells occurs via the


Immunology_Janeway

Immunology_Janeway. Fig. 15.48 Acute rejection of a kidney graft through the direct pathway of allorecognition. Donor dendritic cells in the graft (in this case a kidney) carry complexes of donor HLA molecules and donor peptides on their surfaces. The dendritic cells are carried via the blood to secondary lymphoid organs (a lymph node is illustrated here), where they move to the T‑cell areas. Here, they activate the recipient’s T lymphocytes, whose receptors can bind specifically to the complexes of allogeneic donor HLA (both class I and class II) in combination with donor peptides. After activation, the effector T cells travel in the blood to the grafted organ, where they attack cells that display the peptide:HLA molecule complexes for which the T cells are specific.


Immunology_Janeway

Immunology_Janeway. blood, not lymphatics. The activated alloreactive effector T cells can then circulate to the graft, which they attack directly (Fig. 15.48). This recognition pathway is known as direct allorecognition (Fig. 15.49, upper panel). Indeed, if the grafted tissue is depleted of antigen-presenting cells by treatment with antibodies or by prolonged incubation, rejection occurs only after a much longer time. A second mechanism of allograft recognition leading to graft rejection is the uptake of allogeneic proteins by the recipient’s own antigen-presenting cells and their presentation to T cells by self MHC molecules. This is known as indirect allorecognition (see Fig. 15.49, lower panel). Peptides derived from both the foreign MHC molecules themselves and minor histocompatibility antigens can be presented by indirect allorecognition.


Immunology_Janeway

Immunology_Janeway. Direct allorecognition is thought to be largely responsible for acute rejection, especially when MHC mismatches mean that the frequency of directly alloreactive recipient T cells is high. Furthermore, a direct cytotoxic T-cell attack on graft cells can be made only by T cells that recognize the graft MHC molecules directly. Nonetheless, T cells with specificity for alloantigens presented on self MHC can contribute to graft rejection by activating macrophages, which cause tissue injury and fibrosis. T cells with indirect allospecificity are also likely to be important in the development of an antibody response to a graft. Antibodies produced against nonself antigens from the same species are known as alloantibodies.


Immunology_Janeway

Immunology_Janeway. Fig. 15.49 Direct and indirect pathways of allorecognition contribute to graft rejection. Dendritic cells from an organ graft stimulate both the direct and indirect pathways of allorecognition when they travel from the graft to secondary lymphoid tissues. The upper panel shows how the allogeneic HLA class I and II allotypes of donor type on a donor dendritic cell (donor DC) will interact directly with the T‑cell receptors of alloreactive CD4 and CD8 T cells of the recipient (direct allorecognition). The lower panel shows how the death of the same antigen‑presenting cell produces membrane vesicles containing the allogeneic HLA class I and II allotypes, which are then endocytosed by the recipient’s dendritic cells (recipient DC). Peptides derived from the donor’s HLA molecules (yellow) can then be presented by the recipient’s HLA molecules (orange) to peptide‑specific T cells (indirect allorecognition). Presentation by HLA class II molecules to CD4 T cells is shown here. Peptides


Immunology_Janeway

Immunology_Janeway. can then be presented by the recipient’s HLA molecules (orange) to peptide‑specific T cells (indirect allorecognition). Presentation by HLA class II molecules to CD4 T cells is shown here. Peptides derived from donor HLA can also be presented by recipient HLA class I molecules to CD8 T cells (not shown).


Immunology_Janeway

Immunology_Janeway. Graft failure dead graft Antibodies against donor blood group antigens bind vascular endothelium of graft, initiating an in˜ammatory response that occludes blood vessels Graft becomes engorged and purple-colored because of hemorrhage Fig. 15.50 Preexisting antibody against donor graft antigens can cause hyperacute graft rejection. Prior to transplantation, some recipients have made antibodies that react with donor ABO or HLA class I antigens. When the donor organ is grafted into such a recipient, these antibodies bind to the vascular endothelium in the graft, initiating the complement and clotting cascades. Blood vessels in the graft become obstructed by clots and leak, causing hemorrhage of blood into the graft. The graft becomes engorged, turns purple from the presence of deoxygenated blood, and dies. 15-33 Antibodies that react with endothelium cause hyperacute graft rejection.


Immunology_Janeway

Immunology_Janeway. Antibody responses are an important potential cause of graft rejection. Preexisting alloantibodies against blood group antigens and polymorphic MHC antigens can cause rapid rejection of transplanted organs in a complement-dependent reaction that can occur within minutes of transplantation. This type of reaction is known as hyperacute graft rejection. Most grafts that are transplanted routinely in clinical medicine are vascularized organ grafts linked directly to the recipient’s circulation. In some cases the recipient may have preexisting antibodies against donor graft antigens. Antibodies of the ABO type can bind to all tissues, not just red blood cells. In addition, antibodies against other antigens can be produced in response to a previous transplant or a blood transfusion. All such preexisting antibodies can cause rapid rejection of vascularized grafts because they react with antigens on the vascular endothelial cells of the graft and initiate the complement and blood clotting


Immunology_Janeway

Immunology_Janeway. preexisting antibodies can cause rapid rejection of vascularized grafts because they react with antigens on the vascular endothelial cells of the graft and initiate the complement and blood clotting cascades. The vessels of the graft become blocked, or thrombosed, causing its rapid destruction. Such grafts become engorged and purple-colored from hemorrhaged blood, which becomes deoxygenated (Fig. 15.50). This problem can be avoided by ABO-matching as well as cross-matching donor and recipient. Cross-matching involves determining whether the recipient has antibodies that react with the white blood cells of the donor. Antibodies of this type, when found, have hitherto been considered a serious contraindication to transplantation of most solid organs, because in the absence of any treatment they lead to near-certain hyperacute rejection.


Immunology_Janeway

Immunology_Janeway. For reasons that are incompletely understood, some transplanted organs, particularly the liver, are less susceptible to this type of injury, and can be transplanted despite ABO incompatibilities. In addition, the presence of donor-specific MHC alloantibodies and a positive cross-match are no longer considered an absolute contraindication for transplantation, as treatment with intravenous immunoglobulin has been successful in a proportion of patients in whom antibodies against the donor tissue were already present.


Immunology_Janeway

Immunology_Janeway. A similar problem prevents routine use of animal organs—xenografts—in transplantation. If xenografts could be used, it would circumvent a limitation in organ replacement therapy: the shortage of donor organs. Pigs have been suggested as a source of organs for xenografting, but most humans have antibodies that react with a ubiquitous cell-surface carbohydrate antigen (α-Gal) of other mammalian species, including pigs. When pig xenografts are placed in humans, these antibodies trigger hyperacute rejection by binding graft endothelial cells and initiating complement and clotting cascades. The problem of hyperacute rejection is exacerbated in xenografts because complement-regulatory proteins such as CD59, DAF (CD55), and MCP (CD46) (see Section 2-16) work less efficiently across a species barrier. A recent step toward xenotransplantation has been the development of transgenic pigs expressing human DAF as well as pigs that lack α-Gal. These approaches might one day reduce or eliminate


Immunology_Janeway

Immunology_Janeway. barrier. A recent step toward xenotransplantation has been the development of transgenic pigs expressing human DAF as well as pigs that lack α-Gal. These approaches might one day reduce or eliminate hyperacute rejection in xenotransplantation.


Immunology_Janeway

Immunology_Janeway. 15-34 Late failure of transplanted organs is caused by chronic injury to the graft. The success of immunosuppression means that about 90% of cadaveric kidney grafts are still functioning a year after transplantation. There has, however, been little improvement in rates of long-term graft survival: the half-life for functional survival of renal allografts remains about 8 years. Although traditionally the late failure of a transplanted organ has been termed chronic rejection, it is typically difficult to determine whether the cause of chronic allograft injury involves specific immune alloreactivity, nonimmune injury, or both.


Immunology_Janeway

Immunology_Janeway. The pattern of chronic injury to transplanted organs is variable, depending on the tissue. A major component of late failure of vascularized transplanted organs is a chronic reaction called chronic allograft vasculopathy, which is a prominent cause of injury in heart and kidney allografts. This is charac-terized by concentric arteriosclerosis of graft blood vessels, which leads to hypoperfusion of the graft and its eventual fibrosis and atrophy (Fig. 15.51). Multiple mechanisms may contribute to this form of vascular injury, although the major cause is thought to be recurring, subclinical acute rejection events, whether due to the development of allospecific antibodies reactive to the vascular endothelium of the graft (so-called donor-specific antibodies), or to allograft-reactive effector T cells, or both. Some forms of immunosuppressive therapy (for example, calcineurin inhibitors such as cyclosporin) also cause vascular injury, although this is typically more limited to very small


Immunology_Janeway

Immunology_Janeway. T cells, or both. Some forms of immunosuppressive therapy (for example, calcineurin inhibitors such as cyclosporin) also cause vascular injury, although this is typically more limited to very small arteries and causes a different pattern of injury, referred to as arteriolar hyalinosis, that is marked by proteinaceous deposits that narrow the vascular lumen. In transplanted livers, chronic rejection is associated with loss of bile ducts, the so-called ‘vanishing bile duct syndrome,’ whereas in transplanted lungs, the major cause of late organ failure is accumulation of scar tissue in the bron-chioles, termed bronchiolitis obliterans. Alloreactive responses can occur months to years after transplantation, and may be associated with gradual loss of graft function that is hard to detect clinically. Other important causes of chronic graft dysfunction include: ischemia– reperfusion injury, which can promote sterile inflammatory signals at the time of grafting due to the restoration of blood


Immunology_Janeway

Immunology_Janeway. Other important causes of chronic graft dysfunction include: ischemia– reperfusion injury, which can promote sterile inflammatory signals at the time of grafting due to the restoration of blood flow after a period of poor perfusion of the organ to be transplanted; viral infections that emerge as a result of immunosuppression; and recurrence of the same disease in the allograft that destroyed the original organ. Irrespective of etiology, chronic allograft injury is typically irreversible and progressive, ultimately leading to complete failure of allograft function. 15-35 A variety of organs are transplanted routinely in clinical medicine. Three major advances have made it possible to use organ transplantation rou-tinely in the clinic. First, surgical techniques for performing organ replace-ment have advanced to the point where such surgeries are now relatively routine in most major medical centers. Second, networks of transplantation centers have been organized to procure healthy


Immunology_Janeway

Immunology_Janeway. have advanced to the point where such surgeries are now relatively routine in most major medical centers. Second, networks of transplantation centers have been organized to procure healthy organs that become available from cadaveric donors. Third, the use of powerful immunosuppressive drugs Endothelial injury enables immune effectors to enter the wall of the artery and to in˜ict increasing damage


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Immunology_Janeway. Fig. 15.51 Chronic rejection in the blood vessels of a transplanted kidney. Left‑hand panel: chronic rejection is initiated by the interaction of anti‑HLA class I alloantibodies with blood vessels of the transplanted organ. Antibodies bound to endothelial cells recruit Fc receptor‑bearing monocytes and neutrophils. Right‑hand panel: accumulating damage leads to thickening of the internal elastic lamina and to infiltration of the underlying intima with smooth muscle cells, macrophages, granulocytes, alloreactive T cells, and antibodies. The net effect is to narrow the lumen of the blood vessel and create a chronic inflammation that intensifies tissue remodeling. Eventually the vessel becomes obstructed, ischemic, and fibrotic.


Immunology_Janeway

Immunology_Janeway. Rabbit anti‑thymoglobulin and anti‑CD52 monoclonal antibody (alemtuzumab) are used to deplete T cells and other leukocytes before transplantation. Anti‑CD3 monoclonal antibody prevents the generation of signaling by the T‑cell receptor complex, whereas cyclosporin and tacrolimus interfere with the translocation of nuclear factor of activated T cells (NFAT) to the nucleus by inhibiting calcineurin. The CTLA‑4–Fc fusion protein belatacept binds B7 and prevents the generation of co‑stimulation via CD28. Basiliximab, an anti‑CD25 antibody, binds to the high‑affinity IL‑2 receptor on partially activated T cells and prevents IL‑2 signaling. Sirolimus interferes with activation of the mTOR cascade, which is required for differentiation of effector T cells. Azathioprine and mycophenolate inhibit the replication and proliferation of activated T cells.


Immunology_Janeway

Immunology_Janeway. that inhibit T-cell activation, thereby limiting the development of anti-allograft effector T cells and antibodies, has markedly increased graft survival rates (Fig. 15.52). The different organs or tissues that are frequently transplanted and allograft survival rates are listed in Fig. 15.53. The most frequently transplanted solid organ is the kidney, the organ first successfully transplanted between identical twins in the 1950s. Transplantation of the cornea is even more frequent; this tissue is a special case because it is not vascularized, and corneal grafts between unrelated people are usually successful without immunosuppression.


Immunology_Janeway

Immunology_Janeway. Many problems other than graft rejection are associated with organ transplantation. First, donor organs are difficult to obtain. Second, the disease that destroyed the transplant recipient’s organ might also destroy the graft, as in the destruction of pancreatic β cells in autoimmune diabetes. Third, the immunosuppression required to prevent graft rejection increases the risk of cancer and infection. The problems most amenable to scientific solution are the development of more effective means of immunosuppression that prevent rejection with minimal impairment of more generalized immunity, the induction of graft-specific tolerance, and the development of xenografts as a practical solution to organ availability.


Immunology_Janeway

Immunology_Janeway. The numbers of organ and tissue grafts performed in the United States in 2014 are shown. HSC, hematopoietic stem cells (includes bone marrow, peripheral blood HSCs, and cord blood transplants). *Number of grafts includes multiple organ grafts (for example, kidney and pancreas, or heart and lung). For solid organs, 5‑year survival of the transplanted graft is based on transplants performed between 2002 and 2007. Data from the United Network for Organ Sharing. #Kidney survival listed (81.4%) is for kidneys from living donors; 5‑year survival for cadaveric donor transplants is 69.1%. †Pancreas survival listed (53.4%) is when transplanted alone; 5‑year survival when transplanted with a kidney is 73.5%. ** Includes autologous and allogeneic transplants. ‡Successful HSC engraftment is assessed within weeks of transplant, not years. Nearly all solid organ grafts (e.g., kidney, heart) require long‑term immunosuppression. 15-36 The converse of graft rejection is graft-versus-host disease.


Immunology_Janeway

Immunology_Janeway. 15-36 The converse of graft rejection is graft-versus-host disease. Transplantation of hematopoietic stem cells (HSCs) from peripheral blood, bone marrow, or fetal cord blood is a successful therapy for some tumors derived from hematopoietic cells, such as certain leukemias and lymphomas. By replacing genetically defective stem cells with normal donor ones, HSC transplantation can also be used to cure some primary immunodeficiencies (see Chapter 13) and other inherited blood cell disorders, such as severe forms of thalassemia. In leukemia therapy, the recipient’s bone marrow, the source of the leukemia, must first be destroyed by a combination of irradiation and aggressive cytotoxic chemotherapy.


Immunology_Janeway

Immunology_Janeway. One of the major complications of allogeneic HSC transplantation is graftversus-host disease (GVHD), in which mature donor T cells present in preparations of HSCs recognize the tissues of the recipient as foreign, causing a severe inflammatory disease in multiple tissues, but particularly involving the skin, intestines, and liver and characterized by rashes, diarrhea, and liver dysfunction (Fig. 15.54). Because the consequences of GVHD are particularly aggressive when there is mismatch of MHC class I or class II antigens, HLA matching between donor and recipient is more critical than in solid organ transplantation. Most transplants are therefore undertaken only when the donor and recipient are HLA-matched siblings or, less frequently, when there is an HLA-matched unrelated donor. Therefore, GVHD mostly occurs in the context of disparities between minor histocompatibility antigens, so immunosuppression must be used in every HSC transplant.


Immunology_Janeway

Immunology_Janeway. The presence of alloreactive donor T cells can be demonstrated experimentally by the mixed lymphocyte reaction (MLR), in which lymphocytes from a potential donor are mixed with irradiated lymphocytes from the recipient. If the donor lymphocytes contain naive T cells that recognize alloantigens on the recipient lymphocytes, they will proliferate or kill the recipient target cells (Fig. 15.55). However, the limitation of the MLR in the selection of HSC donors is that the test does not accurately quantify alloreactive T cells. A more accurate test is a version of the limiting-dilution assay (see Appendix I, Section A-21), which precisely counts the frequency of alloreactive T cells. Effector CD4 and CD8 T cells enter host tissues and cause injury T cells circulate in blood to secondary lymphoid tissues. Alloreactive cells interact with dendritic cells and proliferate efferentlymphskinlymphnodebloodvesselAllogeneic hematopoietic cell transplant contains mature and memory T cells


Immunology_Janeway

Immunology_Janeway. Fig. 15.54 Graft-versus-host disease is due to donor T cells in the graft that attack the recipient’s tissues. After bone marrow transplantation, any mature donor CD4 and CD8 T cells present in the graft that are specific for the recipient’s HLA allotypes become activated in secondary lymphoid tissues. Effector CD4 and CD8 T cells move into the circulation and preferentially enter and attack tissues of the graft recipient, particularly epithelial cells of the skin, intestines, and liver that have been damaged by the conditioning regimen of chemotherapy and irradiation prior to transplantation.


Immunology_Janeway

Immunology_Janeway. Fig. 15.55 The mixed lymphocyte reaction (MLR) can be used to detect histoincompatibility. Peripheral blood mononuclear cells, which include lymphocytes and monocytes, are isolated from the two individuals to be tested. The cells from the person who serves as the stimulator (yellow) are first irradiated to prevent their proliferation. Then they are mixed with the cells from the other person, who serves as the responder (blue), and cultured for 5 days (top panel). In the culture, responder lymphocytes are stimulated by allogeneic HLA class I and II molecules expressed by the stimulator’s monocytes and the dendritic cells that differentiate from the monocytes. The stimulated lymphocytes proliferate and differentiate into effector cells. Five days after mixing, the culture is assessed for T‑cell proliferation (bottom left panel), which is due to CD4 T cells recognizing HLA class II differences, and for cytotoxic T cells (bottom right panel) produced in response to HLA class I


Immunology_Janeway

Immunology_Janeway. for T‑cell proliferation (bottom left panel), which is due to CD4 T cells recognizing HLA class II differences, and for cytotoxic T cells (bottom right panel) produced in response to HLA class I differences. The mixed lymphocyte reaction is instrumental in distinguishing MHC class II from MHC class I.


Immunology_Janeway

Immunology_Janeway. Although GVHD is harmful to the recipient of an HSC transplant, it can have beneficial effects that are crucial to the success of the therapy. Much of the therapeutic effect of HSC transplantation for leukemia can be due to a graft-versus-leukemia effect, in which the donor T cells in the allogeneic preparations of HSCs recognize minor histocompatibility antigens expressed by the leukemic cells and kill the leukemic cells. One of the treatment options for suppressing the development of GVHD is the elimination of mature T cells from the preparations of donor HSCs in vitro before transplantation, thereby removing alloreactive T cells. Those T cells that subsequently mature from the donor marrow in vivo in the recipient are tolerant to the recipient’s antigens. Although the elimination of GVHD has benefits for the patient, there is an increased risk of leukemic relapse, which provides strong evidence in support of the graft-versus-leukemia effect.


Immunology_Janeway

Immunology_Janeway. Immunodeficiency is another complication of donor T-cell depletion. Because most of the recipient’s T cells are destroyed by the combination of chemotherapy and irradiation used to treat the recipient before transplant, donor T cells are the major source for reconstituting a mature T-cell repertoire early after transplant. This is particularly true in adults, who have poor residual thymic function and therefore a limited ability to repopulate their T-cell repertoire from T-cell precursors. Thus, if too many T cells are depleted from the graft, transplant recipients experience, and can die from, opportunistic infections. The need to balance the beneficial effects of the graft-versus-leukemia effect and immunocompetence with the adverse effects of GVHD caused by donor T cells has spawned much research. One particularly promising approach is to prevent donor T cells from reacting with recipient antigens that they could meet shortly after the transplant. This is accomplished by depleting


Immunology_Janeway

Immunology_Janeway. research. One particularly promising approach is to prevent donor T cells from reacting with recipient antigens that they could meet shortly after the transplant. This is accomplished by depleting the recipient’s antigen-presenting cells. Here, the donor T cells are not activated during the initial inflammation that accompanies the transplant, and thereafter they do not promote GVHD. However, it is unclear whether there would be a graft-versus-leukemia effect in this context.


Immunology_Janeway

Immunology_Janeway. 15-37 Regulatory T cells are involved in alloreactive immune responses.


Immunology_Janeway

Immunology_Janeway. As in all immune responses, regulatory T cells are thought to have an important immunoregulatory role in the alloreactive immune responses involved in graft rejection. Experiments on the transplantation of allogeneic HSCs in mice have thrown some light on this question. Here, depletion of CD25+ Treg cells in either the recipient or the HSC graft before transplantation accelerated the onset of GVHD and subsequent death. In contrast, supplementing the graft with either fresh or ex vivo expanded Treg cells delayed, or even prevented, death from GVHD, with similar results in early human studies. Also, treatment with a low dose of IL-2, which is thought to preferentially expand Treg cells, has shown positive effects in preventing GVHD. Similar observations have been made in experimental mouse models of solid organ transplantation, where the transfer of either naturally occurring or induced Treg cells significantly delayed allograft rejection. These experiments suggest that enriching or


Immunology_Janeway

Immunology_Janeway. models of solid organ transplantation, where the transfer of either naturally occurring or induced Treg cells significantly delayed allograft rejection. These experiments suggest that enriching or generating Treg cells in preparations of donor HSCs might provide a possible therapy for GVHD in the future.


Immunology_Janeway

Immunology_Janeway. Another class of regulatory T cells, CD8+CD28– T cells, have an anergic phenotype and are thought to maintain T-cell tolerance indirectly by inhibiting the capacity of antigen-presenting cells to activate CD4+ T cells. These cells have been isolated from transplant patients, and can be distinguished from alloreactive CD8 T cells because they do not display cytotoxic activity against donor cells and express high levels of the inhibitory killer receptor CD94 (see Section 3-25). This suggests that CD8+CD28– T cells interfere with the activation of antigen-presenting cells and have a role in the maintenance of transplant tolerance. 15-38 The fetus is an allograft that is tolerated repeatedly.


Immunology_Janeway

Immunology_Janeway. 15-38 The fetus is an allograft that is tolerated repeatedly. All of the transplants discussed so far are the result of advances in modern medicine. However, one ‘foreign’ tissue that is repeatedly grafted and tolerated is the mammalian fetus. The fetus carries paternal MHC and minor histocompatibility antigens that differ from those of the mother (Fig. 15.56), and yet a mother can successfully bear many children expressing the same nonself proteins derived from the father. The mysterious lack of fetal rejection has consistently puzzled immunologists, and no comprehensive explanation has yet emerged. One problem is that acceptance of the fetal allograft is so much the norm that it is difficult to study the mechanism that prevents rejection; if the mechanism for rejecting the fetus is rarely activated, how can one analyze the mechanisms that control it?


Immunology_Janeway

Immunology_Janeway. The mechanisms contributing to ‘fetomaternal tolerance’ are likely multifactorial and redundant. Although it has been proposed that the fetus is simply not recognized as foreign, women who have borne children often make antibodies directed against the father’s MHC and red blood cell antigens. However, the placenta, which is a fetus-derived tissue, seems to sequester the fetus from the mother’s T cells. The outer layer of the placenta—the interface between fetal and maternal tissues—is the trophoblast. This does not express MHC class II molecules, and expresses only low levels and a restricted subset of MHC class I molecules, making it resistant to direct alloantigen recognition by maternal T cells. Tissues lacking MHC class I expression are, however, vulnerable to attack by NK cells (see Section 3-25). The trophoblast might be protected from attack by NK cells by the expression of a nonclassical and minimally polymorphic HLA class I molecule, HLA-G, which has been shown to inhibit NK


Immunology_Janeway

Immunology_Janeway. Section 3-25). The trophoblast might be protected from attack by NK cells by the expression of a nonclassical and minimally polymorphic HLA class I molecule, HLA-G, which has been shown to inhibit NK killing.


Immunology_Janeway

Immunology_Janeway. The placenta may also inhibit the mother’s T cells by an active mechanism of nutrient depletion. The enzyme indoleamine 2,3-dioxygenase (IDO) is expressed at a high level by cells at the maternal–fetal interface. This enzyme depletes the essential amino acid tryptophan at this site, and T cells starved of tryptophan show reduced responsiveness. Inhibition of IDO in pregnant mice, using the inhibitor 1-methyltryptophan, causes rapid rejection of allogeneic, but not syngeneic, fetuses.


Immunology_Janeway

Immunology_Janeway. The cytokine milieu at the maternal–fetal interface also contributes to fetal tolerance. Both the uterine epithelium and the trophoblast secrete TGF-β and IL-10. This combination of cytokines suppresses the development of effector T cells in favor of iTreg cells (see Section 9-23). Regulatory T cells are increased during pregnancy, including iTreg cells in the placenta. These cells are important for suppressing responses to the fetus in mice, as iTreg deficiency promotes fetal resorption—the equivalent of spontaneous abortion in humans—as does induction of TH1-inducing cytokines (for example, IFN-γ and IL-12). Provocatively, a regulatory element that controls FoxP3 expression in iTreg


Immunology_Janeway

Immunology_Janeway. Fig. 15.56 The fetus is an allograft that is not rejected. With very few exceptions, the mother and father in human families have different HLA types (top panel). When the mother becomes pregnant she carries for 9 months a fetus that expresses one HLA haplotype of maternal origin (pink) and one HLA haplotype of paternal origin (blue) (bottom panel). Although the paternal HLA class I and II molecules expressed by the fetus are alloantigens against which the mother’s immune system has the potential to respond, the fetus does not provoke such a response during pregnancy and is protected from preexisting alloreactive antibodies or T cells. Even when the mother bears several children to the same father, no sign of immunological rejection is seen.


Immunology_Janeway

Immunology_Janeway. cells, but is not required for FoxP3 expression by nTreg cells, has been found only in placental mammals. This suggests that iTreg cells might have evolved to play an important role in maternal–fetal tolerance. Finally, stromal cells of the specialized maternal uterine tissue that directly interfaces with the placenta— the decidua—appear to repress the local expression of key T cell-attracting chemokines. Collectively, then, both maternal and fetal factors contribute to the formation of an immunologically privileged site akin to other sites of local immune suppression that allow prolonged acceptance of tissue grafts, such as the eye (see Section 15-5). Summary.


Immunology_Janeway

Immunology_Janeway. Summary. Clinical transplantation is now an everyday reality, its success built on MHC matching, immunosuppressive drugs, and advances in surgical techniques. However, even accurate MHC matching does not prevent graft rejection; other genetic differences between host and donor can result in allogeneic proteins whose peptides are presented by MHC molecules on the grafted tissue, and responses to these can lead to rejection. Because we lack the ability to specifically suppress the response to the graft without compromising host defense, most transplants require generalized immunosuppression of the recipient that can increase the risk of cancer and infection. The fetus is a natural allograft that must be accepted for the species to survive. A better understanding of tolerance to the fetus could ultimately provide insights for inducing specific allograft tolerance in transplantation. Summary to Chapter 15.


Immunology_Janeway

Immunology_Janeway. Ideally, the effector functions of the immune system would be targeted only to foreign pathogens and never to self tissues. In practice, because foreign and self proteins are chemically similar, strict discrimination between self and nonself is impossible. Yet the immune system maintains tolerance to self. This is accomplished by layers of regulation, all of which use surrogate markers to distinguish self from nonself to properly direct the immune response. When these mechanisms break down, autoimmune disease can result. Minor breaches of single regulatory barriers probably occur every day but are quelled by the effects of other regulatory layers; thus, tolerance operates at the level of the overall immune system. For disease to occur, multiple layers of tolerance have to be overcome and the effect needs to be chronic. These layers begin with central tolerance in the bone marrow and thymus, and include peripheral mechanisms such as anergy, cytokine deviation, and regulatory T cells.