Cure Myasthenia Gravis

Autoimmune Paleo Cookbook

If you have an autoimmune disease, recipes can often be hard to find and you are often told the huge amounts of things like chocolate and certain foods with too high of a fat content that you can and can't eat. This eBook gives recipes that anyone can prepare without too much trouble. Even if you don't like cooking, this book makes cooking easy and breaks it down into steps. Best of all, the recipes do not taste like healthy medicine recipes. These recipes are delicious foods that anyone would want to eat, even if they didn't have to eat healthy. This book contains over 70 amazing recipes for anyone with an autoimmune disorder. The book comes with two free ebooks: 7 Steps to Living Well With an Autoimmune Disorder and The Top 10 Autoimmune Diseases Checklist. If you want to learn about your autoimmune disease and the best and worst foods for you, this is the book for you!

Autoimmune Paleo Cookbook Summary

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Author: Samantha Miller
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The very first point I want to make certain that Autoimmune Paleo Cookbook definitely offers the greatest results.

As a whole, this manual contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

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The role of genetic predisposition in autoimmune diseases

AIH is detected with a mean annual incidence of 1.9 in 100000 patients 11 . When patients and their first-degree relatives were investigated, 30-40 of them were found to be affected by other autoimmune diseases. The most prevalent concurrent autoimmune diseases were autoimmune thyroiditis, Graves' disease, ulcerative colitis, insulin-dependent diabetes mellitus and vitiligo 12 . This finding indicates that patients with AIH and their first-degree relatives share a genetic predisposition for autoimmune diseases. To date, we know of several factors, such as specific human leucocyte antigen (HLA) alleles, which increase the risk of developing AIH. However, these risk factors cannot account for all patients with AIH and other pathogenic causes must be postulated. Most likely to be involved are other susceptibility genes regulating the immune responses and or the establishment and maintenance of tolerance. A model gene for such factors is the autoimmune regulator gene (AIRE). Defects in...

AIRE a model gene for the development of organspecific autoimmune diseases

A model gene for a general predisposition for organ-specific autoimmune diseases is the autoimmune regulator (AIRE), which was recently cloned. Severe reduction of AIRE function causes a genetic disease, called autoimmune polyendocrine syndrome type 1 (APS1) 13 . Patients with APS1 usually develop mucocutaneous candidiasis at least once in their lives and a broad spectrum of different autoimmune diseases 20 . The most frequent autoimmune diseases are hypoparathyroidism (80 ) and adrenal insufficiency (70 ). In addition to endocrine disorders, ectodermal dystrophies are frequently noted as well as hepatogastroin-testinal dysfunction (Table 23.1). Ten to twenty per cent of patients with APS1 develop AIH. AIRE is the first gene known outside of the MHC locus which is strongly associated with the development of autoimmune diseases in humans. AIRE encodes a nuclear transcription factor 22 , characterized by two plant homeodomain-type (PHD-type) zinc finger motifs, a newly described SAND...

Immunologic Tolerance and Autoimmunity

PATHOGENESIS OF AUTOIMMUNITY, 334 Genetic Basis of Autoimmunity, 336 Role of Infections in Autoimmunity, 340 Other Factors in Autoimmunity, 341 autoimmunity, and the diseases they cause are called autoimmune diseases. Elucidating the mechanisms of self-tolerance is the key to understanding the pathogen-esis of autoimmunity. In this chapter, we discuss immunologic tolerance mainly in the context of self-tolerance and how self-tolerance may fail, resulting in autoimmunity. We also mention the relevance of tolerance to unresponsiveness to foreign antigens and the potential of tolerance induction as a therapeutic strategy for immunologic diseases and to prevent the rejection of cell and organ transplants. Because of the importance of self-tolerance for the health of individuals and the therapeutic promise of tolerance, there has been great interest in understanding this phenomenon and learning how to apply it to humans.

Neonatal Exposure to Physiological Ovary Derived Ag Induces Tolerance and Neonatal Immunization with Selfpeptide

In a gain of function experiment, when male mice were engrafted with neonatal ovaries as neonates, their response to pZP3 as adults was reduced to the level of female mice (Pramoonjago et al., unpublished data). In contrast, in studies involving neonatal injection of Ag (usually of foreign origin), the neonates develop a Th2-biased response rather than tolerance (Singh et al. 1996 Garza et al. 1997 Adkins 2000). On the other hand, we have found that neonatal response to the self-peptide frequently led to autoimmune response and autoimmune disease. Indeed, neonatal mice mounted autoimmune responses and elicited autoimmune memory in situations where adult mice would be resistant (Tung et al. 2001). Thus, the nature of neonatal immune response can vary greatly depending on the nature of the antigenic stimulus.

Neonatal Immunization Induces Autoimmune Disease Besides Autoimmune Ovarian Disease

The studies on murine AOD and other autoimmune models indicate that neonatal mice are more sensitive than adults to disease induction, and this is in turn influenced by factors including endogenous Ag expression, resistance to apoptosis, and environmental factors. We next describe the response of neonatal mice to ZP3 immune complex that results in a new intergenerational autoimmune disease known as neonatal AOD (nAOD). The nAOD model has permitted more precise dissection of the underlying mechanisms because of this and the relevance of the model to autoimmunity of the d3tx mice, it will be described in more detail.

Genetic Basis of Autoimmunity

From the earliest studies of autoimmune diseases in patients and experimental animals, it has been appreciated that these diseases have a strong genetic component. For instance, type 1 diabetes shows a concordance of 35 to 50 in monozygotic twins and 5 to 6 in dizygotic twins, and other autoimmune diseases show similar evidence of a genetic contribution. Linkage analyses in families, genome-wide association studies and large scale resequencing efforts are revealing new information about the genes that may play causal roles in the development of autoimmunity and chronic inflammatory disorders. From these studies, several general features of genetic susceptibility have become apparent. Most autoimmune diseases are complex polygenic traits, in which affected individuals inherit multiple genetic polymorphisms that contribute to disease susceptibility and these genes act with environmental factors to cause the diseases. Some of these polymorphisms are associated with several autoimmune...

Role of Infections in Autoimmunity

Viral and bacterial infections may contribute to the development and exacerbation of autoimmunity. In patients and in some animal models, the onset of autoimmune diseases is often associated with or preceded by infections. (One notable and unexplained exception is the NOD non-obese diabetic mouse strain, a model of type 1 diabetes, in which infections tend to ameliorate insulitis and diabetes.) In most of these cases, the infectious microorganism is not present in lesions and is not even detectable in the individual when autoimmunity develops. Therefore, the lesions of autoimmunity are not due to the infectious agent itself but result from host immune responses that may be triggered or dysregulated by the microbe.

Other Factors in Autoimmunity

The development of autoimmunity is related to several factors in addition to susceptibility genes and infections. Hormonal influences play a role in some autoimmune diseases. Many autoimmune diseases have a higher incidence in females than in males. For instance, SLE affects women about 10 times more frequently than men. The SLE-like disease of (NZB x NZW)F1 mice develops only in females and is retarded by androgen treatment. Whether this predominance results from the influence of sex hormones or other gender-related factors is not known. Autoimmune diseases are among the most challenging scientific and clinical problems in immunology. The current knowledge of pathogenic mechanisms remains incomplete, so theories and hypotheses continue to outnumber facts. The application of new technical advances and the rapidly improving understanding of self-tolerance will, it is hoped, lead to clearer and more definitive answers to the enigmas of autoimmunity.

Suppression of Autoimmune Disease by Regulatory Cells from Donors with or Without the Relevant SelfAg

Taken together, the in vivo studies in d3tx mice support Ag-specific suppression of autoimmune diseases by CD4+CD25+ T cells, though the findings do not rule out additional suppression by nonspecific means. Our study on Ag specificity further emphasizes the dynamic nature of immune suppression by the CD4+CD25+ T cells

Role of CD137CD137L Interaction in the Pathogenesis of Autoimmune Diseases

CD137 CD137L pathway is involved in the generation of a fully competent T cell response (Blazar et al., 2001 DeBenedette et al., 1999 Tan et al., 1999, 2000). Absence of CD137 CD137L interactions prevent the development of certain autoimmune diseases (Seo et al., 2003, 2004). Elevated serum levels of soluble forms of receptor and ligand were detected in patients with various autoimmune diseases (Jung et al., 2004 Michel et al., 1998 Sharief, 2002). These studies suggest CD137 CD137L interactions may play a role in the pathogenesis of autoimmune disease.

Mechanisms Involved in CD137 Agonistmediated Inhibition of Autoimmune Diseases

Compelling data have been shown that agonistic anti-CD137 monoclonal antibodies displayed potent immunomodulatory function in various autoimmune disease models including CD4+ T cell-mediated and both CD4+ T cell and B cell-involved, organ-specific and systemic autoimmune diseases. Multiple mechanisms are involved in CD137 engagement-induced inhibition of autimmunity, which includes (1) increase of T lymphocyte apoptosis, (2) generation of CD8+ regulatory T cells, (3) CD4+ T cell anergy, (4) autoreactive B cell apoptosis. INF-y plays an important role in various events.

Autoimmunity and Tumor Immunity

Removal of CD25+CD4+ TR cells may elicit autoimmunity in addition to provoking tumor immunity. This raises the issue of how tumor immunity can be evoked without autoimmunity by manipulating natural TR cells. It is of note in this regard that the intensity and the range of autoimmune responses (i.e., the severity, the incidence, and the spectrum of autoimmune diseases) elicited by removal of TR cells depend on the degree and duration of depleting CD25+CD4+ TR cells, and, more importantly, the genetic background of the hosts (Sakaguchi et al. 1995,1996). For example, in genetically autoimmune-prone BALB c mice, generation of effective tumor immunity can be achieved without deleterious autoimmunity by limiting the period of depleting CD25+CD4+ TR cells, whereas, in genetically autoimmune-resistant C57BL 6 mice, complete depletion of CD25+CD4+ TR cells leads to tumor rejection without producing autoimmune disease (S. Yamazaki et al., unpublished results). Thus, autoimmunity and tumor...

Pathogenesis of Autoimmunity in CLL

The most obvious explanation for autoimmune disease in CLL would be that the autoantibodies were the product of the tumor. I am constantly surprised by the many eminent immunologists who believe this to be so. The CLL cell does secrete immunoglobulin. Stevenson et al. (59) demonstrated secretion of small amounts of idiotypic IgM by CLL cells using a highly sensitive radioimmunoassay. The immunoglobulin secreted by CLL cells is often autoreactive. Stimulation by phorbol ester induced the CLL cells from 12 14 patients to secrete IgM that reacted with a variety of autoantigens, including the Fc portion of IgG, both single- and double-stranded DNA, histones, cardiolipin, and cytoskeletal proteins (60). Similar polyreactive antibodies have been described by Sthoeger et al. (61), who demonstrated that the antibodies were of the same light chain types as the surface IgM of the CLL cells and therefore not the product of contaminating normal B-cells. They also...

Pathogenesis Of Autoimmunity

Postulated Mechanisms Autoimmunity

The possibility that an individual's immune system may react against autologous antigens and cause tissue injury was appreciated by immunologists from the time that the specificity of the immune system for foreign antigens was recognized. In the early 1900s, Paul Ehrlich coined the rather melodramatic phrase horror autotoxicus for harmful ( toxic ) immune reactions against self. Autoim-munity is an important cause of disease in humans and is estimated to affect 2 to 5 of the U.S. population. The term autoimmunity is often erroneously used for any disease in which immune reactions accompany tissue injury, even though it may be difficult or impossible to establish a role for immune responses against self antigens in causing these disorders. Because inflammation is a prominent component of these disorders, they are sometimes grouped under immune-mediated inflammatory diseases, which does not imply that the pathologic response is directed against self antigens (see Chapter 18). The...

Autoimmunity in chronic hepatitis C

Hepatic infection with HCV is known to induce several hepatic and extrahepatic autoimmune manifestations. Extrahepatic manifestations include mixed cryoglo-bulinaemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, Sjorgen syndrome and autoimmune thyroid disease 4 . Not surprisingly, numerous autoantibodies are found to be associated with chronic hepatitis C, i.e. antinuclear antibody (ANA), smooth muscle antibody (SMA), LKM-1 and antithyroid autoantibodies 5 . However, in the majority of cases, these antibodies are not markers of real autoimmune diseases. LKM1 autoantibodies, for example, are detected in patients with AIH-2 and in 0-7 of patients with chronic hepatitis C

Treatment of Autoimmunity in CLL

Triggered the autoimmunity has to be weighed against the prospect that treating the disease will eliminate the complication. 2.5.4. Management of Post-Fludarabine Autoimmunity A special risk is the retriggering of autoimmunity by re-exposure to purine analogs and even chlorambucil may retrigger the complication (135). However it is possible to reintroduce fludarabine while the patient is maintained on cyclosporin (120). Whether it is safe to use purine analogs in patients with a positive Coombs' test or evidence of pre-existing AIHA is difficult to answer. Some patients have had an exacerbation of their hemolysis or thrombocytopenia when

Myasthenia Gravis

MG is a chronic autoimmune disease of the neuromuscular junction characterized by fluctuating weakness and fatigability of skeletal and extraocular muscles. The natural history is characterized by exacerbations and remissions. Symptoms increase during the day, and may be masked by rest. Patients may have respiratory (and swallowing) difficulties during myasthenic crisis, requiring artificial ventilation and airway protection respiratory compromise is the most common cause of death in MG patients. In 1997, the death rate was reported to be less than 10 . While the etiology of MG is not known, it is perhaps the best understood of the autoimmune diseases.18 Unlike some types of GBS, microbial infections have not been shown to cause any of the chronic autoimmune diseases. However, onset and exacerbation of symptoms of MG may follow febrile illness and insect bites, and some data suggest a possible role for molecular mimicry. A genetic basis is suggested by the finding that 30 of patients...

Dass S Vinay and Byoung S Kwon

CD137 and CD137L belong to the tumor necrosis factor (TNF) superfamily, a group of cysteine-rich cell surface molecules. With a few exceptions, both CD137 and its ligand, CD137L, are activation induced. CD137 activates CD8+ T cells more strongly than CD4+ T cells, and is a potent inducer of IFN-y. Stimulation through CD137L also relays activation signals to B cells and monocytes. These signals elicit activation of NF- kB via the TRAF-NIK pathway and lead to the induction of a plethora of immune modulators that accentuate the ongoing immune reaction. CD137 and CD137L-deficient mice develop normally, have normal numbers of T and B cells and only demonstrate modest immune malfunction. However, in vivo administration of agonistic anti-CD137 mAb protects strongly against a variety of autoimmune and non-autoimmune diseases. The basis of this protection is unclear however, it seems to involve an indoleamine dioxygenase (IDO)-dependent process in which pathogenic T cells are killed suppressed...

CD4CD25 Regulatory T Cell Selection in the Thymus

Early studies showing that CD4+CD25+ T cells possess important regulatory activities pointed to thymic processes in their formation. In these studies, thymectomy of 3-day-old neonatal mice (d3Tx) led to the development of organ-specific autoimmune diseases unless mice were given unfractionated CD4+ T cells, or just the CD4+CD25+ subset of T cells, within 2 weeks of thymectomy (Shevach 2000). Sakaguchi's group went on to show that approximately 3 -5 of CD4SP thymocytes also express CD25, and that these CD4SP CD25+ thymocytes are as suppressive as peripheral CD4+CD25+ regulatory T cells in in vitro suppression assays (Itoh et al. 1999). Furthermore, 1 week Indeed, early clues that regulatory T cells were important in preventing autoimmune disease came in studies in which mice expressing an encepha-latogenic CD4+ TCR as a transgene were protected against the development of autoimmune encephalitis when maintained on a background that permitted endogenous TCR gene rearrangement (termed T...

Conclusions and Future Directions

Finally, why do CD4+CD25+ regulatory T cells co-exist with CD4+CD25-T cells expressing the same TCR in the transgenic systems that have been studied to date Even in the context of varying degrees of deletion, CD4+ CD25+ regulatory T cells expressing the transgenic TCR are typically present as mixtures with CD4+CD25- T cells. Perhaps stochastic processes governing FoxP3 expression cause a subset of autoreactive thymocytes to develop along the CD4+CD25+ regulatory T cell pathway, while others do not. But in this model, the selection of CD4+CD25+ regulatory T cells appears to still depend on the ability of the thymocyte TCR to receive a signal from an agonist peptide ligand, and the processes that protect CD4+CD25- thymocytes expressing the same TCR from deletion in these settings are not obvious. An intriguing possibility is that the thymus typically exports mixtures of clonally related CD4+CD25+ and CD4+CD25- T cells it is clear from the autoimmune diseases that can develop under...

Prognostic Indicators

A long list of prognostic indicators were reviewed by Molica in 2001 (64) and Montserrat and Rozman in 1988 (53). Some of these indicators are clinical stage, lymphocyte count (ALC), lymphocyte morphology, size, immunophenotype, molecular cytogenetics, lymphocyte doubling time, bone marrow histology, response to chemotherapy, autoimmune disease, other medical problems, and a number of serum factors. In addition to cytogenetics, CD38 expression and Ig gene sequence have emerged as potential prognostic indicators that will be clinically useful. Immunophenotyping has for the most part played a role in both establishing B-cell monoclonality and contributing significantly to the differential diagnosis of CLL. Zwiebel and Cheson in 1998 (65) noted that the usefulness of many prognostic factors remains uncertain unless they are evaluated in prospective randomized studies.

The Paradox of Foreign Antigen Recognition by Regulatory T Cells

The above description of self-reactivity within the naturally arising regulatory T cell population fits with the original identification of regulatory T cells as a critical mechanism for the prevention of autoimmunity. However, it has become increasingly evident that TR play an important role in the regulation ofvirtually all immune responses. While initial studies focused on defining the progression of a variety of autoimmune responses in the absence or presence

Annexinopathies

Although a mutation in an annexin has never been categorically proven to be the cause of a disease state, they have been implicated in pathologies as diverse as autoimmunity, infection, heart disease, diabetes and cancer. 'Annexinopathies' were first described by Jacob H. Rand to describe the pathological sequelae in two disease states, the overexpression of annexin 2 in a patients with a haemorrhagic form of acute promyelocytic leukaemia, and the under-expression of annexin 5 on placental trophoblasts in the antiphospholipid syndrome. In this chapter we will outline some of the more recent observations in regard to these conditions, and describe the involvement of annexins in some other major causes of human morbidity

Tr Appear to Have a Diverse TCR Repertoire That Is Different from the CD25 TCR Repertoire

This diversity may explain the apparent ability of the naturally arising regulatory T cell population to participate in regulation of immune responses to pathogens such as Leishmania. Although TR were shown to inhibit a sterilizing immune response in the Leishmania infection model, thereby allowing for the maintenance of functional memory T cells, these and other analogous results provide insufficient support for the idea that the naturally arising TR population evolved to control infectious immunity. From a general perspective, the potential benefits of preserving a chronic low level infection to maintain functional memory T cells over a sterilizing immune response to pathogens are not immediately obvious. Furthermore, it is possible that TR involvement in responses to pathogens may be happenstance due to the diversity of the regulatory T cell receptor repertoire and the shared features of inflammation associated with both chronic infection and autoimmunity.

Glomerular filtration rate

The serum concentrations of several low molecular protein markers have been proposed as alternatives, including a -microglobulin, -microglobulin, retinol binding protein - and, more recently, cystatin C. The former markers have inherent disadvantages in that their circulating levels are influenced by factors other than changes in GFR (e.g. their rate of synthesis changes in an acute phase reaction). However, it appears that serum cystatin C may be a more viable alternative marker of GFR than serum creatinine. It is a protein that is freely filtered at the glomeru-lus, it is not an acute phase reactant and, apart from some rare autoimmune diseases, its circulating concentration does not appear to be influenced by pathological changes other than by an alteration in the GFR.

What Is the Tissue Distribution of TR Target Self Antigens

We already discussed earlier studies suggesting that regulatory T cells need to specifically recognize tissue-derived self-antigens for their survival and or functional activity in the periphery (Seddon and Mason 1999 Taguchi et al. 1994) and subsequent work supporting tissue specificity of TR-mediated protection from autoimmunity (Green et al. 2002 Walker et al. 2003a). However, the recognition of tissue-specific antigens by some TR does not exclude the recognition of ubiquitously presented self-antigens by others. Such recognition is predicted by TCR transgenic models in which regulatory T cell development is directed by a transgene driving expression of the cognate antigen in a variety of tissues (Cozzo et al. 2003). Furthermore, the development of regulatory T cells in H-2M-deficient mice, which express primarily a single peptide-MHC class II complex, CLIP I-Ab, or in mice expressing Ea peptide covalently bound to I-Ab molecules, strongly argues for the existence of Tr recognizing...

Formation of phosphate conjugates

The unexpected (and mostly unexplored) activity of phosphotransferases toward xenobiotic substrates is forcefully illustrated by the recently reported activation of FTY720 (37, Figure 14), a novel immunomodulator showing great promise in transplantations and to treat autoimmunity.71 The agent itself appears inactive, being phosphorylated in rats and humans to the active monophosphate. Recent studies have implicated spingosine kinases as the catalysts and have shown that the reaction is highly product enantioselective. Indeed, FTY720 itself is prochiral (it bears two enantiotopic -CH2OH groups), and the enzymatic reaction results exclusively in the phosphorylated enantiomer of (S)-configuration (38), which is also the only active one.

The MM96 Solution to the Thymic Sorting of Emergent TCR Repertoires Differential Roles of TECs and THCs on Treg

Within this framework, tolerance to all antigens expressed by THCs has a deletional basis, notwithstanding borderline TCR affinity ranges or cell frequencies, which might always be demonstrated in extreme conditions. This seems to be the case in the experimental system introduced by Medawar and colleagues (Billingham et al. 1953), where tolerance is induced if hemopoietic cells (but not those of other peripheral tissues ) are injected at birth (but not later ) into semi-allogeneic hosts. Thus, if some evidence for dominant, CD4 T cell-dependent mechanisms has been produced (Roser 1989), it seems that Medawar's tolerance essentially results from deletion (Gruchalla and Streilein 1982). Likewise, it would be expected that tolerance to all proteins that are present in circulation at high concentrations, and may be presented by THCs, is recessive as well. This is suggested in classical experiments on physiological tolerance to C5 (Harris et al. 1982 Zal et al. 1994), although Treg may...

Evolutionary Significance and a Possible Handle on Treg Regulation

Caramalho and colleagues have reported the surprising finding that murine Treg express transcripts for seven of nine Toll-like receptors they have studied, and that four of these are not expressed by conventional CD4 T cells, either before or after activation (Caramalho et al. 2003). Furthermore, they have shown that Treg actually respond to pro-inflammatory agents and inflammatory conditions that are known to involve this set of innate receptors (Caramalho et al., submitted). The expression of TLRs on T cells has been extended to humans (Komai-Koma et al. 2004) and, together with the findings of Treg amplification by conventional T cell responses (Almeida et al. 2002 Caramalho et al., submitted), shed new light on the operation of Treg and the general physiological regulation of this cell subset. In addition, these findings could contain the solution for current controversies on Treg markers, on distinct cellular and molecular mechanisms of regulation, eventually, on the range of...

Apoptosis and Cell Death

Apoptosis (programmed cell death) is characterised morphologically by increased cytoplasmic granularity, cell shrinkage and nuclear condensation. The most prominent feature of apoptosis is the activation of an endogenous endonuclease that degrades nuclear DNA at linker sections to fragments. It has been suggested that a decrease in the rate of apoptosis plays a role in the pathogene-sis and age-related events such as tumorigenesis. Energy restriction increases apoptosis, which may be the mechanism for its effect in suppressing tumours, ameliorating autoimmune diseases, and prolonging life span. Programmed cell death is an endpoint for many cellular events, but it has not been examined in nutrition studies 48 .

Cd5 B Cells And The Possible Role Of Clonal Lymphocytes Of Unknown Significance In

CD5 is a highly conserved single-chain 67-kDa transmembrane glycoprotein containing three scavenger receptor cysteine-rich (SRCR) domains. CD5 expression is found on all human T cells, but only on a subset of B cells. Despite its sequence conservation, CD5 expression in T cells and B cells varies widely from species to species in some, all B cells are CD5 positive. Studies on CD5-deficient mice have shown that CD5 functions as a negative regulator of B-cell receptor-mediated signaling. Murine CD5 + (B1) B cells may represent a distinct lineage of B-cell development, arising early and self-renewing, producing low affinity, polyreactive antibodies that may contribute to the development of autoimmune diseases.12 Whether CD5 expression in human B cells marks a functionally distinct lineage, or whether it reflects its function as an activation antigen, is unclear.

Significance of Reverse Signal Transduction for the Biology of the CD137 Receptor Ligand System

CD137 (4-1BB, induced by lymphocyte activation, ILA) is a member of the tumor necrosis factor (TNF) receptor family (Kwon and Weissman, 1989 Schwarz et al., 1993). CD137 has originally been identified as a potent T cell costimulatory molecule and a promising target for immunotherapy of cancer (Melero et al., 1997). Recent evidence also demonstrates a role for CD137 signaling in T cells for inhibiting immune responses and autoimmune disease (Foell et al., 2003 2004). The other chapters of this book and several recent reviews provide a comprehensive overview over the various activities of CD137 signaling on immune functions and their potential therapeutic applications (Al-Shamkhani, 2004 Croft, 2003 Kwon et al., 2000 Sica and Chen, 2000).

Principles of the Immune System

Autoimmunity, allergy, immunosuppression The immune system can be divided into the nonadaptive (or innate) part and the adaptive immune system. The adaptive immune system has 'memory,' i.e., it can react faster and better on a renewed contact with the chemical, even after years of not having had any exposure. The cells of the innate immune system use surface receptors to recognize bacterial structures, and initiate defense reactions against them directly. Moreover, the innate defense reaction may include recruitment and instruction of cells of the adaptive immune response, for instance via secretion of cytokines or chemokines. Adaptive immune responses by T cells and B cells can in principle respond to any given structure, i.e., any protein (Tcells and B cells), lipid (some specialized Tcells, B cells), sugar chain, or chemical substance (B cells only), and mount a humoral or cellular response. Antibody producing B cells, cytokine producing helper Tcells, and killer Tcells capable of...

Origin of Tregs Thymus and Peripheral Induction

In a normal thymus, 2 -5 of CD4+CD8- thymocytes express CD25, and these cells are functionally competent, as illustrated by their ability to suppress naive T cell activation in vitro and to protect mice from developing autoim-munity upon adoptive transfer (Itoh et al. 1999). Similar to their peripheral counterparts, CD25+CD4+CD8- thymocytes express Foxp3, and in Foxp3-deficient mice both populations are lacking (Hori et al. 2003a Fontenot et al. 2003). Furthermore, an earlier study reported that neonatal day 3 thymectomy results in the development of organ-specific autoimmunity due to the diminished number of CD25+CD4+ Tregs in the periphery (Sakaguchi et al. 1995). These studies indicate that the normal thymus is continuously producing potentially pathogenic self-reactive CD25-CD4+ T cells as well as functionally mature CD25+CD4+ Tregs. Thus, the thymus contributes to the maintenance of self-tolerance not only by deleting or inactivating the majority of self-reactive T cells during...

Treg Lineage and Development

In mice, Tregs were first described as population of T cells that were capable of suppressing immune responses in a variety of experimental models and were defined by the surface markers CD4 and the IL-2R receptor alpha chain (CD25) (Sakaguchi et al. 1995). The discovery that the X chromosome-encoded gene forkhead box P3 (Foxp3) was the genetic basis for the autoimmune disorder in human patients suffering from IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome and in the spontaneous mouse mutant scurfy allowed for the further understanding of Treg biology (Bennett et al. 2001 Brunkow et al. 2001 Hori et al. 2003 Wildin et al. 2001). Foxp3 is critical for the development of thymic derived Tregs (also called natural Tregs) (Fontenot et al. 2003) and sustained high expression of Foxp3 is required to maintain the suppressor function and phenotypic characteristics of peripheral nTregs (Wan and Flavell 2007 Williams and Rudensky 2007). In a recent review,...

Development Of Lmb2 For The Treatment Of Cd25 Malignancies

Containing all three of them, but with low affinity (Kd 10-8 M) to CD25 alone, also called p55 or Tac.54 In contrast, the mAb anti-Tac binds to CD25 with high affinity (Kd 10 10 M).55 CD25 is overexpressed in a variety of hematologic malignancies, including adult T-cell leukemia (ATL) and HCL, other T- and B-cell leukemias and lymphomas, and Hodgkin's disease.56-58 CD25 usually far outnumbers other subunits of the IL-2R on cells, and in some tumors is the only IL-2R subunit present. To construct an anti-CD25 recombinant immunotoxin, the variable heavy domain of anti-Tac (VH) was fused to the variable light domain via a 15-amino-acid linker to the variable light domain (VL), which in turn was fused to PE40.59 Both anti-Tac(Fv)-PE40 and the slightly shorter derivative anti-Tac(Fv)-PE38 (Figure 33.1) bound well to CD25, and were very cytotoxic to CD25+ cell lines and activated human T cells, which mediate autoimmune disease.5960 LMB-2 induced complete regression of CD25+ human xenografts...

Acquired Localised Lipodystrophies Hemifacial Lipoatrophy

Atrophy of the subcutaneous fat makes the face asymmetrical due to depression of the cheek and the supramandibular region. Cutis, muscles, and bones are unaffected. No renal, neurological, or autoimmune diseases have been reported in association with HFLD. Skull X-ray rules out involvement of the facial bones. Electromyography reveals no sensory or motor abnormalities of the facial mus

Neuro Ophthalmic Aspects of Orbital Disease

Orbital diseases are distinct from primary ocular disorders in that they require consideration of a much larger group of differential diagnoses. Thus, ptosis may be attributable to a simple problem in the anterior segment, but may also be the clinical presentation of a more general disorder, such as Horner's syndrome, oculomotor paralysis, or myasthenia gravis. One must also consider orbital involvement in primary disorders of the periorbital structures, including the paranasal sinuses and the intracranial space.

CD4CD25 Regulatory T Cells

That using the 'S-word' became a certain way of having one's paper rejected. However, during the mid-1990s this slowly began to change when Sakaguchi and co-workers described a subset of immunosuppressive T cells capable of preventing autoimmune disease in mice. These cells were characterized by the expression of CD4 and CD25, the interleukin-2 (IL-2) receptor a chain 10 . Rather than calling them suppressor T cells, these cells are now referred to as CD4+CD25+ regulatory T cells (Tregs). When stimulated in vitro, the CD4+CD25+ Tregs were found to be anergic and suppressive 11 . In vivo depletion of this subset by day-3 thymectomy resulted in the spontaneous development of organ-specific autoimmunity such as gastritis and thyroiditis, and reconstitution of the mice with CD4+CD25+ Tregs prevented disease 10, 12, 13 . Since then, many groups have investigated the presence and function of these cells in both rodents and humans, and this is accompanied by a steep increase in the number of...

Thymic Generation of CD4CD25 Regulatory T Cells

Sakaguchi and co-workers demonstrated that CD4+CD25+ regulatory T cells could be detected in the thymus as well as in peripheral lymphoid organs 10, 12, 13 . Thymectomy on day 3 led to the spontaneous development of organ-specific autoimmunity such as gastritis and thyroiditis however, thymectomy at day 0 or day 7 did not result in disease. This was explained either by a lack of peripheral CD4+CD25- effector T cells at day 0, or by sufficient influx of suppressive CD4+CD25+ T cells into the periphery at day 7. Importantly, reconstitution of the mice with CD4+CD25+ Tregs from either the thymus or peripheral lymphoid organs such as spleen or lymph nodes prevented disease 10, 12, 13 . These data demonstrated that CD4+CD25+ Tregs can be found in both the thymus and the periphery. Furthermore, these studies provided evidence for thymic generation but did not exclude the possibility that CD4+CD25+ Tregs can be generated in the periphery. A later study by the same group showed that CD4+CD25+...

Influence of Soluble CD137 and Soluble CD137 Ligand on CD137 Ligand Signaling

Soluble CD137 ligand is generated by proteolytic cleavage and levels of sCD137 ligand are enhanced in sera of patients suffering from hematological malignancies and autoimmune disease (Salih et al., 2001 Jung et al., 2004 Salih etal., 2004). In contrast to sCD137 which seems to be purely antagonistic, sCD137 ligand is active and can provide costimulation to T cells (Salih et al., 2001). This implies that sCD137 ligand only inhibits reverse signaling through CD137 ligand while initiating signaling through CD137.

The Attenuation Of Immune Receptor Signaling

Recruitment of Cbl-b to the TCR complex and associated adaptor proteins leads to the monoubiquitination, endocytosis, and lysosomal degradation of the TCR complex, and this may be a mechanism for the attenuation of TCR signaling (Fig. 7-22). CD28 signals block the inhibitory activity of Cbl-b, and this is one mechanism by which costimulation augments TCR signals. In knockout mice lacking Cbl-b, the T cells respond to antigen even without CD28-mediated costim-ulation and produce abnormally high amounts of IL-2. These mice develop autoimmunity as a result of the enhanced activation of their T cells.

Current and Future Applications Preclinical Research Applications

Dynabeads CD3 CD28 and Dynabeads ClinExVivo CD3 CD28 have been and continue to be used extensively in preclinical studies evaluating the use of novel adoptive T cell transfer approaches for treating cancer, infectious disease, autoimmunity, and disorders associated with chemotherapy and allogeneic transplantation. T cells have been effectively expanded from cancer patients, chronic lymphocytic leukemia CLL 38 , multiple myeloma MM 57 , non-Hodgkin's lymphoma NHL 50,58 , renal cell carcinoma RCC 59 , prostate cancer PC 60 , breast cancer BC 45 , HIV-infected patients 61,62 , and patients with autoimmune disease 63-65 .

Biomimetic Surfaces In Vivo

Although in vitro studies are essential for the development of new biomaterials, a material that has shown promise in vitro must ultimately be tested in vivo to demonstrate the effect of the various surface treatments or material constructs. To date, few studies have been published which demonstrate the effects of peptide or growth factor modified materials in vivo. Tweden et al. (100) modified cardiovascular devices (polytetrafluoro-ethylene vascular patches and polyethyleneterephthalate cardiac valves) with a peptide containing RGD (PepTite) and assessed their biological response using vascular and cardiac valve models in the dog. In the vascular model, modified materials enhanced endothelial-like cell attachment and layer formation compared to unmodified controls. In addition, a reduced neointima formed on the polyethyleneterephthalate-modified material compared with controls. This latter result was similar to what was reported using the valve model. The coated materials produced a...

Clinical Presentation Definition

Ously, this is usually confined to just one muscle. Ocular myositis is often marked by visible hyperemia in the anterior segment of the eye, directly over and around the tendinous insertion of the affected muscle. Inflammatory orbital diseases are often accompanied by associated signs, such as lid swelling, ptosis, and or exophthalmos. In a few cases, there may be an association with myasthenia gravis or a collagen vascular disease.

Disclaimer Not for patient use To be used as a research guide only

Disease biomarkers are usually based on large population studies that monitor diseases such as cancer (CEA, PSA),69 diabetes (hemoglobin A1c), and autoimmunity (rheumatoid factor).73 These markers not only allow the possibility for early detection that may influence success of treatment, but also serial analysis to potentially indicate whether disease

Conversion of Oligosaccharides to Glycolipids

Class I-like CD1d molecules (134). iNKT cells play a major role as the bridging system between innate and adaptive immunity (135). Upon activation, iNKT cells secrete signaling peptides to regulate a number of disease states in vivo, including malignancy, infection as well as autoimmune diseases (136,137). The lysosomal iso-globotrihexosylceramide (iGb3, Gala1,3Galp1,4Glcp1,1'Cer) was discovered as an endogenous ligand of iNKT cells (133).

TNFa and Semimature DCs

In this regard, TNFa may play a role, since it has been shown that injection of DCs cultivated in presence of TNFa acted in a tolerogenic fashion 14 . In these experiments, DCs were able to block autoimmunity in a murine model of multiple sclerosis (EAE). This suppressive effect was mediated by the induction of IL-10-producing regulatory T cells. The subsequent phenotypic analysis revealed that the DCs expressed regular amounts of MHC class II and T cell co-stimulatory molecules, i.e., according to the authors these DCs displayed a mature phenotype as judged by their surface-marker expression. In contrast, these DCs failed to secrete IL-1 , IL-6, TNFa and in particular IL-12. The importance of IL-12 production for full maturation of DCs and acquisition of an immunostimulatory phenotype is further substantiated by results showing that IL-10 as well as cAMP are potent agonists of IL-12p70 secretion. In fact, DCs treated with these agents are resistant to terminal maturation and induce T...

Chronic inflammatory demyelinating polyradiculoneuropathy

CIDP is thought to be an autoimmune disorder caused by either humoral or cell-mediated immunity to axonal, myelin, or other Schwann cell antigens. The autoantigens associated with CIDP are generally unknown. However, MMN is associated with anti-GM1 IgM antibodies, the levels of which decrease with clinical improvement.

Immunogenetic markers as determinants of outcome and fibrogenesis in alcoholic liver disease

More recently, attention has focused on the cytokine genes. Ongoing studies at the Centre for Liver Research in Newcastle, UK, have linked TNF-238 and IL-10-627with alcoholic cirrhosis but not with alcoholic hepatitis 36, 37 . The IL-10 gene promoter encodes three SNPs which have been linked with susceptibility to autoimmune disease 38 but not with autoimmune liver disease 28, 29 . These are A to G at position 1082, C to T at position 819 and A to C at position 592 (sometimes termed 627 2 ). In 285 patients with ALD, 50 of those with advanced ALD expressed at least one A allele at position 592 ( 627) compared with 33 of controls (n 227) and 34 of heavy drinkers without ALD (n 107) 37 . The authors also reported a strong association with the A allele at position 1082 ( 1117) which was assigned to linkage between A 627 and A 1117 37 .

Selective Adhesion Molecule Inhibitors

In Crohn's disease, an organ-specific autoimmune disease in which the immune system attacks the intestinal mucosa, the therapeutic target of natalizumab is a4 7 integrin, which, like a4pl integrin, is recognized by a4 integrin-specific antibodies. This integrin has multiple functions, including mediating migration of gut-homing T cells via its counter-receptor in the gut, MadCAM.

Selection Processes in the Maturation of MHCRestricted ap T Cells

To display peptides) mainly on thymic epithelial cells in the cortex. The outcome of this recognition is determined primarily by the strength of the encounter between TCRs and self antigen-MHC complexes. Positive selection is the process that preserves T cells that recognize self MHC (with self peptides) with low avidity. This recognition preserves cells that can see antigens displayed by that individual's MHC molecules. At the same time, the cells become committed to the CD4 or CD8 lineage based on whether the TCR on an individual cell respectively recognizes MHC class II or MHC class I molecules. Also, in every individual, T cells that recognize self antigens with high avidity are potentially dangerous because such recognition may trigger autoimmunity. Negative selection is the process in which thymocytes whose TCRs bind strongly to self peptide antigens in association with self MHC molecules are deleted (see Fig. 8-20). The net result of these selection processes is that the...

Dermatitis Herpetiformis Duhring

Dermatitis herpetiformis (DH) represents a bullous or pruritic autoimmune disorder with subepidermal blister formation which is considered to be a specific cutaneous manifestation of celiac disease, although most DH patients do not present gastrointestinal symptoms. The autoantigen of dermatitis herpetiformis, epidermal transglutaminase, is targeted by autoantibodies of the IgA class. Immunofluorescent staining of unin-volved perilesional skin biopsies reveals granular IgA deposition in the papillary dermis (Fig. 8.2K-M). DH patients show an intense pruritus with eruption of ery-thematous papules and herpetiform vesicles distributed symmetrically on the extensor surfaces. In addition to a gluten-free diet, the sulphonamide diamino-diphe-nyl sulfone (dapsone) is most commonly used in the treatment ofDH.

Clinical Experience with Rituximab Therapy

The current application of rituximab in autoantibody mediated autoimmune diseases was catalyzed by findings that treatment of B-cell NHL improved symptoms of lymphoma-associated autoimmune phenomena, since malignant B-cell clones are capable of secreting low-affinity self-reactive antibodies, for example auto-antibodies specific for self antigens on red blood cells leading to autoimmune hemolytic anemia (Boye et al. 2003). Moreover, the rationale for applying rituximab in primary autoimmune disorders is the long-term depletion of pathogenic, autoantibody-secreting B-cell clones, thus restoring tolerance. Follow-up of rituxi-mab-induced B-cell depletion in 24 patients with active RA showed that B-cell repopulation in the peripheral blood occurred around 8 months after rituximab treatment. Increased numbers of na ve and immature B cells (CD19+, IgD+, CD38high, CD10low, CD24high) were identified during repopulation in the peripheral blood similar to the B-cell populations found following...

Rituximab in Pemphigus

Recalcitrant clinical variants of pemphigus. As reported for lymphoma patients and other autoimmune diseases, four i.v. treatments with rituximab at 375 mg m2 over 4 weeks induced a complete and sustained B-cell depletion in the peripheral blood which usually lasted for 6 - 9 months. As recently reviewed, all clinical studies and case reports using rituximab in severe recalcitrant pemphigus demonstrated good clinical responses with remissions lasting from several months to 2 years. A recent open-label study including one PF and four PV patients with therapy resistant disease showed that clinical improvement correlated with persistent B-cell depletion. However, clinical remission was not accompanied by a significant decrease of desmoglein (Dsg)-specific autoantibodies in all the patients (Arin et al. 2005). Another ongoing clinical study including a total of ten PV patients receiving the standard dose (four weekly doses of 375 mg m2) demonstrated a decrease of Dsg1- Dsg3-specific...

Development of an In Vitro Assay System of Suppression

With the demonstration that CD4+CD25+ T cells were capable of inhibiting the induction of autoimmune disease, several groups set out to purify this subset and develop an in vitro assay system to test the suppressive function of these cells. It was shown that soluble anti-CD3-induced CD4+ T cell proliferation Tcellswere added

Central Role of TNFa in Inflammation

Proteinases and the release of pro-inflammatory cytokines (IL-1, IL-6, IL-8, GM-CSF). TNF-a-conveyed induction of pro-inflammatory cytokines, leukocyte chemotaxis and angiogenesis possibly play a fundamental role in autoimmune diseases of the skin, presumably diseases which are characterized by elevated TNF- serum concentrations, fever and an increase of acute phase proteins. Elevated serum levels of TNF-are detectable in many autoimmune diseases including RA, psoriasis and Crohn's disease.

Inhibition of TNFa by Biologics

A new class of TNF-a inhibitors are the so-called biologics, which are either recombinant monoclonal antibodies or soluble TNF receptor fusion proteins. These proteins can be either isolated from animal tissues or commonly synthesized by biotechnological methods. The more defined understanding of the pathophysiolo-gy of autoimmune diseases has led to the therapeutic use of biologics in chronic inflammatory disorders (Scheinfeld 2004). At present, a few uncontrolled case reports suggest that the therapeutic blockade of TNF-a maybe a novel option for the short-term control of otherwise recalcitrant autoimmune bullous skin disorders (Table 8.1).

Etiologies of Hypoglycemia

Pathophysiological Endocrinopathy (Addison's disease, Sheehan's syndrome) neoplasms (insulinomas, multiple endocrine adenomatosis MEA type I) liver disease (alcoholism, cirrhosis) chronic renal failure (CRF) and hemodialy-sis miscellaneous (AIDS, autoimmune diseases, pregnancy).

Autoimmune Gastritis Model of CD4CD25 T Cell Mediated Suppression

Over the years, many autoimmune models have been employed to investigate the in vivo biology of suppressor T cells (Shevach 2000). One of the original autoimmune models used in the study of CD4+CD25+ biology is AIG induced by thymectomy on day 3 of life (d3Tx) or CD25- T cell transfer to immunocompromised animals. Another widely utilized autoimmune disease model is inflammatory bowel disease (IBD) or colitis. Transfer of CD4+CD45Rbhi (Powrie et al. 1994) or CD4+CD25- T cells (Liu et al. 2003

Immunopathology of AIG

Experimental AIG in mice resembles human autoimmune gastritis, the underlying pathology of pernicious anemia (Alderuccio et al. 2002). Pernicious anemia is one of the more prevalent autoimmune diseases and is the most common cause of vitamin B12 deficiency, as antibodies and T cells target cells that produce intrinsic factor (Toh et al. 1997). Gastritis in humans and mice is characterized by mononuclear cell infiltrates within the gastric mucosa and submucosa and production of autoantibodies reactive against gastric parietal cells.

Pathogenic CD4T Cells

AIG has been described in mice carrying a single TCR a chain transgene (Sakaguchi et al. 1994). These mice spontaneously develop AIG, but also have CD4+CD25+ cells present in the periphery of an adult (A. Thornton, unpublished observation). One hypothesis is that introduction of atypical gene expression within the thymus could delay the development of CD4+CD25+ cells, which generally begin to emigrate on day 3-4 of life. This delay, in combination with neonatal lymphopenia and early, localized expression of autoantigen, could result in autoimmune disease. All these circumstances, as well as increased autoreactive T cells, could lead to this fulminant disease.

Dendritic Cells Presenting HKATPase

How autoreactive CD4+ T cells become activated to initiate autoimmune disease is an actively investigated area of the pathophysiology of many autoimmune diseases. In the peripheral tissues, dendritic cells (DCs) sample the environment, acquiring self-antigens from tissue sites, perhaps by the phagocytosis of apoptotic cells (Steinman et al. 2003). These DCs migrate to the draining lymph nodes where they present the antigen in the context of MHC to specific T cells. It has recently been shown that the autoantigen H K ATPase is processed and presented in the gastric LN of unmanipulated BALB c mice (Scheinecker et al. 2002). DCs likely pick up this antigen in the gastric mucosa, ingesting naturally apoptotic parietal cells. In this regard, close contact between DCs and parietal cells in the gastric mucosa has been observed. Although there is constant turnover and presentation of the autoantigen in the steady state, this does not lead to spontaneous autoimmunity. There are several...

Models of AIG Induction

These models have been separated into four main categories (1) lymphopenic, (2) nonlymphopenic, (3) transgenic, and (4) spontaneous (Alderuccio et al. 2002). The most common model is thymectomy on day 3 of life (d3Tx). In susceptible strains of mice, such as BALB c, d3Tx resulted in AIG as well as several other organ-specific autoimmune diseases (Kojima and Prehn 1981). The underlying cause of this was the early removal of CD25+ suppressor cells in combination with a state of lymphopenia. The role of CD25+ cells was confirmed when Sakaguchi et al. could reproduce the same autoimmune profile in immunocompromised mice upon transfer of CD25- T cells (Sakaguchi et al. 1995). The autoimmune diseases induced by both methods, as well as by gastritis-inducing clones, could be completely suppressed with co-transfer of CD25+ T cells if given within 1 week of induction of disease (McHugh et al. 2001a). The suppression was less effective if CD25+ T cells were...

CD137 Expression and T Cell Costimulation

The underlying cellular and molecular events by which CD137-mediated T cell costimulation regulates the function of the immune system are rapidly coming into focus (Watts, 2005). Furthermore, the potential for targeting the CD137 signaling pathway in treating diseases such as autoimmunity and cancer seems promising (Foell et al., 2003, 2004 Melero et al, 1997 Seo et al, 2004 Sun et al., 2002). In the following sections of this review we describe the effects of anti-CD137 treatment of mice and how these antibodies regulate T-dependent humoral immunity. We will also discuss how B cells may suppress the development of anti-tumor immunity and how this condition can be reversed with anti-CD137 mAbs. The studies reported in this review were based on our early studies of anti-CD137 mediated suppression of humoral immunity in mice (Mittler et al., 1999) and the anti-tumor properties of anti-CD137 mAbs (Melero et al., 1997, 1998a).

Involvement of Immunosuppressive Cytokines

Fig. 3A-D In the absence of CD4+CD25+ T cells, additional signals are needed to initiate autoimmunity. In the steady state (A), autoreactive effector cells are kept in check by multiple mechanisms, CD4+CD25+ T cells or tolerogenic DCs. Depletion of CD4+CD25+ T cells does not lead to autoimmunity, indicating another mechanism for control of autoreactive T cells (B). Depletion of CD4+CD25+ T cells in combination with tissue inflammation, or immunization, leads to autoimmunity that is not controlled by other tolerance mechanisms (C). In the presence of CD4+CD25+ T cells, inflammation may activate the autoreactive T cells, but there autoactivity is kept in check by CD4+CD25+ T cells (D) Fig. 3A-D In the absence of CD4+CD25+ T cells, additional signals are needed to initiate autoimmunity. In the steady state (A), autoreactive effector cells are kept in check by multiple mechanisms, CD4+CD25+ T cells or tolerogenic DCs. Depletion of CD4+CD25+ T cells does not lead to autoimmunity,...

B cell activation by protein antigen and helper T cells

Pathogenesis of autoimmunity because T cell tolerance mechanisms can be subverted if somatic mutation drives a B cell clone in the germinal center to become strongly self-reactive. In fact, it is known that dysregulation of B cell selection in germinal centers contributes to autoan-tibody production.

DC Function CD137 Expression and Signaling

IL-6 is an anti-inflammatory Th2 cytokine whose expression and function is prominent in myeloid cell development, humoral immune responses, and in certain autoimmune diseases. These include EAE (Ishihara and Hirano, 2002 Samoilova et al., 1998), RA (Hata et al., 2004 Hwang et al., 2004 Nishimoto and Kishimoto, 2004), juvenile diabetes (Scholin et al., 2004 Vozarova et al., 2001), and SLE (Ohteki et al, 1993 Suzuki et al, 1993 Tang etal., 1991). IL-12 is a pro-inflammatory cytokine that promotes the development of Th1 mediated immune responses, it induces T cells to produce IFN-y and drives both innate and adaptive anti-tumor immune responses (Gao etal., 2003 Kodama et al., 1999 Martinet et al., 2002 Parihar et al., 2002 Smyth et al., 2000 Uekusa et al., 2002). How these two opposing cytokines are coordinately regulated following CD137 signaling, and what their physiological roles are in dendritic cell biology and T cell immunity remains to be...

Effector Mechanisms of Humoral Immunity

Antibodies before they infect cells or when they are released from infected cells. Defects in antibody production result in increased susceptibility to infection with many microbes, including bacteria, fungi, and viruses. Currently used vaccines induce protection primarily by stimulating the production of antibodies. Apart from their crucial protective roles, in allergic individuals and in certain autoimmune diseases, some specific antibodies can be harmful and mediate tissue injury. In this chapter, we discuss the effector mechanisms that are used by antibodies to eliminate antigens. The structure of antibodies is described in Chapter 5 and the process of antibody production in Chapter 11.

YgFc receptors FcyRIphagocyte

The FcyRIIB receptor is an inhibitory Fc receptor that was described earlier in the context of inhibitory signaling in B cells and the phenomenon of antibody feedback (see Chapter 11). FcyRIIB is the only Fc receptor that has an ITIM motif in its cytoplasmic tail. When antibodies are produced during an immune response, these antibodies bind to remaining antigen, and the complex is simultaneously recognized by the antigen receptor and FcyRIIB on antigen-specific B cells. Immune complex-mediated cross-linking of the inhibitory FcyRIIB leads to tyrosine phosphorylation of the ITIM in the cytoplasmic tail, recruitment and activation of the SHIP inositol phospha-tase, and subsequent inhibition of B cell receptor-mediated, ITAM-dependent activation pathways. FcyRIIB is also expressed on dendritic cells, neutrophils, macrophages, and mast cells and may play a role in regulating the responses of these cells to activating Fc receptors and other stimuli. One somewhat empirical but often useful...

Naturally Occurring Regulatory T Cells

Recently the focus has been largely on naturally occurring CD4+ T cells constitutionally expressing the a chain of the IL-2 receptor (CD25) for a review see (Shevach 2002). Even though CD25- regulatory T cells exist (Apostolou et al. 2002 Lehmann et al. 2002), the CD25 marker has been used to define the properties of regulatory cells. The regulatory population was first identified as a subset of CD4+ T cells able to prevent the development of organ-specific autoimmune disease in mice thymectomized on day 3 after birth (Asano et al. 1996 Sakaguchi et al. 1995). Subsequently, the regulatory T cells have been shown to inhibit many autoimmune diseases (Shevach 2000 von Herrath et al. 2003), transfer tolerance to alloantigens (Taylor et al. 2001), hinder antitumor immunity (Shimizu et al. 1999) and regulate the expansion of other

AntiCD137 mAbs Disrupt Hematopoiesis in Mice

We have found that repeated anti-CD137 treated lupus prone NZB W F1 mice develop multi-focal hepatitis. Cessation of anti-CD137 treatment led to the resolution of hepatitis. To determine whether development of hepatitis was or was not related to the susceptibility of NZB W F1 mice to autoimmune disease, we repeatedly injected normal naive mice with therapeutic doses of anti-CD137. Like NZB W F1 mice, we found that normal mice also developed hepatitis. Further

Vpr Mediates Cell Death

Maintenance of proper cell number requires a balance between proliferation, production, and programmed cell death (PCD). Inhibition of apoptosis leads to autoimmune disease and development of malignancies. Conversely, enhanced apoptosis can cause diseases associated with neurodegeneration,

Pathologic Effects of a Normal Complement System

Antibodies against vascularized organ transplants and the immune complexes produced in autoimmune diseases may bind to vascular endothelium and activate complement, thereby leading to inflammation and generation of the MAC with damage to the endothelial surface, which favors coagulation. There is also evidence that some of the late complement proteins may activate prothrombi-nases in the circulation that initiate thrombosis independent of MAC-mediated damage to endothelium.

Monoclonal Antibody And Endocrine Therapy For Breast Cancer And Tumor Immunity

The negative regulatory pathway with the most promise to date is the CTLA4 counterregulatory signaling pathway 76 . CTLA4 signaling serves as a check on the process of T cell priming, both raising the threshold for T cell activation and limiting T cell expansion. Notably, CTLA4 is also expressed at significant levels by Tregs, and modulating this pathway can affect the primary T cell response as well as the complementary Treg response. Although little data exist for breast cancer, several clinical trials have tested monoclonal antibodies specific for CTLA4 as a single agent, either subsequent to or in active sequence with vaccination in other tumor types 77-80 . In the aggregate, these clinical trials have been quite promising, with evidence of increased tumor-specific immune responses and tumor regression. Notably, bioactivity has tracked with symptoms of significant autoimmunity, further supporting the potency of this drug as an immunomodulator with promise. Currently (as of 2007),...

Deficiency of CD4CD25 Regulatory T Cells and d3tx Diseases

It has been proposed that autoimmune disease occurs in the d3tx mice because of depletion of the CD4+CD25+ T cells that have a late ontogeny ( day 5). However, the mechanism responsible for the d3tx disease is likely to be more complex because 3. The neonatal mice have a propensity for autoimmunity for reasons besides CD4+CD25+ T cell deficiency. It is argued that CD4+CD25+ T cell depletion is responsible for d3tx disease because autoimmune disease in the d3tx mice is suppressed by CD4+CD25+ T cells. Besides being a circular argument, it is possible that disease induction and disease suppression are phenomena that are not causally related. The CD4+CD25- T cells are detected in the spleen of 3-day-old mice, whereas the CD4+CD25+ T cells emerge 2-3 days later, thus d3tx should enrich for effector T cells (Asano et al. 1996). This is true for the spleen however, the lymph nodes (LNs) of normal day 3-day-old mice have the same fraction ( 5 ) of CD4+CD25+ cells as adult LNs (Suri-Payer et...

Central Tolerance in T Cells

Self proteins are processed and presented in association with MHC molecules on thymic antigen-presenting cells (APCs). The antigens that are present in the thymus include many circulating and cell-associated proteins that are widely distributed in tissues. The thymus also has an unusual mechanism for expressing protein antigens that are typically present only in certain peripheral tissues, so that immature T cells specific for these antigens can be deleted from the developing T cell repertoire. Some of these peripheral tissue antigens are expressed in thymic medullary epithelial cells under the control of the autoimmune regulator (AIRE) protein. Mutations in the AIRE gene are the cause of a multiorgan autoimmune disease called the autoimmune polyendocrine syndrome (APS). This group of diseases is characterized by antibody-and lymphocyte-mediated injury to multiple endocrine organs, including the parathyroids, adrenals, and pancreatic islets. A mouse model of APS has been developed by...

Peripheral T Cell Tolerance

Peripheral tolerance is the mechanism by which mature T cells that recognize self antigens in peripheral tissues are rendered incapable of subsequently responding to these antigens. Peripheral tolerance mechanisms may be responsible for T cell tolerance to tissue-specific self antigens, especially those that are not abundant in the thymus. The same mechanisms may induce unrespon-siveness to tolerogenic forms of foreign antigens. The mechanisms of peripheral tolerance are anergy (functional unresponsiveness), suppression, and deletion (cell death) (Fig. 14-3). We do not know if tolerance to different self antigens is maintained by one or another mechanism or if all these mechanisms function cooperatively to prevent dangerous autoimmunity.

Studies in Experimental Animal Models

The suppressive effect of GA in EAE is a specific one, since GA lacked any suppressive effect on the immune response in several systems - humoral and cellular immune responses to a variety of antigens and vaccination against various induced infections. GA treatment also did not suppress other experimental autoimmune diseases, including myasthenia gravis, thyroiditis, diabetes, and systemic lupus erythematosus.5,17 However, it has been reported to inhibit another autoimmune disorder, namely experimental uveoretinitis,18 a disease interrelated with MBP and EAE. Recently, GA was also shown to be effective in the case of experimental colitis.19 In addition, GA also had an effect on a murine model for graft-versus-host disease, as well as in three systems of graft rejection.20

Regulation by inhibitory receptors

Much has been learned about the mechanisms of tolerance in T and B lymphocytes, largely from the use of animal models such as genetically modified mice. Application of this knowledge to understanding the mechanisms of tolerance to different self antigens in normal individuals and to defining why tolerance fails, giving rise to autoimmune diseases, is an area of active investigation.

Neonatal Autoimmune Ovarian Disease in the Euthymic Mice Is Mediated by De Novo Pathogenic T Cell Response

To further elucidate the unusual propensity of neonatal mice to autoimmune disease, we studied the mechanism of nAOD with respect to CD4+ CD25+ T cell function and the state of innate immunity, by addressing three questions 1. Why are older mice ( day 5) resistant to autoimmunity 2. Why are mice more susceptible to autoimmunity during the first 5 days of life

Why Are the Older Mice Resistant to nAOD

With CD25 Ab and fed CP2 Ab-positive milk from postnatal day 9, 90 of them developed severe nAOD (Fig. 4A). In contrast, day 9 mice that received CD25 Ab alone were free of nAOD. Therefore, the presence of CD4+CD25+ regulatory T cell function can explain the resistance to nAOD in mice older than 7 days. As mentioned earlier (Sect. 2.1), depletion of CD25+ regulatory T cells in normal mice at this age does not elicit autoimmune disease unless it is accompanied by a second event which, in this case, is autologous immune complex.

Effects of CD137 on CD4 T Cells Positive or Negative

In contrast to these observations, several recent studies show that CD137 agonist mAb might be an inhibitor for the CD4+ T cell-mediated immune response in vivo. An early study by Shuford and colleagues found that administration of agonistic CD137 mAb inhibits CD4+ T-dependent humoral immune responses (Shuford et al, 1997). The inhibitory effect of CD137 agonistic mAb on CD4+ T cell response has been confirmed in several autoimmune disease models by different laboratories (Foell et al., 2003 Seo et al., 2004 Sun et al., 2002a, 2002b). Experimental data to consolidate these findings is still lacking. As cells other than T cells, such as dendritic cells and natural killer cells, also express CD137, it is thus possible that CD137 signal on these cells may contribute to its suppressive effect.

Tregulatory Cells And Tumor Vaccines

As we begin to combine Treg depletion with active cancer vaccination, additional issues must be dealt with for optimal effectiveness. TAA-specific CD4+CD25+ Tregs have been identified 85 . Treg depletion should attempt to deplete TAA-specific Tregs and not other Tregs so as to perturb homeostatic immunity the least. Treg depletion could also induce pathologic autoimmunity. In this regard, Treg depletion may be necessary, but not sufficient to induce autoimmunity 86 . The timing of Treg depletion in relation to active vaccination in a mouse model for colon cancer greatly influenced vaccine-engendered immunity. Treg depletion (using PC61 antibody) was most effective when given at the time of active vaccination 87 . Timing of Treg depletion likely will vary depending on factors related to the balance of TAA-specific effector cells versus Tregs in an individual, the agent used to deplete Tregs, the specific tumor type, and other factors. The potential for depletion of bystander cells was...

Fcy Receptor III FcyRIII Positive Cells and Proinflammatory Cytokines in Neonatal Autoimmune Ovarian Disease Induction

Many in vitro studies describe that murine neonatal T cell, neonatal NK cells, and neonatal APCs are deficient in number and function (Lu and Unanue 1982 Adkins 1999 Muthukkumaretal. 2000 Dakicetal. 2004). In contrast, the in vivo neonatal T cell and B cell responses to viral infections and vaccines are often comparable to adults (Forsthuber et al. 1996 Ridge et al. 1996 Sarzotti et al. 1996). Studies on nAOD indicate that the neonatal lymphoid compartment is far more responsive to autoantigenic stimulation than one might anticipate from the in vitro studies. Perhaps some of the discrepancies between the in vitro and in vivo findings are reconciled if the neonatal innate cells are included in the equation. In nAOD, the innate immune system including neonatal NK cells are documented to have an important role in promoting neonatal autoimmunity by enhancing neonatal APC function in other types of immune responses. It will be important to determine whether the neonatal innate response...

Summary And Conclusions

The fusion protein denileukin diftitox (Ontak) has received attention as a potential agent to deplete functional Treg. As Ontak theoretically depletes any T cell bearing IL-2 receptors (including effector T cells), its utility may be limited in some settings. Additional agents to deplete Tregs are now under study, including cyclophosphamide or agents specifically targeting Tregs. Additional issues to address when to consider combining Treg depletion with active vaccination include the timing of Treg depletion versus vaccination, consideration for depletion of TAA-specific Tregs, collateral damage to newly induced TAA-specific effector cells, and potential for development of pathologic autoimmunity. The role of additional suppressor cell populations in tumor immunopathology aside from CD4+CD25+ Tregs also merits further study.

The Location and Ag Dependency of Suppression

Response to the female specific self-Ag pZP3 indicates female mice are tolerant to ZP3 and this was terminated by ovarian ablation (Garza et al. 2000). In addition, continuous Ag stimulation was found to be required to maintain tolerance, which was terminated within 1 week after ovarian ablation. In our recent study on suppression of AOD in d3tx mice, depletion of the input CD4+CD25+ T cells also promptly led to emergence of severe AOD (Samy et al., unpublished data). Similar reversibility of suppression has been reported in experimental autoimmune encephalomyelitis (EAE) induced by T cells with transgenic TCR to myelin basic protein (Hori et al. 2002). The requirement of persistence of CD4+CD25+ T cells in suppression of autoimmunity argues against the importance of clonal elimination of effector T cells or induction of infectious tolerance.

Genetic Studies on Inbred Strains of Mice

Kojima and Prehn's study (1981) examining susceptibility to d3Tx-induced autoimmune disease in 21 different inbred and congenic strains ofmice found strain variation in organ involvement, incidence, and severity of disease they also found that AIP was the only disease with a clear H2 association. However, H2-linkage has subsequently been extended to include susceptibility to both AOD and AIG (Silveira et al. 2001 Roper et al. 2002). Additional studies were carried out to address the inheritance of d3tx-induced autoimmune disease. The results obtained using reciprocal F1 hybrid, backcross, and F2 intercross populations are consistent with oligogenic control by a limited number of interactingloci. Importantly,however,theyrevealedthat susceptibility to AOD exhibits a maternal parent-of-origin effect in that the incidence of disease observed in F1 hybrid mice is significantly greater when the dam is the susceptible parental strain (Kojima and Prehn 1981). Preliminary attempts to map the...

Positional Candidate Genes for AOD and Aig Qtl That Are Differentially Expressed byCD4CD25 Regulatory T Cells

Comparative microarray analyses between CD4+CD25+ T cells and other T cells in several different models resulted in the identification of a limited set of differentially expressed genes (Bystry et al. 2001 Lechner et al. 2001 Gavin et al. 2002 McHugh et al. 2002 Graca et al. 2002 Zelenika et al. 2002). To identify which of these genes map within the genetic intervals encompassing the AOD and AIG disease susceptibility loci we determined their map locations by searching the MGI and NCBI linkage maps. The locations for the unmapped genes were determined by locating their sequence within the mouse genome using the ENSEMBL or UCSC genome browsers and identifying the closest linked gene or marker whose map location was known. The list of genes that was identified in this way is presented in Table 3. Surprisingly, a number of the differentially expressed genes mapped within the genetic intervals encompassing the AOD and AIG susceptibility loci. Importantly, there were no differentially...

Presence Of Immune Regulatory Cells

There is some concern that manipulation of Treg cells will increase the risk for development of autoimmune disease, particularly in the HSCT setting where Treg cells are already being impacted by the conditioning regimens. However, despite the relatively low numbers of CD4+Foxp3+ cells early after HSCT, development of autoimmune disease has not been an issue following syngeneic HSCT in mice. Perhaps a small number of radioresistant Treg cells are adequate to prevent development of autoimmune immune disease, as has been suggested by Benard and colleagues 19 . In addition, since the time interval between transplant and thymic reconstitution in mice is relatively short, small numbers of Treg cells early post-HSCT may be sufficient to blunt autoreactivity until new thymus-derived Treg cells emerge. Future studies using Treg-deficient, thymus-deficient mice as recipients of Treg cell-depleted HSCT should be able to address these possibilities. The role of Treg cells in cancer immunity...

Positional Candidate Genes for AOD and Aig Qtl

Immunologically relevant positional-candidate genes for Gasa3 on chromosome 6 have yet to be identified within the linkage interval (http www.informatics.jax.org ). Similarly, given the current size of the interval encompassing Aodla, identification of potential candidates is highly speculative. However, Il10rb (interleukin-10 receptor p) at 61 cM is an intriguing candidate since IL10 has been implicated in the establishment and maintenance of CD4+CD25+ T cells (Annacker et al. 2001). Trfr (transferrin receptor or Cd71) at 21.2 cM is a potential candidate for Aod1b. Trfr is downregulated during adult T cell development as well as in ontogeny prior to the appearance of the a p TCR and therefore serves as a marker of immature, proliferating T cells (Brekelmans et al. 1994). Stfa1, Stfa2, Stfa3 (stefin A1, A2 and A3) at 22.85 cM are inhibitors of cysteine endo- and exopeptidases (Bode and Huber 2000) such as cathepsin L and S involved in Ag processing (Pluger et al. 2002 Hsieh et al....

Optimizing Peptidebased Vaccines

Demonstrated a correlation between MHC binding affinity and peptide immu-nogenicity (60). Peptides derived from gp100, whose anchor residues were modified to fit the optimal HLA-A2 binding motif, stimulated tumor-reactive CTL more efficiently than the natural epitopes (61). An unmodified, gp100-derived peptide failed to elicit peptide-specific CTL in melanoma patients after subcutaneous administration with IFA. In contrast, vaccination with the modified peptide induced CTL responses in 91 of cases (13). None of the 11 patients immunized with the modified peptide in IFA alone experienced an objective tumor response. Interestingly, administration of the modified peptide along with high-dose interleukin-2 (IL-2) led to a clinical response rate of 42 in a group of 31 patients. More recently, Eguchi et al. identified the IL-13 receptor alpha2 (IL-13Ralpha2) peptide as an HLA-A2-restricted CTL epitope (62). IL-13Ralpha2 is restricted to, and expressed at, high levels in a majority of human...

Drugs Targeting Alloantibodies and Alloreactive B Cells

For example, plasmapheresis is sometimes used to treat acute antibody-mediated rejection. In this procedure, a patient's blood is pumped through a machine that removes the plasma but returns the blood cells to the circulation. In this way, circulating antibodies, including pathogenic alloreactive antibodies, can be removed. Intravenous immune globulin (IVIG) therapy, which is used to treat several, often antibody-mediated, inflammatory diseases, is also being applied in the setting of acute antibody-mediated rejection. In IVIG therapy, pooled IgG from normal donors is injected intravenously into a patient. The mechanisms of action are not fully understood but likely involve binding of the injected IgG to the patient's Fc receptors on various cell types, thereby reducing alloantibody production and blocking effector functions of the patient's own antibodies. IVIG also enhances degradation of the patient's antibodies by competitively inhibiting their binding to...

Role In Epigenetic Regulation And Dna Demethylation

Systemic Lupus Erythematosus (SLE) While MBD4 is generally inactivated in cancer, in SLE there is increased expression of MBD4. DNA hypomethylation seems to be a pathological feature of CD4+ cells in this autoimmune disease, and it is thought that the modification of the methylation status could contribute to the pathogenesis of SLE. Analysis of the expression profile of MBD4 in patients with SLE versus controls revealed a significant overexpression in patients and an inverse correlation between MBD4 expression and the level of DNA methylation in CD4+ cells 39 . On the basis of the newly discovered role of MBD4 in DNA demethylation, these observations suggest that MBD4 may be important for the pathogenesis of SLE.

Experimental Autoimmune Uveitis EAU

In addition to EAE, experimental autoimmune uveitis (EAU), a widely used animal model of human uveitis, is another CD4+ T-cell mediated organ-specific autoimmune disease which can be inhibited by agonistic anti-CD137 treatment (Shao et al., 2005). Uveitis is a common cause of human visual disability and blindness. EAU can be induced in susceptible rodent strains by immunization with retinal proteins such as the receptor retinoid binding protein (IRBP) (Donoso et al., 1989 Gery etal., 1986), retinal S antigen (S-Ag) (Wacker etal., 1977) andmelanin-associated Ag (MAA) (Bora etal., 1995 Broekhuyse etal., 1992) or by the adoptive transfer ofuveitogenic T cells to syngeneic rodents. TH 1-like response promotes the development of EAU (Tarrant et al., 1998), whereas TH2-like response manifests protective function (Rizzo etal., 1999 Wildner and Thurau, 1995), suggesting the Th1 nature of this type of autoimmune disease. Similar as in EAE model, Shao and colleagues (Shao et al., 2005) observed...

Tolerance and Regulatory T Cells

The majority of patients experience low-grade GVHD after allogeneic SCT, which is either self-limiting or rapidly responsive to therapy, and some patients never show any clinical signs of GVHD. In such patient groups, prophylactic or therapeutic immunosuppressionwithin a few months after SCT. Absence of GVHD after cessation of immunosuppression documents the development of a stable state of tolerance of the donor immune system toward the host. In fact, hematopoietic SCT is the most efficient way to induce tolerance to alloantigens, mainly by deletion of host-reactive T cells that develop from donor-derived precursors in the recipient's thymus (Ildstad and Sachs 1984 Salaun et al. 1990). Central tolerance mechanisms and the problems associated with the recovery of immune competence after transplantation have been reviewed elsewhere (Sprent and Kishimoto 2001 Sykes and Sachs 2001). In contrast, mature donor T cells within the stem cell graft are generally not tolerant toward recipient...

Complex Interactions Among B7H1 B7DC B71 PD1 and Possible Additional Binding Partners

The predominant role of PD-1 is inhibitory for immune responses, and this notion is supported by the phenotypes of lymphoproliferative autoimmune diseases in PD-1-deficient mice (Okazaki and Honjo 2006). There is ample evidence that the major ligand for the suppressive function of PD-1 in vivo appears to be B7-H1 because results obtained from PD-1 or B7-H1 deficient mice as well as blocking antibodies against PD-1 or B7-H1 are often similar (Nishimura et al. 1999, 2001). However, B7-H1 deficient mice do not develop autoimmune diseases, albeit mild to moderate levels of CD8+ T cell accumulation are common in peripheral organs (Dong et al. 2004). In T cell culture systems, studies reveal either positive or negative function of B7-H1 and B7-DC in T cell growth and cytokine production, highlighting a lack of reliable in vitro models for the prediction of their functions in vivo. Possible interpretations for these somewhat confusing data are either

Therapeutic Approaches For Immunologic Diseases 417

CTLs may contribute to tissue injury in autoimmune disorders that are caused primarily by CD4+ T cells, such as type 1 diabetes. Few examples of autoimmune diseases mediated only by CTLs have been documented. Myocarditis with infiltration of the heart by CD8+ T cells develops in mice and sometimes in humans after infection with coxsackievirus B, resulting in a form of dilated cardiomy-opathy. Patients and experimental animals contain CTLs specific for myocyte proteins. It is postulated that the heart lesions are initiated by the virus infection and

Regulatory T Cells and IFNy

IDO has been shown to be an immune regulator which plays a critical role in maintaining maternal T cell tolerance to allogeneic fetuses during pregnancy (Munn et al., 1998), and in CTLA-4 mediated tolerance in transplantation and autoimmunity (Fallarino etal., 2003 Grohmann et al., 2002 Mellor et al., 2003). IDO is a tryptophan-catabolizing enzyme expressed by macrophages and other cell types it has regulatory effects on T cells due to consuming of tryptophan In summary, administration of anti-CD137 in CIA model induces antigen-dependent clonal expansion of CD11c+CD8+T cells and promotes their IFN-y production. IFN-y further induces monocytes and DCs to produce IDO, which causes tryptophan catabolism and production of the metabolite kynurenine, which is thought to kill antigen-activated CD4+ T cells, leading to inhibition of autoimmune disease.

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 unknown, because of which the understanding of the pathogenesis is incomplete. Susceptibility to RA is linked to the HLA-DR4 haplotype. Recent linkage and genome-wide association studies have revealed a large number of genes in which polymorphisms are associated with RA. There is an association with the gene encoding a tyrosine phosphatase, PTPN22, but the role of this enzyme in lymphocyte regulation is poorly understood (see Chapter 14).