Autoimmune Diseases Treatment

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! More here...

Autoimmune Paleo Cookbook Summary


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My Autoimmune Paleo Cookbook Review

Highly Recommended

All of the information that the author discovered has been compiled into a downloadable ebook so that purchasers of Autoimmune Paleo Cookbook can begin putting the methods it teaches to use as soon as possible.

This ebook does what it says, and you can read all the claims at his official website. I highly recommend getting this book.

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

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...

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

Pathogenesis Of 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...

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...

Acquired immune deficiency syndrome dementia

A number of autoimmune neuroinflammatory disorders (see 6.09 Neuromuscular Autoimmune Disorders) affect either the central or peripheral nervous system. Many of these disorders are exceptionally rare such as Moersch-Woltman syndrome (stiff-man), Lambert-Eaton myasthenic syndrome, and myasthenia gravis (MG). While uncommon, these disorders tend to be highly debilitating as they directly alter neuromuscular transmission. The most common of these disorders is MG which affects an estimated 60 000 people in the USA. The primary pathology underlying MG appears to be the production of autoantibodies directed against the alpha subunit of the neuromuscular nicotinic acetylcholine receptor. Through direct interference and complement-mediated lysis of the postsynaptic muscle membrane, the autoantibodies cause disruption in the motor endplate that leads to a weakness in skeletal muscle throughout the body. The autoimmune disorder systemic lupus erythematosus (SLE) and the neuroinflammatory...

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 Antigen Specificity of Naturally Arising TR

The prevailing hypothesis regarding the TCR specificity of naturally arising regulatory T cells is that they recognize self-antigen, and that this interaction is important for TR development and function to suppress autoimmunity. This model was originally prompted by two studies in the 1990s that indirectly suggested that naturally arising TR recognize tissue-specific self-antigens. Initial studies by Taguchi and colleagues suggested that the functional maintenance of CD4+ Tcellscapableofprotectionagainst prostatitisoroophoritisrequired Where does this TCR interaction with antigen occur Early reports suggested that CD25+ T cells originate in the thymus, as animals thymectomized at day 3 of life develop spontaneous autoimmunity which could be rescued by the adoptive transfer of normal CD25+ regulatory T cells (Sakaguchi et al. 1995). Thus, the development of autoreactive cells relative to TR is favored under the conditions of early thymectomy, and these observations suggested that the...

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


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.

Additional Resources Books

Chinese herbs as immunomodulators and potential disease-modifying antirheumatic drugs in autoimmune disorders. Curr Drug Metab 2004 5 181-192. Lai JH. Immunomodulatory effects and mechanisms of plant alkaloid tetrandrine in autoimmune diseases. Acta Pharmacol Sin 2002 23 2093-1101.

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.

CASE 1 Tshsecreting Pituitary Adenoma Case Description

Her past history was unremarkable except for mild hypertension, controlled with a diuretic. There was no family history of thyroid or autoimmune disease. She was taking no medications other than the diuretic and the atenolol. She was 1 yr postmenopausal and had not taken hormonal replacement therapy (HRT).

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...

The Two Basic Immunotoxic Action of Chemicals Unwanted Activation

Secondly, chemicals or their metabolites can act by the immune system. This means they interfere with the response mediated by the specific antigen receptors of B and or Tcells. Chemicals may be recognized as antigen and elicit immune responses, or they may directly or indirectly change self antigens and thus break tolerance. It is generally accepted by now that T cells are the major players in xenobiotic-induced autoimmunity and allergy. Chemicals acting by the immune system lead to sensitization and a memory response. Memory lymphocytes can expand and mediate a stronger immune response on second contact with the chemical, even if it occurs long after the first contact. Adverse immune reactions of this type may lead to allergy or autoimmunity.

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

Innate Antitumor Responses

While these innate responses may contribute to tumor suppression, their aberrant activation may also prove deleterious when normal tissues are perturbed, as during autoimmunity or chronic inflammation. In these settings, the sustained expression of NKG2D ligands leads to downregulation of NKG2D surface expression through increased endocytosis and the consequent suppression of protective responses (Oppenheim et al, 2005). As a result, there may be an onset of a kind of low-level chronic inflammation process, termed smoldering inflammation, which preserves certain characteristics that actually promote tumor progression. Thus, depending on its context, expression of stress ligands may either trigger cytotoxic antitumor reactions or contribute to conditions that can facilitate immune escape.

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.

Adaptive Antitumor Responses

Tregs may play an important role in modulating the dual roles of adaptive immunity in tumor protection and promotion (Dranoff, 2005). Substantial evidence in multiple tumor models indicates that Tregs present a major impediment to cytotoxic T cellmediated tumor rejection, particularly in the context of therapy-induced responses. Indeed, the presence of Tregs defined by the expression of the specific marker FoxP3 in ovarian cancer patients is tightly linked to inferior clinical outcomes (Curiel et al., 2004). On the other hand, Tregs function to maintain immune homeostasis, and their disruption leads to severe autoimmune disease and chronic inflammation. These functions may underlie the striking ability of Tregs to effectuate tumor destruction in murine models of inflammation-induced cancer (Erdman et al, 2005). Moreover, the presence of Tregs in the cellular infiltrates of Hodgkin's lymphomas has been linked to improved survival, perhaps reflecting a dependence of Reed-Sternberg cells...

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.

Suppressive Effects of CD4CD25 Regulatory T Cells on the Innate Immune Response

Importantly, the regulation of APC function by CD4+CD25+ Tregs might also occur in vivo. It was shown recently that transfer of antigen-pulsed mature DCs into mice that were depleted for CD4+CD25+ Tregs resulted in higher Th1 responses compared to nondepleted mice 88 . A different study by Maloy et al. using a T cell-independent mouse model for intestinal inflammation demonstrated that transfer of CD4+CD25+ Tregs resulted in reduced activation and recruitment of neutrophils, monocytes macrophages, DCs and NK cells, which was partly mediated by IL-10 and TGF-3 89 . Together these data indicate that both the adaptive and the innate immune system are subject to CD4+CD25+ Treg-mediated suppression. The ability of Tregs to inhibit the function of many different cell types helps to explain the observations that CD4+CD25+ Tregs are efficient in suppressing many immune-mediated diseases including autoimmunity 12, 90, 91 , transplant rejection 92 , tumor immunity 93-95 , allergy 96 and...

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...

Guillain Barre syndrome

While GBS occurs throughout the world, the axonal forms of the disease are much less common in Europe and North American, and more common in China, Japan, India, and Central America. Contrary to many autoimmune diseases, males are more commonly affected than females.10 Age distribution is bimodal - with peaks in young adults and the elderly. There are no reliable serological markers.

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...

Costimulatory molecule inhibitors

In the adaptive immune response, nonspecific signals are generated from the interaction of pairs of receptors, so-called co-stimulatory molecules.30 Inhibition of the co-stimulatory signal results in suppression of the immune response. The CD28 B7, CTLA4 B7, and CD40 CD40L receptor ligand pairs of co-stimulatory molecules have been the targets of drug development for autoimmune disease. There are two conceptually different approaches to blocking co-stimulation by inhibiting either the induced expression of co-stimulatory molecules or the transmission of their specific intracytoplasmic signal. The latter approach is described here.

Therapeutic Vaccines and Toleragens

While vaccines have traditionally been used as prophylactics, they are increasingly being used as therapies for already established chronic disease.31 For autoimmune disease therapy, a peptide similar to that causing the disease is administered to the patient in theory, the vaccine then stimulates an immune response to the T cells reacting in the disease. This presumes that the autoantigen(s) is known, and that the disease is caused by one or a few antigens. An advantage to this hypothetical mechanism is that the anti-Tcell response should, in theory, be specific for the T cells contributing to disease pathogenesis. Glatiramer acetate is the first vaccine that has been used to treat an autoimmune disease - in this case RRMS32 it was approved by the US FDA in 1996. It is a mixture of many synthetic peptides - random polymers - that mimic the antigenic portion of MBP. It reduces the relapse rate in RRMS, impacts MRI markers of disease activity, is well tolerated, and does not appear to...

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...

Cytokine Regulation Of Immune Tolerance To Tumors

Major players of which include CD8 + cytotoxic T lymphocytes (CTLs), CD4 + Th1 cells, y8-T cells, and NK cells. The effector functions of these cells are responsible for direct target cell killing as well as production of cytokines and other modulators that regulate the function of various cell types, including tumor cells. The cellular immune response is responsible for the host defense of intracellular pathogens however, when the cellular immune response is dysregu-lated, it can also trigger autoimmune diseases (e.g., type I diabetes). As a self-tolerance mechanism, several cytokines are involved in the suppression of cellular immune responses either under steady state or during the resolution phase of infection or trauma, which impedes the development of tumor immunity. In addition, cytokines that skew immune responses to T helper 2 (Th2) cells or to the newly discovered Th17 pathway can also influence immune responses to tumors. Therefore, cytokine inhibition of tumor immunity can...

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

Materials and Methods

Phase 2 was used for the molecular evaluation of the presence of bacterial DNA in patients and hemodialyzers. 38 patients (of the original 81) without evident clinical infection or clear causes of inflammation were selected for this study. Whole blood and dialysate were collected during treatment. Blood was collected just after needle insertion and spent dialysate was collected every hour (4 samples of 50 ml). Samples from the blood and dialysate compartments of the dialyzers were collected following treatment and after filter washing, also collecting the last washing solution for control. Patients were excluded if they had apparently active infection or antibiotic administration within 2 weeks, and or if other sources of inflammation such as periodontal disease, malignancy, autoimmune disease, trauma, infarction, etc., were present.

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,...

Summary And Future Perspectives

Since tumors arise from normal self tissues, the default pathway to tumor-associated antigens is likely to be tolerance, especially tolerance that prevents induction of destructive cellular immune responses. The barriers that prevent antitumor immune responses are related to, if not the same as, those that inhibit autoimmune diseases, which include mechanisms of immune suppression or immune deviation under steady state and during wound healing.

Ocular Surface Diseases

Another series of disorders of the ocular surface is 'dry eye.' Dry eye is characterized by deficits in tear production secretion and deficiencies in the quality of tears, thereby causing ocular discomfort, itching, and a foreign body sensation on the ocular surface.95 It has recently been recognized that several aspects of dry eye involve an inflammatory cascade. Sjogren's syndrome (keratoconjunctivis sicca) is a common (affects 0.5 of adult women) autoimmune disorder of the lacrimal and salivary glands that causes ocular dryness. Treatments for dry eye have traditionally sought to reduce the symptoms of dryness by hydrating and lubricating the ocular surface with artificial tears. However, this is rarely sufficient and pharmacotherapy is necessary to prevent corneal and or conjunctival damage. Therapeutic approaches include use of immune suppressive anti-inflammatory agents, such as the fungal-derived peptide, cyclosporin, and topical corticosteroids, such as methylprednisolone,...

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...

Antibody Feedback Regulation Of Humoral Immune Responses By Fc Receptors

The importance of FcyRIIB-mediated inhibition is demonstrated by the uncontrolled antibody production seen in mice in which the gene encoding this receptor has been knocked out. A polymorphism in the FcyRIIB gene has been linked to susceptibility to the autoimmune disease systemic lupus erythematosus in humans.

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.

Congenital or Acquired Muscle Weakness

Sixth, third or fourth cranial nerve palsies are sometimes seen after head injuries and the surgeon must always bear in mind the possibility of a sixth or other cranial nerve palsy being associated with raised intracranial pressure. Myasthenia gravis is extremely rare in children but it can present as a squint. In some cases of squint there is a degree of facial asymmetry. These patients might also have asymmetrical eyes, one being myopic or hypermetropic relative to the other. Sometimes there is no refractive error but there might be an asymmetry of

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,

Clinical Features Of Hivassociated Castlemans Disease

In general, MCD presents in the fourth or fifth decade of life but occurs earlier in people who are HIV positive. Patients often present with generalized malaise, night sweats, rigors, fever, anorexia, and weight loss. On examination, they have multiple lymphadenopa-thy, hepatosplenomegaly, ascites, edema, and effusions both pulmonary and pericardial. Laboratory investigations may reveal thrombocytopenia, anemia, hypoalbuminemia, and hypergammaglobulinemia. The systemic symptoms are attributed to IL-6 and can be severe enough to cause pancytopenia, organ failure, particularly respiratory and renal, as well as shock, requiring admission into intensive care units. HIV-infected patients with MCD have a greater preponderance for pulmonary complications. MCD is more likely to lead to neuropathic complications than does locally confined Castleman's disease. Patients can develop polyneuropathies, leptomeningeal and CNS infiltration, as well as myasthenia gravis.114 The polyneuropathy is a...

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.

Interfering Antibodies

Human antianimal (heterophilic) antibodies, rheumatoid factor, and autoantibodies in patients with autoimmune diseases are potential sources for false test results. Commercial assays include blocking agents to minimize these analytic interferences, but this method may not be effective in every situation. Exposure to animal antigens (e.g., close contact with animals or treatment with antibody fragments, such as abciximab) can give rise to human antianimal antibodies. The BNP and NT-proBNP assays are mainly based on mouse antibodies, and, therefore, human antimouse antibodies are most relevant to clinical practice. Heterophilic antibodies and autoantibodies may lead either to false positive test results, by bridging between the detection and the capture antibodies in the absence ofthe analyte, or to false negative results, by interfering with the binding ofthe assay antibodies (Fig. 1B,C). Heterophilic antibodies may persist for months to years after initial exposure.

Classification of Diabetes Mellitus and the Metabolic Syndrome

Immune-mediated diabetes, previously referred to as insulin-dependent diabetes, type I diabetes, and juvenile-onset diabetes, accounts for 5-10 of all cases of diabetes. Immune-mediated diabetes typically develops in childhood and adolescence, but has a variable age of onset ranging from infancy to the eighth and ninth decades of life. Abnormalities in glucose homeostasis result from severe insulin deficiency due to cell-mediated autoimmune inflammation (insulitis) and subsequent destruction of the b-cells of the pancreas. In T1DM, daily exogenous insulin administration is a life-sustaining intervention, and the absence of insulin can result in a state of acute metabolic decompensation known as diabetic ketoacidosis (DKA). Individuals with T1DM are at increased risk for other autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. Individuals who present with a...

Regulation of Immunity in the Gastrointestinal Tract by Regulatory T Cells and Cytokines

Oral tolerance is systemic adaptive immune tolerance to antigens that are ingested or otherwise administered orally and is a potential way of treating diseases in which unwanted immune responses occur, such as autoimmunity. Oral tolerance has been most clearly demonstrated in experimental rodent models. Mice fed high doses of a protein antigen may subsequently have impaired humoral and T cell-mediated responses to the same antigen administered by other routes, such as through the skin. A similar phenomenon can be demonstrated when antigens are administered through the nasal passages into the respiratory mucosa, and the more general term mucosal tolerance is used to describe tolerance induced by either oral or nasal antigen administration. The physiologic role of oral tolerance is speculated to be the prevention of potentially harmful immune responses to food proteins and commensal bacteria. The underlying mechanisms of oral tolerance are not well understood but likely include the same...

Immune Privilege in the Eye Brain and Testis The

In contrast to induced tolerance to foreign antigens introduced into the anterior chamber, self antigens in the eye are isolated from the immune system, and systemic tolerance to these antigens is not induced. This lack of tolerance becomes a problem only when eye trauma exposes the eye antigens to the immune system. A striking example of this is sympathetic ophthalmia, in which trauma to one eye causes release of eye antigens leading to autoimmune disease in both the injured eye and the uninjured eye. Presumably, although self antigens in the normal eye are inaccessible to the extraocular immune system to induce tolerance, activated immune effector cells and antibodies that are generated in the periphery when one eye is injured have access to and cause injury to the normal eye. Immune privilege in the testis serves to limit inflammation that may impair male fertility. Many self antigens in the adult testis are first expressed at the time of puberty, well after the development of a...

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...

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.

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