In the following section, we will describe the pathogenesis of selected diseases that are caused by antibodies and T cells and novel therapies for these diseases. The goal of this discussion is not to present clinical details but to focus on how diseases illustrate the principles underlying abnormal immune reactions.
Systemic Lupus Erythematosus: The Prototypic Immune Complex-Mediated Disease
Systemic lupus erythematosus (SLE) is a chronic, remitting and relapsing, multisystem autoimmune disease that affects pre dominantly females, with an incidence in the United States of 1 in 700 among females 20 to 60 years of age (about 1 in 250 among Black females) and a female-to-male ratio of 10:1. SLE is considered the classic human immune complex disease. The principal clinical manifestations are rashes, arthritis, and glo merulonephritis, but hemolytic anemia, thrombocytopenia, and neuropsychiatric disorders are also common. Many different autoantibodies are found in patients with SLE. The most frequent are antinuclear, particularly anti-DNA, antibodies; others include antibodies against ribonucleoproteins, histones, and nucleolar antigens. Immune complexes formed from these autoantibodies and their specific antigens deposit in small arteries and capillaries throughout the body and are responsible for glomerulonephritis, arthritis, and vasculitis. Hemolytic anemia and thrombocytopenia are caused by autoantibodies against erythrocytes and platelets, respectively. The principal diagnostic test for the disease is the presence of antinuclear antibodies; antibodies against double-stranded DNA are specific for SLE.
Pathogenesis of Systemic Lupus Erythematosus
In SLE, genetic and environmental factors contribute to a breakdown of tolerance in self-reactive B and T lymphocytes. Among the genetic factors is the inheritance of particular human leukocyte antigen (HLA) alleles. The odds ratio (relative risk) for individuals with HLA-DR2 or HLA-DR3 is 2 to 3, and if both haplotypes are present, the odds ratio is about 5. Genetic deficiencies of classical pathway complement proteins, especially C1q, C2, or C4, are seen in about 5% of patients with SLE. The complement deficiencies may result in defective clearance of immune complexes and apoptotic cells and failure of B-cell tolerance. A polymorphism in the inhibitory Fc receptor FcγRIIB has been described in some patients; this may contribute to inadequate control of B-cell activation or a failure to attenuate inflammatory responses in innate immune cells. Many other genes have been detected by genome-wide association studies, and the roles of some of these, such as the phosphatase PTPN22, have been discussed in Chapter 15. Environmental factors include expo sure to ultraviolet (UV) light, which is postulated to lead to the apoptotic death of skin cells and release of nuclear antigens.
Recent observations have led to new hypotheses of the pathogenesis of SLE. First, studies in patients have revealed that blood cells show a striking molecular signature (pattern of gene expression) that indicates exposure to IFN-α, a type I interferon that is produced mainly by plasmacytoid DCs. Some studies have shown that plasmacytoid DCs from patients with SLE produce large amounts of IFN-α. Second, studies in animal models have shown that Toll-like receptors (TLRs) that recognize DNA and RNA, notably the DNA-recognizing TLR9 and the single-stranded RNA–recognizing TLR7, play a role in the activation of B cells specific for self nuclear antigens, and a gain-of-function variation in TLR7 is associated with SLE in humans. On the basis of these studies, a model for the pathogenesis of SLE has been proposed (Fig. 1). According to this model, UV irradiation and other environmental insults lead to the apoptosis of cells. Inadequate clearance of the nuclei of these cells, in part because of defects in clearance mechanisms such as complement proteins and nucleases such as TREX1, results in a large burden of nuclear antigens. Polymorphisms in various susceptibility genes for lupus lead to a defective ability to maintain self-tolerance in B and T lymphocytes, because of which self-reactive lymphocytes remain functional. Failure of B-cell tolerance may be due to defects in receptor editing or in deletion of immature B cells in the bone marrow or in peripheral tolerance. Self-reactive B cells that are not rendered tolerant are stimulated by the self nuclear antigens, and antibodies are produced against the antigens. Complexes of the antigens and antibodies bind to Fc receptors on DCs and to the antigen receptor on B cells and may be internalized into endosomes. The nucleic acid components engage endosomal TLRs and stimulate B cells to produce more autoantibodies and activate DCs, particularly plasmacytoid DCs, to produce IFN-α, which further enhances the immune response and may cause more apoptosis. The net result is a cycle of antigen release and immune activation that leads to the production of high-affinity autoantibodies.
Fig1. A model for the pathogenesis of systemic lupus erythematosus. In this hypothetical model, various susceptibility genes interfere with the maintenance of self-tolerance and external triggers lead to persistence of nuclear antigens. The result is an antibody response against self-nuclear antigens, which is amplified by the toll-like receptor (TLR)-dependent activation of dendritic cells (DCs) and B cells by nucleic acids, and the production of type 1 interferons. IgG, Immunoglobulin G; UV, ultraviolet.
Immunological Therapies for Systemic Lupus Erythematosus
The recent advances in our understanding of SLE are leading to novel therapeutic attempts, but success has proven elusive. There has been great interest in depleting B-cells by use of an antibody against the B-cell surface protein CD20, but clinical trials using anti-CD20 have had limited success. An antibody that blocks the B-cell growth factor, BAFF (B-cell–activating factor), is now approved for the treatment of SLE but seems to have only modest efficacy. However, depletion of B cells by CAR-T cells that target CD19 has been remarkably effective in some patients, even those with lupus nephritis. An antibody that blocks IFN-α is approved for the treatment of SLE. Additional approaches that are being tried are to combine B-cell depletion with depletion of long-lived plasma cells using proteasome inhibitors. which lead to the accumulation of misfolded proteins and ultimately cell death, and to activate Tregs by treating patients with low-dose IL-2. Other methods to achieve long-term depletion of plasma cells in patients with SLE, including CAR-T cells CD19 has been remarkably effective in some patients, even those with lupus nephritis. An antibody that blocks IFN-α is approved for the treatment of SLE. Additional approaches that are being tried are to combine B-cell depletion with depletion of long-lived plasma cells using proteasome inhibitors. which lead to the accumulation of misfolded proteins and ultimately cell death, and to activate Tregs by treating patients with low-dose IL-2. Other methods to achieve long-term depletion of plasma cells in patients with SLE, including CAR-T cells and bispecific-antibodies specific for a plasma cell surface protein BCMA (B-cell maturation antigen), are in clinical trials.
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an inflammatory disease involving small and large joints of the extremities, including fingers and toes, wrists, shoulders, knees, and ankles. The disease is characterized by inflammation of the synovium associated with destruction of the joint cartilage and bone, with a morphologic picture indicative of a local immune response. Both cell-mediated and humoral immune responses may contribute to development of synovitis. CD4+ Th1 and Th17 cells, activated B lymphocytes, plasma cells, and macrophages, as well as other inflammatory cells, are found in the inflamed synovium, and in severe cases, well-formed lymphoid follicles with germinal centers (so-called tertiary lymphoid structures) may be present. Numerous cytokines, including IL-1, IL-8, TNF, IL-6, IL-17, and IFN-γ, have been detected in the synovial (joint) fluid. Cytokines are thought to recruit leukocytes whose products cause tissue injury and also to activate resident synovial cells to produce proteolytic enzymes, such as collagenase, that mediate destruction of the cartilage, ligaments, and tendons of the joints. Increased osteoclast activity in the joints contributes to the bone destruction in RA, and this may be caused by the production of the TNF family cytokine RANK (receptor activator of nuclear factor κB) ligand by activated T cells. RANK ligand binds to RANK, a member of the TNF receptor family that is expressed on osteoclast precursors, and induces osteoclast differentiation and activation. Systemic complications of RA include vasculitis, presumably caused by immune complexes, and lung injury with fibrosis.
Although much of the emphasis in studies of RA has been on the role of T cells, antibodies may also contribute to the joint destruction. Activated B cells and plasma cells are often present in the synovia of affected joints. Patients frequently have circulating IgM or IgG antibodies that react with the Fc (and rarely Fab) portions of their own IgG molecules. These auto antibodies are called rheumatoid factors, and their presence is used as a diagnostic test for RA. Another type of antibody that has been detected in over half of patients is specific for citrullinated proteins. (The antibodies are called anticitrullinated protein antibodies, or ACPAs, because they are assayed by binding to citrullinated peptides.) These chemically altered antigens are derived from proteins such as vimentin and fibrinogen, among others, that are modified in an inflammatory environment by the enzymatic conversion of arginine residues to citrulline. About 60% to 80% of patients with RA have rheumatoid factor and/or ACPAs and are said to have seropositive RA, which tends to be more severe than nonseropositive RA. Many asymptomatic seropositive individuals have been studied and observed to gradually develop seropositive RA. Both types of antibodies are diagnostic markers and may be involved in the formation of pathogenic immune complexes.
Pathogenesis of Rheumatoid Arthritis
Like other autoimmune diseases, RA is a complex disorder in which genetic and environmental factors contribute to the breakdown of tolerance to self antigens. The specificity of the pathogenic T and B cells remains unclear, although both B and T cells that recognize citrullinated proteins have been identified. Susceptibility to RA is linked to the HLA-DR4 haplotype and to a few other HLA-DR alleles, all of which share a five-residue segment (called the shared epitope) in the peptide-binding groove. Recent genome wide association studies have revealed a large number of genetic polymorphisms associated with RA, including the gene encoding a tyrosine phosphatase, PTPN22.
The identification of ACPAs has led to new ideas about the pathogenesis of RA (Fig.2). Some of the earliest ACPAs tend to be of the IgA isotype, so it is postulated that this dis ease is initiated at mucosal sites, including the respiratory tract. According to one model, environmental insults, such as smoking and some infections, induce the citrullination of self proteins, leading to the creation of new antigenic epitopes. Because these chemically modified epitopes are neoantigens that are not present normally, there may not be tolerance to these antigens. Individuals who have the HLA alleles that are capable of presenting these epitopes may mount T-cell and antibody responses against the proteins. If these modified self proteins are also present in joints, the T cells and antibodies attack the joints. Th17 and perhaps Th1 cells secrete cytokines that recruit leukocytes into the joint and activate synovial cells to produce collagenases and other enzymes. The net result is the progressive destruction of cartilage and bone. The chronic immune responses in the joints may lead to formation of tertiary lymphoid organs in the synovium, and these may maintain and propagate the local immune reaction.
Fig2. A model for the pathogenesis of rheumatoid arthritis. According to this model, citrullinated proteins induced by environmental stimuli elicit T-cell and antibody responses in genetically susceptible individuals. The T cells and antibodies enter joints, respond to the self-proteins, and cause tissue injury mainly by cytokine secretion and perhaps also by antibody-dependent effector mechanisms. Protein modifications other than citrullination may lead to the same result. HLA, Human leukocyte antigen.
Immunological Therapies for Rheumatoid Arthritis
The realization of the roles of cytokines and T cells in the disease has led to remarkable advances in treatment, in which specific molecules have been targeted on the basis of scientific understanding. Chief among these new therapies are antagonists of TNF, which have transformed the course of the disease in many patients from one of progressive and inexorable joint destruction to one of smoldering but manageable chronic inflammation. Various other targeted therapies have been developed in the past 5 to 10 years. The blockade of cytokines other than TNF has been effective, including an antibody that blocks the IL-6 receptor, an IL-1 antagonist, and small molecules that inhibit JAK signaling. Inhibition of T-cell activation has been accomplished by the blockade of B7-CD28 costimulation with CTLA 4-Ig. B-cell depletion with anti-CD20 antibody and B-cell inhibition by small molecule BTK antagonists have also proven to be efficacious, although the mechanisms under lying these effects are not well understood.
Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune disease of the CNS in which autoantibodies and CD4+ T cells of the Th1 and Th17 sub sets react against self myelin antigens, resulting in inflammation with activation of macrophages around nerves in the brain and spinal cord, destruction of the myelin, abnormalities in nerve con duction, and neurologic deficits. It is the most common neurologic disease of young adults. Pathologic examination reveals inflammation in the CNS white matter and demyelination. MS is characterized clinically by weakness, paralysis, and ocular symptoms with exacerbations and remissions; CNS imaging suggests that in patients with active disease, there is frequent new lesion formation.
Pathogenesis of Multiple Sclerosis
Multiple immune mechanisms have been implicated in the destruction of myelin that is the hallmark of MS.
• For many years, largely based on analysis of animal models in which the disease is induced by immunization with myelin proteins with strong adjuvants, it has been believed that MS is primarily a T-cell–mediated disease in which CD4+ T cells (Th1 and Th17) and CD8+ T cells react against myelin antigens and produce cytokines that activate recruited and resident macrophages, which then destroy the myelin sheath. However, it has been recently appreciated that these animal models may overestimate the contribution of T cells and do not accurately mimic the human disease.
• More recent studies, and the results of clinical trials showing the efficacy of B-cell depletion, suggest that B cells are criti cal for disease pathogenesis. The B cells may be playing multiple roles—they produce autoantibodies that react against glialCAM (glial cell adhesion molecule) and other glial proteins; they may present self antigens to T cells; and they may produce inflammatory cytokines. Somatically mutated and clonally expanded B cells that recognize glialCAM have been detected in the cerebrospinal fluid of patients and these auto antibodies may contribute to disease.
• Epidemiological and immunological data supports the contribution of recent Epstein-Barr virus (EBV) infection and cross-reactivity between EBV EBNA1 and some human glial proteins, a phenomenon known as molecular mimicry (see Chapter 15). EBV-activated B cells may also produce increased amounts of autoantibodies against multiple antigens.
• Progressive MS is associated with neurodegeneration, which may be the result of chronic inflammation or intrinsic abnormalities in glial cells, such as mitochondrial and metabolic abnormalities.
The fundamental defect in MS is a failure of self-tolerance, which may be related to the inheritance of susceptibility genes. Identical twins have a 25% to 30% concordance rate for development of MS, whereas nonidentical twins have a 6% concordance rate. These observations implicate genetic factors in the development of the disease but also indicate that genetics contributes only part of the risk. Genetic polymorphisms associated with MS include the HLA locus, with HLA-DRB1∗1501 showing the strongest linkage. Genome-wide association studies and other genomic analyses have revealed over 100 genetic variants that contribute to disease risk; most of these map to genes involved in immune function. One interesting association is with a polymorphism in the noncoding region of the gene for the IL-2 receptor α chain, CD25. This polymorphism may alter the generation and maintenance of effector T cells and/or Tregs. Other studies have suggested that the peripheral maintenance of Tregs is defective in patients with MS, but how much this contributes to a failure of self-tolerance is not known. As in other autoimmune diseases, the disease is propagated by a process known as epitope spreading. Tissue breakdown results in the release of new protein antigens and the expression of previously sequestered epitopes that activate more autoreactive T cells.
Immunological Therapies for Multiple Sclerosis
Immunotherapy for MS has, in the past, relied on approaches whose scientific bases are not well understood. These include administration of β-interferon, which may alter cytokine responses, and treatment with a random polymer of four amino acids, which is postulated to bind to HLA molecules and block antigen presentation. Recently, several new immune modifying therapies based on rational principles have been developed. One is an antibody against the α4 subunit of the α4 β1 integrin, also known as VLA-4 (very late antigen 4). The antibody blocks leukocyte migration into the CNS and has been shown to be beneficial for patients. However, in a small number of patients, this treatment resulted in the reactivation of a latent JC virus infection, causing a severe and sometimes fatal CNS disease. Another recently approved drug to treat MS also interferes with leukocyte migration. The drug, called fingolimod (FTY720), blocks the sphingosine 1-phosphate–mediated pathway of T-cell egress from lymphoid tissues. B-cell depletion with anti-CD20 antibody is beneficial in both the relapsing form of MS as well as in primary progressive MS. As discussed earlier, these results suggest an important role of B cells, likely both in the generation of antibodies as well as in the activation of pathogenic T cells. Most therapies are more effective in early MS, which is characterized by inflammation, than in progressive MS, which is characterized by neurodegeneration and is the major cause of permanent disability. This realization is leading to new attempts to restore myelination and repair damaged axons and neurons.
Type 1 Diabetes
Type 1 diabetes, previously called insulin-dependent diabetes, is a multisystem metabolic disease resulting from impaired insulin production due to autoimmune attack on the insulin producing β cells in the pancreas, and affects about 0.2% of the US population, with a peak onset at 11 to 12 years of age. The incidence of the disease appears to be increasing in North America and Europe. The disease is characterized by hyper glycemia and ketoacidosis. Chronic complications of diabetes include progressive arteriosclerosis, which can lead to ischemic necrosis of limbs and internal organs, and microvascular obstruction causing damage to the retina, renal glomeruli, and peripheral nerves. Type 1 diabetes requires continuous hormone replacement therapy. There is usually a long lag of many years between the initiation of autoimmunity and overt clinical disease because 90% or more of the islets have to be destroyed before clinical manifestations are seen.
Pathogenesis of Type 1 Diabetes
Several mechanisms may contribute to β-cell destruction, including inflammation mediated by CD4+ Th1 cells reactive with islet antigens (including insulin), CTL-mediated lysis of islet cells, local production of cytokines (TNF and IL-1) that damage islet cells, and autoantibody-mediated destruction of islet cells. In the few cases in which the pancreatic lesions have been examined at the early active stages of the disease, the islets show cellular necrosis and lymphocytic infiltration consisting of both CD4+ and CD8+ T cells. This lesion is called insulitis. Autoantibodies against islet cells and insulin are also detected in the blood of these patients. In susceptible children who have not developed diabetes (such as relatives of patients), the presence of antibodies against islet cells is predictive of the development of type 1 diabetes. An informative animal model of the disease is the nonobese diabetic (NOD) mouse, which develops spontaneous diabetes. In this model, there is evidence for defective survival and function of Tregs and resistance of effector T cells to suppression by Tregs. Another interesting idea that has emerged mostly from the mouse model is that posttranslational modification of islet antigens may lead to the creation of new epitopes that elicit immune responses, similar to the neoantigens in RA, discussed previously.
Multiple genes are associated with type 1 diabetes. Most attention has been focused on the role of HLA genes. Between 90% and 95% of White people with type 1 diabetes have HLA-DR3 or DR4, or both, in contrast to about 40% of healthy subjects, and 40% to 50% of patients are DR3/DR4 heterozygotes, in contrast to 5% of healthy subjects. The actual HLA genes that may play a role in the pathogenesis may be HLA-DQ alleles that are in linkage disequilibrium with the DR alleles. Several non-HLA genes also contribute to the disease. The first of these to be identified is insulin, with tandem repeats in the promoter region being associated with disease susceptibility. The mechanism of this association is unknown; it may be related to the level of expression of insulin in the thymus, which determines whether insulin-specific T cells will be deleted (negatively selected) during their maturation. Several other polymorphisms have been identified in patients and in NOD (nonobese diabetic) mice, including in IL2 and CD25 genes. Different polymorphisms in these genes may increase or decrease the risk for developing the disease, but how these polymorphisms affect T-cell responses is not fully established. Some studies have suggested that viral infections (e.g., with coxsackievirus B4) may precede the onset of type 1 diabetes, perhaps by initiating cell injury, inducing inflammation and the expression of costimulators, and triggering an autoimmune response. However, epidemiologic data suggest that repeated infections protect against type 1 diabetes, and this is similar in the NOD mouse model. In fact, it has been postulated that one reason for the increasing incidence of type 1 diabetes in higher resource countries is the control of infectious diseases.
Immunological Therapies for Type 1 Diabetes
The most interesting new therapeutic strategies for type 1 diabetes are focused on inducing tolerance with diabetogenic peptides from islet antigens (such as insulin) and inducing or giving Tregs to patients. An anti-CD3 antibody that is thought to activate Tregs delays disease progression and is approved for high-risk individuals.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a heterogeneous group of disorders characterized by chronic remitting inflammation in the small or large bowel that is likely a result of inadequately regulated responses to commensal bacteria. The two main types of IBD are Crohn’s disease, which can affect the entire thick ness of the wall in any part of the gastrointestinal tract but most frequently involves the terminal ileum, and ulcerative colitis, which is restricted to the colonic mucosa.
Pathogenesis of Inflammatory Bowel Disease
Although the causes of Crohn’s disease and ulcerative colitis are poorly understood, several types of evidence suggest that these disorders are a result of defects in the regulation of immune responses to commensal organisms in the gut in genetically susceptible individuals. A number of immunologic abnormalities may contribute to the development of IBD (Fig. 3).
• Defects in innate immunity to gut commensals. Loss-of function mutations in the gene that encodes the NOD2 cytoplasmic innate immune sensor are associated with a subset of Crohn’s disease and may lead to reduced innate defenses against intestinal microbes. Many other genetic variants compromise immunity and likely contribute to increased commensal bacterial invasion through the intestinal epithelium.
• Abnormal Th17 and Th1 responses. Analysis of T-cell responses in animal models and patients with IBD indicates that there is an active Th17 response in the affected parts of the bowel. Genetic studies have shown that polymorphisms in genes encoding the IL-23 receptor that are associated with Th17 development carry increased risk for IBD, although the effect of the polymorphisms on expression or function of the receptor are not known. Crohn’s disease is also characterized by granulomatous inflammation driven by interferon γ (IFNγ)-producing Th1 cells.
• Defective function of regulatory T cells. It is possible that IBD may be caused by inadequate Treg-mediated sup pression of immune responses to commensal organisms. The evidence supporting this hypothesis originally came from mouse models in which an absence of Tregs leads to colitis. In humans, FOXP3 mutations result in a failure to develop Tregs and cause the disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, which includes severe gut inflammation in addition to autoimmune involvement of many other tissues. Mutations in the receptor for IL-10, an immune-suppressive cytokine made by Tregs (and other cells), cause early-onset severe colitis.
• Polymorphisms of genes that are associated with macroautophagy and the unfolded protein response to endoplasmic reticulum stress are risk factors for IBD. Macroautophagy is a process in which cells sequester cytoplasmic organelles within autophagosomes, which then fuse with lysosomes, promoting the destruction of the organelles. Variants of autophagy genes (including ATG16L1 and IRGM) that are associated with Crohn’s disease impair autophagy in Paneth cells, and for unclear reasons, this reduces secretion of lysozyme and defensins into the intestinal lumen.
Fig3. Postulated pathogenesis of Crohn’s disease. Bacteria from the intestinal lumen enter into the lamina propria, where they induce the development of Th1 and Th17 cells. Cytokines produced by these cells cause inflammation and tissue damage. IFN-γ, Interferon-γ; IL, interleukin; TNF, tumor necrosis factor.
Immunological Therapies for Inflammatory Bowel Disease
TNF antagonists were the first biologic agent used to treat IBD. The findings of exaggerated Th1 and Th17 responses are the basis for treating patients with a monoclonal antibody that binds a polypeptide (p40) shared by IL-23 and IL-12. IL-23 is required for Th17-mediated immune responses, and IL-12 is required for Th1 responses (see Chapter 10). Clinical trials of IL-17 antagonist treatment for Crohn’s disease have not shown efficacy, suggesting that excessive production of IL-17 may not, by itself, be responsible for this disorder. Another biologic agent approved for Crohn’s disease is a monoclonal antibody specific for the α4 β7 integrin, which is expressed on gut-homing lymphocytes.
Celiac Disease
Celiac disease (gluten-sensitive enteropathy) is an inflammatory disease of the small bowel mucosa caused by immune responses against ingested gliadin, a major protein component of the broader group of proteins called gluten present in wheat and other grains. Celiac disease is characterized by chronic inflammation in the small bowel mucosa, leading to atrophy of villi, malabsorption, and various nutritional deficiencies that lead to extraintestinal manifestations. The disease is treated by restricting diets to gluten-free foods.
Pathogenesis of Celiac Disease
CD4+ T-cell responses to gliadin are likely involved in disease pathogenesis (Fig4). T cells specific for gliadin peptides are found in patients with celiac disease, and the inflammatory process in the bowel includes T cells and T-cell cytokines. The risk of developing celiac disease is strongly associated with HLA-DQ2 and DQ8 alleles, and there is evidence that these HLA class II molecules can present modified gluten peptides to mucosal CD4+ T cells in affected individuals. A host enzyme transglutaminase 2 (TG2) converts glutamine, a neutral amino acid in gluten peptides, to the negatively charged residue glutamic acid; the negatively charged peptides bind more efficiently to DQ2 and DQ8 and activate specific T cells that secrete cytokines that contribute to intestinal inflammation. TG2 also generates covalent conjugates of gliadin to TG2 itself. This conjugation with gliadin generates “self–non-self” protein conjugates allowing gliadin peptide–specific helper T cells to provide help to B cells that recognize TG2 epitopes. This results in a break in tolerance and the generation of IgG autoantibodies to TG2 that are a diagnostic feature of the disease. Patients produce IgA and IgG anti bodies specific for deamidated gliadin as well as autoantibodies specific for TG2. Whether these antibodies contribute to disease development is not known, but IgA and IgG antibodies to deamidated gliadin are a useful diagnostic and prognostic tool in the clinic. In addition to CD4+ T-cell responses, killing of intestinal epithelial cells by CD8+ CTLs and NK cells may also contribute to the disease, although the source of the peptides recognized by the CTLs or what the NK cells are responding to is not clear.
Fig4. Postulated pathogenesis of celiac disease. Gliadin is con verted to a peptide that is presented by lamina propria dendritic cells to CD4+ T lymphocytes. Cytokines produced by the T cells damage the intestinal epithelium. Antibody responses to transglutaminase 2 (TG2) are frequently detected but their role in causing epithelial injury is unclear. HLA, Human leukocyte antigen; IFN-γ, interferon-γ.
Psoriasis
Psoriasis is the prototypic IL-17–mediated chronic inflammatory autoimmune disease. It involves primarily the skin and also affects the joints and other tissues in some cases.
Pathogenesis of Psoriasis
The responsible self antigens are not clearly defined, but possible candidates include cathelicidin (an antimicrobial protein) and a keratin, both produced by keratinocytes, and other pro teins made by melanocytes. The autoimmune response may be triggered by infection or other unknown stimuli. Several lines of evidence have established the central role of IL-17–producing cells in the resulting inflammation. High levels of IL-17 and the Th17-inducing cytokine IL-23 are found in psoriatic lesions, as are large numbers of IL-17–producing CD4+ and CD8+ T cells as well as γδ T cells. Genome-wide association studies have revealed disease-associated polymorphisms in the IL-23 receptor gene and other genes associated with Th17 development. It is postulated that once IL-17–producing T cells are activated, presumably by one or more self antigens, the IL-17 they produce stimulates inflammation and activates DCs to produce TNF and other, Th17-inducing cytokines. This reaction sets up a vicious cycle of continuing inflammation.
Immunological Therapies for Psoriasis
Effective new biologic therapies have been developed based on this model. The first such agents to be used in the disease were TNF antagonists. These were followed by an antibody specific for the p40 chain that is shared by IL-12 and IL-23, mentioned earlier in the therapy of IBD. The most successful of these bio logic agents are antibodies that block IL-17, IL-17R or IL-23, which are very effective in most patients.
