New Treatment of Autoimmune Diseases

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! Read more here...

Autoimmune Paleo Cookbook Overview

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Highly Recommended

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My opinion on this e-book is, if you do not have this e-book in your collection, your collection is incomplete. I have no regrets for purchasing this.

Autoimmunity and autoimmune diseases

Autoimmunity, as opposed to autoimmune disease, is vital to the development of a normal immune response. As we discussed previously, T cells recognise antigen only in association with self-MHC molecules they will not respond if the antigen is presented by foreign MHC molecules, thus confirming that the reaction involves specific recognition of self molecules. This is an example of autoimmunity which is productive. A further example is the recognition of self-idiotypes by anti-idiotypic antibodies, which is essential for the diversification and regulation of immune responses. Apart from these instances, the immune system does not normally react to itself, i.e. it is tolerant to self. Self-tolerance occurs early in foetal development and is vital for health and the normal functioning of the immune response its breakdown resulting in autoimmune disease which may be debilitating or even fatal. How can such autoimmunity develop One suggestion is that an antigen may be hidden from the...

Sexlinked factors in autoimmune disease

Generally, women are much more susceptible than men to most connective tissue diseases which include autoimmune diseases. The incidence of the latter is demonstrably affected by both sex hormones and genes linked to the X, or Y, chromosomes. It is well known that many hormones affect the lymphoid system, the effect of gonadal hormones being particularly apparent. Indeed, it has been shown that elevated oestrogen levels exacerbate autoimmune disease whilst androgen has a protective, immunosuppressive role.

Chemicals And Pharmaceuticals In Autoimmune Disease

With the worldwide explosion of manufacturing industry and pollution, an association between exposure to certain chemicals and the development of specific autoimmune diseases has been clearly established. These agents may interact with tissues resulting in the expression of modified self-antigens, which are the target for an autoimmune response. Similarly, pharmaceuticals may induce disease. For example, treatment with methyldopa has been associated with the development of autoimmune haemolytic anaemia.

Immunopathology of autoimmune diseases

Autoimmune diseases form a large, heterogeneous group with a wide variety of clinical signs and symptoms. Despite this disparity, the immunopathology of all these diseases may be considered to be the result of particular hypersensitivity reactions, each disease being the result of one or more type of response. Type III hypersensitivity reactions are seen in autoimmune diseases where the autoantibody binds to self-antigens free in tissue fluids or in the general circulation. The resulting complexes are free to circulate throughout the body. However, they may become quite large (depending on the relative concentrations of antibody and antigen) and therefore, insoluble. This results in their precipitation in the tissues and blood vessels. Particularly vulnerable are tissues with large filtering membranes such as the kidneys, joints and choroid plexus, where the presence of immune complexes results in the activation of the complement cascade and inflammatory sequelae (Figure 5.4). As a...

The immunology of autoimmune disease

Autoimmune diseases result from an abnormal immune response to self-antigens. In all these diseases, there is a breakdown of normal regulatory mechanisms and a lack of tolerance to the self-antigens concerned. The complex immunological responses that occur in these diseases are responsible for the resulting pathology and an understanding of these responses is vital for effective disease management. Table 5.7 Target antigens involved in autoimmune diseases Myasthenia gravis Primary biliary cirrhosis Autoimmune thyroid disease

Which of the following statements concerning the classification of autoimmune disease is Incorrect

(b) Clinically, autoimmune diseases have been divided into systemic or non-organ-specific and organ-specific. (c) Systemic lupus erythematosus is a classical example of an organ-specific autoimmune disease. (e) Insulin-dependent diabetes mellitus is an example of an organ-specific autoimmune disease.

Autoimmune Disease In Humans

Autoimmune diseases affect about 1 in 15 people in the United States. A partial list of some of the more common human autoimmune disorders is shown in Table 12.1. Almost every organ and tissue in the body can be a target for autoimmune disease. There are a number of generalizations about autoimmune disease that seem to hold true. Although there are some relatively organ-specific autoimmune diseases, in fact almost all autoimmune diseases affect more than one system in the body. The relatively restricted diseases are just that relatively restricted. Patients with Some Representative Human Autoimmune Diseases. Some Representative Human Autoimmune Diseases. Myasthenia gravis3 insulin-dependent (Type 1) diabetes, for example, almost always have other autoimmune problems. The spectrum of diabetes-associated autoimmune diseases (pernicious anemia, Grave's disease, Hashimoto's thyroiditis, to name just a few) is so broad that sometimes it's easier to think of diabetes as just one part of a...

Approaches To Treating Autoimmune Disease

Current therapies for autoimmune disease are not terribly effective. For the most part they are based on mild immunosuppres- A new approach for not just managing, but curing, autoimmune disease is based on hematopoietic stem cell autotransplantation. This approach, which has worked well in animals and is now in human clinical trials, is based on the following knowledge and assumptions. First, we know that what a T cell or B cell recognizes as foreign depends on what kinds of receptors T cells and B cells randomly generate. Some of us will randomly generate receptors that cross react with self molecules, but, because this is a completely random process (chapter 2), each of us even genetically identical twins will generate different subsets of self-reactive cells. Each of us also generates different groups of receptors that are reactive with various environmental antigens, such as microbial antigens. Autoimmunity arises, we think, because the tolerance mechanisms acting to control...

Treatment of Autoimmune Diseases

This chapter describes some common human autoimmune diseases. These can be divided into two broad categories organ-specific and systemic autoimmune disease (Table 20-1). Such diseases affect 5 -7 of the human population, often causing chronic debilitating illnesses. Several experimental animal models used to study autoimmunity and various mechanisms that may contribute to induction of autoimmune reactions also are described. Finally, current and experimental therapies for treating autoimmune diseases are described.

Autoimmunity Can Be Associated with the MHC or with Particular TCell Receptors

Several types of studies have supported an association between expression of a particular MHC allele and susceptibility to autoimmunity, an issue covered in detail in Chapter 7. The strongest association between an HLA allele and an autoimmune disease is seen in ankylosing spondylitis, an inflammatory disease of vertebral joints. Individuals who have HLA-B27 have a 90 times greater likelihood of developing ankylosing spondylitis than individuals with a different HLA-B allele. However, the existence of such an association should not be interpreted to imply that the expression of a particular MHC allele has caused the disease, because the relationship between MHC alleles and development of autoimmune disease is complex. It is interesting to note that, unlike many other autoimmune diseases, 90 of the cases of ankylosing spondylitis are male. The presence of T-cell receptors containing particular Va and Vp domains also has been linked to a number of autoimmune diseases, including...

Tolerance Induction in Autoimmunity With MAb

MAb have been used either to prevent the onset of experimental autoimmune diseases, or to treat overt autoimmunity (see Note 5). For the prevention of autoimmunity, animals are often treated from the neonatal period (98). In some experiments, anti-CD3 MAb have been shown to be successful in treating overt diabetes in NOD mice, restoring a state of dominant tolerance mediated by Treg cells (73,74)

NK Cells in Autoimmune Disease

NK cells are not only found at sites of normal immune responses but have also been shown to accumulate in target organs of autoimmunity, for example, in the inflamed joints of RA (Dalbeth and Callan 2002 Tak et al. 1994), in brain lesions of MS (Traugott 1985), in psoriasis lesions (Cameron et al. 2002), and in the inflamed islets of Langerhans in IDDM (Miyazaki et al. 1985 Poirot et al. 2004 and our unpublished data). The presence of NK cells in target organs of autoimmunity, implying a role in disease at this site, is interesting in relation to findings reporting decreased NK cell numbers and impairment of NK cell function in peripheral blood in patients (Cameron et al. 2003 Yabuhara et al. 1996 and reviewed in Baxter and Smyth 2002 Flodstrom et al. 2002b Grunebaum et al. 1989). Data from us and others show that rodents with diabetes also have compromised peripheral NK cells (Johansson et al. 2004 Poulton et al. 2001). It is not clear whether the reported alterations in blood NK...

Which of the following statements concerning autoimmunity is Correct

(a) Autoimmunity is vital to the development of a normal immune response. (c) Autoimmune disease arises as a result of the development of self-tolerance. (d) Autoimmunity may develop as a result of exposure in adult life to an antigen which was hidden from the immune system in the early stages ofdevelopment.

Proposed Mechanisms for Induction of Autoimmunity

A variety of mechanisms have been proposed to account for the T-cell-mediated generation of autoimmune diseases (Figure 20-8). Evidence exists for each of these mechanisms, B cells, is thought to induce an autoimmune response, in this case resulting in tissue damage. In all likelihood, several mechanisms are involved in each autoimmune disease. Adapted from V. Kumar et al, 1989, Annu. Rev. Immunol. 7 657. and it is likely that autoimmunity does not develop from a single event but rather from a number of different events. In addition, susceptibility to many autoimmune diseases differs between the two sexes. As noted earlier, Hashimoto's thyroiditis, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and scleroderma preferentially affect women. Factors that have been proposed to account for this preferential susceptibility, such as hormonal differences between the sexes and the potential effects of fetal cells in the maternal circulation during pregnancy, are...

Autoimmunity Can Develop Spontaneously in Animals

Hashimotos Lymph Nodes

A number of autoimmune diseases that develop spontaneously in animals exhibit important clinical and pathologic similarities to certain autoimmune diseases in humans. Certain inbred mouse strains have been particularly valuable models for illuminating the immunologic defects involved in the development of autoimmunity. New Zealand Black (NZB) mice and F1 hybrids of NZB and New Zealand White (NZW) mice spontaneously develop autoimmune diseases that closely resemble systemic lupus ery-thematosus. NZB mice spontaneously develop autoimmune hemolytic anemia between 2 and 4 months of age, at which time various auto-antibodies can be detected, including antibodies to erythrocytes, nuclear proteins, DNA, and T lymphocytes. F1 hybrid animals develop glomerulonephritis from immune-complex deposits in the kidney and die prematurely by 18 months. As in human SLE, the incidence of autoimmunity in the (NZB X NZW)F1 hybrids is greater in females. An accelerated and severe form of systemic autoimmune...

Evidence Implicating the CD4 T Cell MHC and TCR in Autoimmunity

The inappropriate response to self-antigens that characterizes all autoimmune diseases can involve either the humoral or cell-mediated branches of the immune system. Identifying the defects underlying human autoimmune diseases has been difficult more success has been achieved in characterizing the immune defects in the various animal models. Each of the animal models has implicated the CD4+ T cell as the primary mediator of autoimmune disease. For example, the evidence is quite strong that, in mice, EAE is caused by CD4+ TH1 cells specific for the immunizing antigen. The disease can be transferred from one animal into another by T cells from animals immunized with either MBP or PLP or by T-cell recognition of antigen, of course, involves a trimol-ecular complex of the T-cell receptor, an MHC molecule, and antigenic peptide (see Figure 9-16). Thus, an individual susceptible to autoimmunity must possess MHC molecules and T-cell receptors capable of binding self-antigens.

Molecular Mimicry May Contribute to Autoimmune Disease

For several reasons, the notion that microbial or viral agents might play a role in autoimmunity is very attractive. It is well accepted that migrant human populations acquire the diseases of the area to which they move and that the incidence of autoimmunity has increased dramatically as populations have become more mobile. This, coupled with the fact that a number of viruses and bacteria have been shown to possess Molecular mimicry has been suggested as one mechanism that leads to autoimmunity. One of the best examples of this type of autoimmune reaction is post-rabies encephalitis, which used to develop in some individuals who had received the rabies vaccine. In the past, the rabies virus was grown in rabbit brain-cell cultures, and preparations of the vaccine included antigens derived from the rabbit brain cells. In a vaccinated person, these rabbit brain-cell antigens could induce formation of antibodies and activated T cells, which could cross-react with the recipient's own brain...

CD4 T Cells and TH1TH2 Balance Plays an Important Role in Autoimmunity in Some Animal Models

A similar experimental protocol has been used to isolate T-cell clones specific for thyroglobulin and for M. tuberculosis from EAT and AA animals, respectively. In each case, the T-cell clone induces the experimental autoimmune disease in normal animals. Examination of these T cells has revealed that they bear the CD4 membrane marker. In a number of animal models for autoimmune diseases it has been possible to reverse the autoimmunity by depleting the T-cell population with antibody directed against CD4. For example, weekly injections of anti-CD4 monoclonal antibody abolished the autoimmune symptoms in (NZB X NZW) F1 mice and in mice with EAE. Most cases of organ-specific autoimmune disease develop as a consequence of self-reactive CD4+ T cells. Analysis of these cells has revealed that the TH1 TH2 balance can affect whether autoimmunity develops. TH1 cells have been implicated in the development of autoimmunity, whereas, in a number of cases, TH2 cells not only protect against the...

Monoclonal Antibodies May Be Used to Treat Autoimmunity

Monoclonal antibodies have been used successfully to treat autoimmune disease in several animal models. For example, a high percentage of (NZB X NZW) F1 mice given weekly injections of high doses of monoclonal antibody specific for the CD4 membrane molecule recovered from their autoimmune lupus-like symptoms (Figure 20-11). Similar positive results were observed in NOD mice, in which treatment with an anti-CD4 monoclonal antibody led to disappearance of the lymphocytic infiltration and diabetic symptoms. The association of autoimmune disease with restricted TCR expression in a number of animal models has prompted researchers to see if blockage of the preferred receptors with monoclonal antibody might be therapeutic. Injection of PL J mice with monoclonal antibody specific for the Vp 8.2 T-cell receptor prevented induction of EAE by MBP in adjuvant. Even more promising was the finding that the Vp 8.2 monoclonal antibody could also reverse the symptoms of autoimmunity in mice...

Classification of autoimmune disease

In the 1950s, Witebsky established the criteria for determining the aetiology of human diseases which were thought to be autoimmune. Witebsky's postulates were modelled on those of Koch and required the presence of autoantibody or a cell-mediated immune response to a self-antigen, which having been identified, could induce a similar disease in an experimental host mediated by the same immunological mechanism. Since these criteria were established, our knowledge of immunology has increased by leaps and bounds. However, they remain a good guide for identifying autoimmune diseases. Clinically, autoimmune diseases have been divided into systemic or ''non-organ-specific and ''organ-specific'' diseases. However, this categorisation is not absolute. Many autoimmune diseases have both organ-specific and non-organ-specific complications. In addition, more than one type of disease may occur in the same individual. The classical example of a non-organ-specific autoimmune disease is systemic...

Are Peptides Suitable Agents for Therapeutics in Autoimmune Diseases

Synthetic peptides have long been recognized as potential candidates for therapeutic vaccines in autoimmune diseases (Fairchild 1997 Anderton 2001 Sela and Mozes 2004 Larch and Wraith 2005, Root-Bernstein 2006). One important advantage of short peptides is that in the absence of adjuvant, their immunogenicity is very weak, making them very attractive immunomodulatory agents. In general, however, pep-tides are short-lived molecules, which degrade rapidly in biological fluids, and this poor stability has been used to deny their potential usefulness. It should be mentioned that in contrast to what is generally believed, all peptides are not immediately cleaved in serum certain sequences possess a sufficient intrinsic stability allowing their target, such as major histocompatibility complex (MHC) molecules or albumin, which serves at the periphery as a carrier sponge. However, to overcome this instability drawback, several attempts have been made, replacing standard peptides by more...

Myasthenia Gravis

Myasthenia gravis (MG) is a disease characterized by extreme muscular weakness, usually beginning in the head and neck but in most cases extending to the entire body. It is twice as frequent in women as in men, and is seen earlier in women (average age of onset 28 years, vs. 42 years in men). The disease in men is often more limited as well. The first visible signs of myasthenia are usually drooping eyelids and sagging neck and facial muscles. Patients may experience difficulty in breathing and swallowing, and may have vision problems as well. The defect in MG is an interesting one and involves one of the most highly restricted antiself attacks of any of the autoimmune diseases. Patients with MG make antibodies that affect the response to a neurotransmitter called acetylcholine (ACh). ACh is released from the tip of a nerve cell at the point where it attaches to a muscle and is picked up by a special acetylcholine receptor (AChR) on the muscle being served. This causes the muscle to...

Why Autoimmunity

Who needs autoimmunity Where does it come from It could be viewed as just another way nature has of being sure we don't hang around too long, using up valuable resources. But in fact, with a few exceptions most autoimmune diseases are not all that life threatening. They make life miserable, but they don't usually kill us. So how do they fit into the grand scheme of things Why does the immune system turn against self Although many autoimmune diseases seem almost certainly to come to grips with the possibility that the immune system does, on occasion, decide to attack self, unprovoked by outside agents. Is this simply one more cross we must bear, one more price we must pay for an immune system that does a pretty good job most of the time Or could it be that autoimmunity is a normal part of human biology, playing a more profound role than malicious aggravation

Autoimmune Disorders

Dle Blisters

Lupus erythematosus (LE) is a chronic inflammatory autoimmune disease of connective tissue. The more widespread form of the disease, systemic lupus erythematosus (SLE), involves the skin and other organs. The discoid form (DLE) involves only the skin. It is seen as rough, raised, violet-tinted papules, usually limited to the face and scalp. There may also be a butterfly-shaped rash across the nose and cheeks that is typical of this disease.

Immune Mediated Diseases Where Do We Stand

The progress in basic immunology during the past 50-60 years has been associated with the emergence of clinical immunology as a new discipline in the 1970s. It was defined as the application of basic immunology principles to the diagnosis and treatment of patients with diseases in which immune-mediated mechanisms play an etiological role. Immune-mediated diseases such as autoimmune diseases, allergic diseases, and asthma are important health challenges in the United States and worldwide. For instance, autoimmune diseases afflict 5-8 of the US population asthma and allergic diseases combined represent the sixth leading cause of chronic illness and disability in the United States and the leading cause among children. As shocking as these numbers and other data in this chapter are, they cannot adequately reflect the physical and emotional devastation to individuals, families, and communities coping with hundreds of immune-mediated disorders nor do they capture the enormous...

Immune Mediated Diseases Statistics

According to the modern and common point of view, immune-mediated diseases are represented by a big group of the immune system diseases and even a large group of the diseases directly or indirectly associated with the immune system. The diseases of the immune system include (i) immunodeficiencies (primary or inherited and secondary or acquired) and (ii) immunoproliferative disorders, such as malignancies of the immune system (i.e., multiple myeloma, lymphomas, and leukemias), autoimmune diseases, and immune hypersensitivities (i.e., allergies). The disorders where the immune system is not the primary cause of a disease, although plays an obvious role in the pathogenesis, include, for instance, cancer and infectious diseases (Figure 1). Figure 1. Schematic presentation and classification of immune-mediated diseases, their research, diagnosis, and therapy. Left column combines diseases of the immune system, such as primary immunodeficiencies, autoimmune diseases (rheumatoid arthritis,...

Regulation of Self Tolerance

There has been considerable progress in understanding how sets of gene products coordinate self tolerance mechanisms and how failure of these controls can predispose to autoimmune disease (2). Many of the genes and proteins involved are conserved between commonly used experimental animals and humans, allowing extrapolation between mechanisms defined in animals and clinical investigations. The strategies used to regulate self-reactive receptors during T- or B-lymphocyte differentiation are (1) cell deletion, (2) editing of the offending receptor to reduce binding to self Ag (3), (3) use of intrinsic mechanisms that result in clonal anergy or biochemical tuning and, should the cells evade these mechanisms, (4) extrinsic controls that limit the supply of crucial growth factors, costimulatory molecules (CD40 ligand CD154 , B7 family ligands and Toll-like receptor TLR ligands), inflammatory mediators, and other factors. These extrinsic controls also include active suppression by regulatory...

Dendritic Cells and Tolerance

Notably, there is also evidence that mature DCs can promote tolerance. In a cell culture system in which human monocyte-derived DCs cross-presented Ag to CD8+ T cells in the absence of CD4+ T-cell help, maturation of DCs with tumor necrosis factor (TNF)-a and prostaglandin E2 led to proliferation of T cells with tolerogenic properties (16). In separate studies using human autol-ogous DCs and T cells in the absence of Ag, mature but not immature DC induced CD4+ T cells expressing the transcriptional repressor Forkhead winged helix protein-3 (Foxp3) (Treg) that inhibited allogeneic mixed leukocyte reactions (17). In vivo, bone marrow-derived DCs matured with TNFa, but not lipopolysaccharide or anti-CD40 Ab, protected mice from CD4+ T cellmediated experimental autoimmune encephalomyelitis, despite strong expression of MHC class II and costimulatory molecules (18). It also is evident that immature or mature DC can prime Treg that prevent autoimmunity (19-21), as discussed below.

Genomic and Proteomic Analysis of Immune Tolerance

Level of immune responses related to tolerance and immunity. However, earlier and more informative indicators and prognosticators of the pathological or tolerant states in graft rejection and autoimmunity are now being sought via proteomic approaches, such as protein arrays, surface-enhanced laser desorption ionization time-of-flight mass spectrometry, and two-dimensional gel electrophoresis combined with mass spectrometry (110,111). Although these technologies are in their infancy with regards to applications in immunological systems, they have potential, in the long-term, for greater sensitivity and provision of information than is currently available using enzyme immunoassay and other clinical or laboratory measures. Likewise, microarray analysis continues to evolve as a broadly applicable and powerful method to identify candidate genes, expression levels of which are altered during diverse biological processes. Recent studies have aimed, through array analysis, to dissect the...

Human genome amplification

The genetic risk of several autoimmune diseases is linked to the major his-tocompatibility complex, with a particular association with certain susceptibility alleles. Identification of the HLA class I or II alleles has been done traditionally by serology in a complement-mediated microcytotoxicity assay. Several reports have compared the results of HLA typing by serology and by restriction fragment length polymorphism, and it has been suggested that 25 or more of alleles may be incorrectly assigned by serology. Moreover, the restriction fragment length polymorphism is more accurate and provides results more quickly (2 hours). The main disadvantages are cost and difficulty of implementation. The PCR (site directed mutagenesis-amplification-created restriction site) has been applied to the diagnosis of cancer and autoimmune diseases by identifying gene mutations in BRACA-1, ras oncogene, b-thalassemia, medium chain acyl coenzyme A dehydrogenase deficiency, hereditary hemo-chromatosis,...

Interference with Functions Survival of Effector T Lymphocytes

Treg are currently considered to be responsible for maintaining peripheral tolerance 141, 148, 165, 166, 179, 207 , including transplantation tolerance and the prevention of autoimmune diseases 141, 148 . Treg have a beneficial role in preventing autoimmunity but are the most potent opponents of antitumor immune cells in cancer and play an important role in suppressing TA-specific immunity 141, 147 . Studies indicate that CD4+CD25bright FoxP3+T cells are present in blood or lymph nodes of subjects with cancer and accumulate at tumor sites 31, 146, 147, 206 . To date, at least three types of CD4+ Treg have been described in humans (i) naturally occurring CD4+CD25brightFoxp3+T cells (nTreg), which arise in the thymus and can suppress responses of both CD4+CD25- and CD8+CD25- T cells in a contact-dependent, cytokine-independent, Ag-nonspecific manner 81, 110, 183 (ii) CD4+CD25negative Foxp3low cells known as Type-1 regulatory (Tr1) T cells, which arise in the periphery upon encountering...

Antibody Engineering Yesterday And Today

The resurgence of interest in antibody-based therapeutics was the direct consequence of the introduction of genetically engineered immunoglobulins and the refinement of targets for antibody therapy. MAbs or their recombinant derivatives now account for the single largest group of biotechnology-derived molecules in clinical trials and have a prospective market of several billion dollars. Their applications include the prophylaxis, therapy, or control of allergic and autoimmune diseases complications of angioplasty sepsis a variety of inflammatory diseases many viral and bacterial infections organ transplantation rejections and solid and hematologic tumors (4-10).

Role of DCs in Central Tolerance

The primary site where self-tolerance is imposed on the T cell repertoire is the thymus. Here, developing T cells are exposed to self-antigen presented by BM-derived DCs in the thymic medulla under conditions that ensure deletion of high affinity TCRs (reviewed in ref. 57), either by deletion of the cells bearing them (negative selection) or by editing of the TCR to an acceptable specificity (58). Although it has long been recognized that TCRs reactive with antigens expressed ubiquitously, or accessible via the circulation, will be purged from the repertoire, recent studies of ectopic antigen synthesis in the thymus have indicated that a number of peripheral tissue-specific self-antigens appear to be synthesised there expressly to ensure negative selection of the TCR repertoire (59). A particular subset of thymic epithelial cells (TECs) present in the thymic medulla appears to be responsible for synthesis of these self-antigens, and the process is driven by a dedicated transcriptional...

Peripheral Tolerance to Low Affinity Self Antigen

In contrast to the high affinity T cell repertoire described above, the self-reactive T cell repertoire is of relatively low affinity. Insufficient self-antigen is generally available in the periphery to provide an activation signal for these cells and they remain naive. However, they can, under defined circumstances, make significant anti-self-responses that have the potential to develop into fullblown autoimmune disease. This implies that the threshold at which the thymus imposes deletional tolerance must be quite close to the normal activation threshold in the periphery. Why the thymic threshold is not set lower remains an interesting question, but it is reasonable to assume that preservation of a sufficiently large repertoire of anti-foreign specificities requires that purging for anti-self-reactivity be limited. What are the circumstances in which activation of low affinity anti-self T cells will generate autoimmune pathology Although it has long been held that infection with a...

Helper and effector CD4 T cells

The great majority of autoimmune disease that are though to be T cell mediated have been associated with CD4+ 16 rather than CD8+ T cell response, though this perception may be changing 73 . Such syndromes may, of course, reflect the breaking of self-tolerance by exposure to molecular mimics of self-components expressed by invading viruses or bacteria 88, 108 . The broad alternative is that this apparent autoimmunity is directed at persistent, but as yet uncharacterised, viruses 114 .

CD4 Regulatory T Cells Constitutively Expressing CD25

The evidence in support of a role for CD4+CD25+ regulatory T cells (Treg) in the maintenance of self-tolerance in the normal, low affinity self-reactive T cell compartment is now well accepted. Not only is a deficit in Treg associated with development of spontaneous autoimmune disease, but reconstitution of this T cell subpopulation can prevent disease in animal models (95). Treg are selected by their specificity for self-antigen in the thymus, and the currently available evidence suggests that they represent those cells with the highest anti-self-affinity among the population that escapes negative selection, i.e., that they have an anti-self affinity intermediate between that of cells that are deleted and cells that undergo conventional positive selection (96,97). In one experimental model, it has been demonstrated that thymic epithelium is the source of the selecting antigen (98). However, the process of selection is dependent on CD28-B7 interactions, suggesting that antigen is...

CD8 Regulatory T Cells

CD8+ T cells were the first suppressor cells identified. Qa-1-restricted regulatory CD8+ T cells (51,52) are specific for self Ag (not yet identified) presented by nonclassical MHC class 1b molecules (Qa-1). Interestingly, Qa-1 is expressed preferentially on activated, but not resting T cells and its surface expression is short-lived. This pattern is compatible with the observation (44) that the role of Qa-1 on regulatory CD8+ T cells in the control of autoimmune disease is evident during secondary, but not primary, immune responses. This supports the idea that initial stimulation of the immune system can promote the generation activation of Qa-1-restricted CD8+ T cells (recognizing self peptides) that can then control successive activation of T cells. Even for Qa-1 restricted CD8+ T cells, the mechanisms involved in their suppressive activity have not been delineated (differentiation into specific CTL and or secretion of inhibitory lymphokines have been suggested). In addition to...

Antigen presentation pathways and their role in human disease

Analysis of the relationship between TAP binding affinity and HLA class I binding affinity across the full spectrum of HLA alleles is difficult because of the extensive polymorphism of HLA molecules. We addressed the problem by (a) generating a computational model, (b) combining the initial model with a selected set of laboratory experiments for model refinement, and (c) using the refined model to analyse the functional relationship between TAP and HLA class I molecules (Daniel et al 1998). The working ANN model was used to search for patterns of TAP-binding within sets of HLA-binding peptides. The proportion of HLA-binding peptides with affinity to TAP varied for each HLA class I allele with a range of 15 for HLA-B*5401 to 100 for HLA-B*2703 (Brusic et al 1999). On the basis of these results we hypothesize that HLA alleles constitute two separate classes those that are TAP-efficient for peptide loading (HLA-B27, -A3 and -A24) and those that are TAP-inefficient (HLA-A2, -B7 and -B8)....

Simone Mocellin Carlo Riccardo Rossi and Pierluigi Pilati Introduction

Here we review the current knowledge regarding IL-10 functions with respect to the cell types involved in adaptive immunity, emphasize new insights on IL-10 molecular cellular targets, and summarize the available data on the relationship between IL-10 and some pathological conditions such as infectious diseases, autoimmunity, allergy, cancer and transplantation. Taken together, currently available data lead to the conclusion that IL-10, while suppressing Th1 and some Th2 type immune response, favours humoral immunity and CTL functions by acting both directly on relevant cells and indirectly through its influence on other immune cells such as T regulatory cells, dendritic cells, and NK cells.

Effects on B Cells and Immunoglobulin Production

Studies involving administration of IL-10 protein, IL-10 gene delivery, IL-10 transgenic animals or inhibition of IL-10 activity by neutralizing mAb or gene knock-out animals suggest that the in vivo role of IL-10 in B cell function is limited.5-7 For instance, plasma immunoglobulin levels are normal in IL-10 - - mice.8 An important exception is represented by a model of antibody-dependent autoimmunity such as systemic lupus erythematosus (SLE), in which IL-10 neutralization does affect disease onset.9

Autoantibody Responses

Some clinically important autoantibodies are directed against hormone receptors, for example thyrotoxicosis in Basedow's disease is caused by autoantibodies that stimulate the TSH receptor, and myasthenia gravis is caused by blockage of the acetylcholine receptor by specific autoantibodies. Other antibody-induced diseases mediated by antibodies, directed against hormones and other cellular self antigens, include Hashimoto thyroiditis (induced by anti-thyroglobulin and anti-mitochondrial autoantibodies), pernicious anemia (anti-intrinsic factor), pemphigus vulgaris (anti-desmosome) Guillain-Barre syndrome (ascending paralysis caused by specific myelin auto-antibodies), and scleroderma (involving anti-collagen antibodies). Other immunopathologies involving autoantibodies include transplant rejection as a result of endothelial damage (especially in xenogeneic transplants), and tumor rejection caused by antibodies against tumor-associated antigens present on neoplastic cells (especially...

Neuromuscular Transmission Can Be Altered by Toxins Drugs and Trauma

Compounds such as physostigmine (eserine) are potent inhibitors of AChE and produce a depolarizing blockade. In carefully controlled doses, they can temporarily alleviate symptoms of myasthenia gravis, an autoimmune condition that results in a loss of postsynaptic ACh receptors. The principal symptom is muscular weakness caused by endplate potentials of insufficient amplitude. Partial inhibition of the enzymatic degradation of ACh allows ACh to remain effective longer and, thus, to compensate for the loss of receptor molecules.

Hematopoietic Cell Chimerism in Immunological Tolerance

Successful and consistent methods to induce T- and B-cell tolerance to allo- and xenografts in rodent models, and possibly in both nonhuman primates (NHP) and humans (78,85,86). Although these developments are impressive, there remain several barriers and questions that currently limit the widespread application of the induction of hematopoietic chimerism in allograft and autoimmune tolerance induction (87,88). To date, experiments involving NHP and limited clinical trials, have established that even rigorous induction regimens, including use of cyclophosphamide, total body irradiation, thymic irradiation, and anti-thymocyte globulin, may only establish a transient state of mixed chimerism following bone marrow cell infusion. Less severe protocols must be established to safely and more widely exploit chimerism induction as a means to reduce immunosuppressive drug treatment of patients for allograft rejection and autoimmunity. Furthermore, it is critical that these protocols (at least...

Contraindications

The aminoglycosides are contraindicated in patients with hypersensitivity to aminoglycosides. The amino-glycosides should not be given to patients requiring long-term therapy because of the potential for ototoxic-ity and nephrotoxicity. One exception is the use of streptomycin for long-term management of tuberculosis. These drugs are contraindicated in patients with preexisting hearing loss, myasthenia gravis, parkinson-ism, and during lactation or pregnancy. Neomycin, amikacin, gentamicin, kanamycin, netilmicin, and tobramycin are Pregnancy Category D drugs the remainder are Category C.

Implications and Future Directions

What is the constitutive role of corneal APCs in maintaining tolerance What factors of the ocular microenvironment promote or actively maintain their highly immature phenotype What is the role of the resident BM-derived cells in mediating wound healing and regulating matrix-keratocyte interactions There is little doubt that a better understanding of these issues could shed important insights into tolerance induction, autoimmunity, and allergy to name a few.

Choroid Plexus To Cerebrospinal Fluid To Epenoyma

Postinfectious encephalitis is most commonly seen after measles (about 1 per 1000 cases), more rarely after rubella and varicella, and it used to be seen in 1-2 per 100,000 primary vaccinations against smallpox The pathologic picture is predominantly demyelination without neuronal degeneration, changes unlike those produced by the direct action of viruses on the central nervous system. Allied with the failure to recover virus from the brain of fatal cases, this has led to the view that postinfectious encephalitis is probably an autoimmune disease.

The Immune Response within the

Only 95, 96 does not transfer suppression. Only the transfer of APC and CD25+ CD4+ Treg cells together or the transfer of only restimulated CD25 + CD4+ Treg cells will transfer suppression of retinal inflammation in other mice immunized for EAU. In addition, in contrast to ACAID where CD4+ Treg cells are afferent suppressors 97 , the post-EAU CD25+ CD4+ Treg cells suppress only efferent activity of the autoimmunity. MC5r-knockout mice reveal the role of the ocular microenvironment in mediating the induction of post-EAU Treg cells and their role in autoimmunity. In a soon to be published work, we have found that there is no regulatory immunity in the spleens of MC5r-knockout mice following an episode of EAU 98 . Such post-EAU mice when re-immunized with autoantigen have a rapid onset of uveitis that has a severity of inflammation that exceeds the initial episode of EAU, from simple infiltration and vasculitis to hemorrhage and retinal detachment. In comparison, re-immunized post-EAU...

Bacteria We Can Live With

From experiments in mice that failure to take in such bacteria can cause major nutritional problems, and it is thought that living in an increasingly germ-free (in relative terms) environment may also cause problems for humans including, aside from digestive difficulties, things like allergies and autoimmune disease.

Adoptive Transfer of Experimental Autoimmune Uveitis

Somewhat simpler than active EAU, this begins with the transfer of lymphocytes from already immunized donors to recipients 10, 11 . Thus, the initial stages of immunization, including adjuvant effects and the activation of disease-causing T cell subsets, do not occur in the recipients. T cells prepared from the lymph nodes of animals undergoing active EAU are restimulated in culture and adoptively transferred to syngeneic animals in which they cause inflammation in the eye and consequent tissue damage. Disease onset is more rapid than in active EAU, beginning on day 4 in rats 5, 12 and days 8-10 in mice 10, 11 . Adoptive transfer of a few million newly activated syngeneic autoreactive T cells to a naive animal can readily induce disease, suggesting the pathogenic role of autoreactive T cells in disease. The mechanism by which an organ-specific autoimmune disease can be adoptively transferred by a few million autoreactive T cells, of which only a fraction enters the autoimmune organ,

Autoreactive T Cell Lines and Clones

To characterize the mechanism by which autoreactive T cells initiate autoimmune disease and to determine the various structural and functional features that distinguish between subsets of autoreactive T cells and other antigen-specific, non-pathogenic T cells, enriched T cell populations have been prepared to determine the requirements for T cell activation 12 and the usage of the T cell antigen receptor 13-15 and accessory molecules 16, 17 , as well as to assess the various cell-interacting cytokines produced by these cells 18-20 . The need for the characterization of the structure and function of autoreactive T cells by isolating antigen-specific T cell lines and clones became especially apparent when it is realized that limiting dilution analysis indicates that the number of autoreactive T cells in immunized rodents or in humans suffering from multiple sclerosis rarely exceeds 1 in 10,000 T cells 21, 22 and that the overwhelming majority of activated T cells associated with disease...

Electromyography and electroneurography

EMG abnormalities are helpful in the diagnosis of polymyositis, myasthenia gravis, myotonic dystrophy, Eaton-Lambert syndrome, and McArdle disease. Characteristic findings in polymyositis are mentioned in Chapter Z. Note, however, that trichinosis and several muscular dystrophies may cause a myopathic EMG pattern similar to that of polymyositis. In myasthenia gravis, repetitive stimulation gives a characteristic decremental response, which is opposite to the pattern seen in Eaton-Lambert syndrome. In myotonic dystrophy, electrical silence after a brief voluntary contraction does not occur instead, there is a burst of electrical activity that subsides in minutes. In McArdle disease, the muscular cramping that occurs is electrically silent.

Intrathymic Selection New Insight into Tumor Immunology

Central tolerance to self-antigens is formed in the thymus where deletion of clones with high affinity to self' takes place. Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. During the last years, it has been shown that medullary thymic epithelial cells (mTECs) are the unique cell type expressing a diverse range of tissue-specific antigens. Promiscuous gene expression is a cell autonomous property of thymic epithelial cells and is maintained during the entire period of thymic T cell output. The array of promiscuously expressed self-antigens was random and included well-known targets for cancer immunotherapy, such as a-fetoprotein, P1A, tyrosinase, and gp100. Gene expression in normal tissues may result in tolerance of high-avidity cytotoxic T lymphocyte (CTL), leaving behind low-avidity CTL that cannot provide effective immunity against tumors expressing the relevant target antigens. Thus, it may be evident that tumor...

Manipulation of Cosignaling Pathways

A balance between stimulatory and inhibitory molecular signals is necessary for maintaining tolerance. Signaling through both the original and newer members of the B7-CD28 pathway provides second signals that can regulate the activation, inhibition and fine tuning of T-cell responses (96). The five new B7 family members, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, B7-H4, and ICOS ligand, are expressed on professional APC and regulate T-cell activation and tolerance. The novel CD28 family members, PD-1, ICOS, and BTLA are expressed inducibly on T cells and regulate previously activated T cells. PD-1 and BTLA are also expressed on B cells. The PD-1 PD-L1 PD-L2 pathway plays a critical role in regulation of T-cell activation and tolerance, whereas the ICOS-ICOSL pathway appears to be important in stimulating effector T-cell responses, T cell-dependent B-cell responses, and in regulation of T-cell tolerance. As recently discussed (96), manipulation of the PD-L1 PD-1 and ICOSL ICOS pathways in...

Gaze into Cells MHCBinding Motifs

The fact that these motifs have been formed by anchoring amino acid residues necessary for high-affinity binding of the peptide with respective MHC molecule also indicated that APC expressing different MHC haplotypes can present various peptides of the same antigen (Rammensee et al. 1993 1995). For example, the nucleoprotein of influenza virus contains the epitope that binds with H-2Kd in positions AA147-155 (TYQRTRALV) and with H-2Db in positions AA366-374 (MTEMNENSA). For human MHC molecules, the epitope for binding with HLA-A2 is within AA85-94 (KLGEFYNQM), and with HLA-A3 within AA265-273 (ILRGSVAHK), with HLA-B8 within AA380-388 (IAWYRSRLE), and with HLA-B27 in AA383-391 (SRYWAIRTR) (underlined are anchoring, i.e., motif forming, residues). The highest binding affinity of influenza virus nucleoprotein-derived peptides with H-2Db is achieved if the peptide has the canonical motif (Cerundolo et al. 1991). To see whether the expression of certain MHC molecule influenced the efficacy...

Aire and Thymic Selection

Aire (autoimmune regulator), the gene responsible for the clinical disorder autoimmune polyendocrinopathy syndrome type I, has recently been identified as an important mediator of central tolerance. Structural characteristics and biochemical data suggest that Aire might play a direct role in transcription and function as an ubiquitin ligase. Aire up-regulates the transcription of certain organ-specific self-antigens in medullary thymic epithelial cells (mTECs) and has a role in the negative selection of organ-specific thymocytes (Su and Anderson 2004). Aire promotes the tolerance of thymocytes by inducing the expression of a battery of peripheral-tissue antigens in mTECs. The mechanism whereby Aire exerts its tolerance-promoting function is not primarily positive selection of regulatory T cells but rather negative selection of T effector cells. Surprisingly, supplementing its influence on the transcription of genes encoding peripheral-tissue antigens, Aire somehow enhances the...

Complement and Ocular Diseases

The role of complement in autoimmune uveitis is not well understood. Complement activation products such as C3b and C4b are present in the eyes of patients with anterior uveitis 10 . In experimental autoimmune uveoretinitis caused by retinal S-antigen, complement activation is important for inflammation 11 . Recently, a rodent model of experimental autoimmune anterior uveitis (EAAU) was used to explore the role of complement and CRPs in the pathogenesis of ocular autoimmune disease. EAAU is an autoimmune disease of the eye and is an animal model of idiopathic human anterior uveitis 12 . This report demonstrated that the induction and progression of autoimmune uveitis is complement restricted. The expression of cytokines, chemokines and adhesion molecules necessary for the development of EAAU required complement activation. Furthermore, the local (i.e. intraocular) activation of complement was required to induce EAAU. It was also shown that various ocular tissues upregulate the...

Generation of Regulatory T Cells

It has recently become evident that DC can be used for immune regulation, either for treatment of autoimmunity or for transplant rejection (27,28). The immune regulatory aspects of DC include the direct killing of T cells, induction of T-cell anergy or the generation of regulatory T cells (Treg). The tolerogenicity of DC could, therefore, be exploited by combining donor-derived thymic tissue with immature DC isolated from the recipient. These DC could be collected, expanded, and reintroduced into the transplant recipient, a strategy that is supported by the fact that antigen-pulsed thymic DC have been shown to re-enter the thymus of na ve recipients and induce tolerance to a nonself antigen (29).

Philip G Ashton Rickardt

T lymphocytes express receptors (T-cell receptor) that are not only specific for antigenic pep-tide but also molecules encoded by the major histocompatibility complex (MHC) that present peptide on the surface of cells (MHC-restricted antigen recognition). However, the vast majority of T cells are tolerant to their own MHC molecules and do not give rise to autoimmune disease. This MHC-restricted, but tolerant, repertoire of T cells is determined by selection triggered by the appropriate recognition of peptide MHC on thymic stromal cell by immature thymocytes. We have developed a fetal thymus organ culture (FTOC) system based on transporter associated with antigen processing (TAP) 1-deficient mice to examine the role of peptide MHC in triggering the differentiation of T cells restricted to class I MHC (positive selection). We also describe an FTOC system to study central T-cell tolerance, which occurs through clonal deletion in the thymus (negative selection).

Childhood Rheumatic Diseases

Etiology and pathogenesis The rheumatic diseases of childhood represent a diverse group. Their etiologies are varied and their pathogenesis unclear. Lyme disease and acute rheumatic fever result from exposure to known infectious agents, but the majority of childhood rheumatic diseases result from the combination of genetic predisposition, autoimmunity, and unknown environmental factors.

Adverse Effects Ofantibodyadministration

Polyclonal, monoclonal, and chimeric antibodies have been used for treatment of cancers, autoimmune diseases, clotting disorders, infectious diseases, and graft rejection (Fanger etal., 1992). Administration ofall forms of antibodies evokes an antibody response after 1-2 weeks oftreatment. Because the murine antibodies are more foreign to the human host, responses occur with a greater frequency and a higher intensity compared with the responses to humanized antibody.

Immunotherapeutic Vaccines

Vaccines were initially conceived to prevent the infectious diseases associated with morbidity and mortality. The vaccine concept was extended to therapeutic reagents to cure chronic infection caused by persistent viruses or bacteria, autoimmune diseases, or cancers. The concept of therapeutic vaccines derives from the understanding of T-cell biology and pathophysiology T-cells are not simply good soldiers fighting microbes or tumor cells but also vicious mercenaries contributing to the destruction of tissues that leads to autoimmune diseases. Therapeutic vaccines against chronic infectious diseases (Mycobacterium leprae, HSV virus hepatitis B virus) are aimed at harnessing the immune response in carriers or cancer patients who are otherwise tolerant or unresponsive to microbial or tumor-associated antigens. In the case of autoimmune disease, therapeutic vaccines are used to eliminate autoreactive lymphocytes.

Preadministration Assessment

Before the nurse gives a cholinergic drug to a patient with myasthenia gravis, the primary health care provider performs a complete neurologic assessment. The nurse assesses for signs of muscle weakness, such as drooling (ie, the lack of ability to swallow), inability to chew and swallow, drooping of the eyelids, inability to perform repetitive movements (eg, walking, combing hair, using eating utensils), difficulty breathing, and extreme fatigue.

Differential diagnosis

Ocular symptoms and swallowing difficulties are prominent. Patients complain of increasing weakness with use of muscles and restoration of strength after rest. Muscle enzymes are normal, the result of the edrophonium test is positive, and the electromyogram has a characteristic pattern (see Chapter, .10).

Biological Effects of IFNg

IFN-y production is characterized as the hallmark of the Thl phenotype and IFN-y has been shown to downregulate the generation of IL-4- and IL-10-producing Th2 T cells (reviewed in Szabo et al. 2003). Interestingly, IFN-y has been shown to enhance Th2 polarization and the survival of IL-4 producing cells if present during the initial T cell priming (Bocek et al. 2004). Most recently IFN-y has been shown to inhibit the development of a new subset of T cells (Harrington et al. 2005), characterized by their ability to produce IL-17 (Bettelli et al. 2006 Harrington et al. 2005). These cells play an important role in the development of a number of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE) (Bocek et al. 2004). The inhibition of their development by IFN-y begins to shed new light on the role of IFN-y in the development and progression of these diseases.

Death Receptors and the

Apoptosis is an indispensable part of adaptive immunity, as the immune system must not only deal with pathogens, it must deal with its own potentially damaging cells to prevent the formation of self-reactive responses that could lead to autoimmunity. Many aspects of apoptosis in the immune system rely on the Fas FasL system, where peripheral deletion and control of clonal expansion are regulated by the Fas antigen (CD95) and its lig-and, FasL (CD178) 7, 8 . FasL is a type II membrane protein belonging to the TNF family. FasL is expressed primarily on activated T cells, some tumor cells, and immune-privileged sites such as the eye and the testis 9 . FasL induces apoptosis in cells expressing the Fas receptor. Fas is a type I membrane protein of the TNF receptor family that was discovered due to the ability of specific antibodies to induce apoptosis in lymphoid tumor lines expressing the molecule. Two naturally occurring mutations in mice have emphasized the...

Clinical Applications

Despite the multitude of papers that have investigated the properties of IFN-y, the clinical use of IFN-y is still somewhat limited. In the USA, IFN-y has been approved for only two specific uses treatment of chronic granulomatous disorder (CGD), as these patients are more susceptible to fungal and bacterial infections, and severe osteoporosis. Current clinical trials are limited, with a major effort being made in the use of IFN-y for the treatment of idiopathic pulmonary fibrosis. In this condition, IFN-y administration resulted in a survival benefit in certain subgroups. Other trials involving IFN-y include analysis of the effects on lung immune function in Mycobacterium tuberculosis-infected patients tolerance and toxicity of IFN-y alone or in combination with tumor necrosis factor in AIDS-related complex patients the effects of IFN-y in hepatitis C patients that do not respond to IFN-a the use of adenovirus vectors expressing IFN-y in cancer patients and evaluation of antifibrotic...

Pathologic Manifestations

AIDS is characterized by the progressive loss of reaction to antigenic stimulation and vulnerability to infection. Response is first lost to recall antigen, next to alloantigen, and finally to mitogen. In pediatric AIDS, failure to resist common bacterial infections is frequently seen, whereas in adults, this is less common, reflecting the adult's more mature humoral immunity. In both populations, loss of resistance to intracellular parasites, viruses, protozoa, fungi, and mycobacteria demonstrates impaired cell-mediated immunity. Polyclonal B-cell activation contributes to inappropriate antibody production, autoimmune disease, and B-cell lymphomas.

Other Dr Jekyll and Mr Hyde Like Tumor Antigens 551 Dr Jekyll CEA

Using human CEA-transgenic mouse models immune tolerance has been successfully overcome by certain vaccination strategies that generate CEA-specific, MHC-restricted CTLs, T cell proliferation, CD4+ T cell responses and anti-CEA antibody generation, which resulted in tumor rejection in these mice 77-81 . Very recently it was shown that genetically modified DCs that express CEA and Th1-type cytokines IL-12 and GM-CSF, can overcome peripheral immune tolerance to CEA and induce strong cellular antitumor activity in transgenic mice without creating autoimmunity 82, 83 . Similar results were achieved with a vaccine based on anti-Id antibody pulsed DCs, which induced both humoral and cellular (CTLs, helper and memory T cells) immune responses in the vaccinated CEA-transgenic mice and provided protective antitumor immunity. The anti-Id antibody was raised against anti-CEA antibody and mimics a single protective epitope of human CEA. This might be of advantage in comparison to CEA protein or...

Consumer concerns about regulatory safeguards for medical devices

In racially and ethnically diverse countries such as the USA, the potential for racial and ethnic differences in responses to implanted medical devices has become an issue of concern among consumer groups. The NRC for Women & Families, the National Medical Association, and the Congressional Black Caucus of the US Congress have all expressed their concern that implant makers rarely include racial and ethnic minorities in their studies. Since individuals of African or Asian ancestry are more likely to have keloid scarring, and since individuals of African ancestry are more susceptible to autoimmune diseases, medical implants may be more risky for those groups. However, it is impossible to know whether this is the case if no studies have been done.

Chagas Disease Is Caused by a Parasite

Although the mechanism by which T. cruzi suppresses expression of the a subunit is still unknown, the suppression can be induced across a filter that prevents contact between the lymphocytes and protozoa. This finding suggests that a diffusible factor mediates suppression. Such a factor, once isolated, might have numerous clinical applications for regulating the level of activated T cells in leukemias and autoimmune diseases.

Mononuclear Phagocytes In Specific Immunity

Changes in the cell surface expression of the MHC Class II gene product HLA-DR have been recorded in both non-organ and organ-specific autoimmune diseases. For example, epithelial cells in the thyroid of many patients with Graves' disease show high levels of HLA-DR an antigen not usually found on normal thyroid epithelium. In addition, abnormal presentation of foreign antigens (resulting from an unusual association between an antigen such as a drug or microorganism and HLA-DR) has been implicated as a cause of systemic lupus erythematosus. Such an association would appear as an altered self-antigen, thus providing a new epitope that may be recognised, and reacted to, by Th cells. As a consequence, the latter produce lymphokines that stimulate the differentiation and proliferation of activated, self-reactive, B cells. cells not usually involved in this process. This may therefore increase the chance of unusual presentation of self-antigens and recognition by T cells leading to the...

Role of IL10Producing Regulatory T Cells in the Persistence of Infection

In the anti-leishmanial response of genetically resistant strains of mice, IL-10 has been suggested to be produced primarily by the infiltrating CD4+ IFN-y-expressing T cells in the lesions.65,66 IL-10 and IFN-y-producing cells constitute approximately 25 of the total IFN-y-expressing population of CD4+ cells in the lesions.66 These cells may correspond to the CD4+ CD25+ regulatory T cells (Tr) observed in cancer, autoimmune diseases, and transplantation.75,76 IL-10 and IFN-y producing cells may differ from Tr cells in that Tr cells produce IL-10 but may exert immunosuppressive effects via IL-10-independent, cell-contact-dependent

Five Classes of Antibodies

Laboratory mice have been highly inbred into strains where all the animals are genetically identical and their genes and antigens are well known. Studies on these mice have been essential in determining how the immune system normally works, and how it fails to work in autoimmune diseases and the inability to prevent cancer cells from proliferating.

Apoptosis as a Cytotoxic Mechanism Induced by Cytotoxic Lymphocytes

Apoptosis or programmed cell death plays an important role in the induction of tumor cell death 9 . Dysregulation of this process may lead to pathological diseases such as cancer and autoimmune diseases 10 . The molecular machinery for executing apoptosis is inherently in place in most cells including tumor cells but it is only triggered with the proper stimulus. There are two major cytotoxic mechanisms by which cytotoxic lymphocytes induce apoptosis, namely, the granule exocytosis pathway mediated by perforin and granzymes and the death receptor signaling pathways, which involve the TNF-related ligand family of proteins (FasL, TNFa, TRAIL) reviewed by 11 . The induction of the granule exocytosis pathway requires direct lymphocytes to tumor cell contact and TCR MHC engagement and recognition in order to initiate the release of cytotoxic granules containing perforin, granzymes and other cytotoxic constituents. Granzymes trigger apoptosis by either activating a caspase-dependent central...

Rheumatic clinical syndromes

Rheumatic diseases include many syndromes of different origins and pathogenic mechanisms. These range from autoimmune diseases to nonspecific inflammation, purely pain noninflammatory syndromes, and infectious rheumatic diseases. Initially, most of these syndromes have been described in AIDS patients, which makes it difficult to ascertain whether each of these disease groups are truly associated with AIDS or it is merely a casual cooccurrence and that these rheumatic complaints are detected only because of the increased awareness of any clinical symptoms during the follow-up of HIV-infected individuals. Nevertheless, some syndromes seem to be true associations and HIV infection seems to predispose to them. These are the ReA variants of the seronegative spondyloarthritides autoimmune syndromes and, expectedly, infectious rheumatic diseases. Lastly, there are the rheumatic complaints resulting from antiretroviral therapy and other therapeutic measures of HIV infection. It is predictable...

Preventing Access to the MHC in Experimental Autoimmune Encephalomyelitis

Such high affinity T cells as DAGGGY may escape annihilation rather readily and then provide the individual with a potentially dangerous self-directed repertoire, only manageable if a regulatory circuit is available to control its proclivities. To again refer to Fig. 1, it is unknown for each of the concentric rings representing areas of diminishing T-cell affinity, how much a determinant would have to be exposed to successfully obliterate the high affinity members of the repertoire. But one can easily see how important it is to have a fully functional regulatory system in place to serve as a last ditch defense in the avoidance of autoimmunity, caused by such subversive T cells.

Chronic Inflammation Develops When Antigen Persists

Some microorganisms are able to evade clearance by the immune system, for example by possessing cell-wall components that enable them to resist phagocytosis. Such organisms often induce a chronic inflammatory response, resulting in significant tissue damage. Chronic inflammation also occurs in a number of autoimmune diseases in which self-antigens continually activate T cells. Finally, chronic inflammation also contributes to the tissue damage and wasting associated with many types of cancer.

Immune Privilege 11 The Problem

A functional central nervous system (CNS) is essential for mammalian survival therefore, the CNS must be defended from insults and other pathogens. The molecules (e.g., free radicals, cytokines, proteases) produced in vast quantities by the activated immune system to combat pathogens have the demonstrated potential to disrupt CNS function (1-3). To balance these opposing needs, (sufficient defense of the CNS without loss of CNS function), the CNS and immune system have developed a unique relationship referred to as immune privilege. Disruptions in this unique relationship leading to disregulated CNS inflammation are now thought to contribute to the onset and progression of many diverse types of CNS pathology, including CNS autoimmune diseases such as multiple sclerosis (MS), Rasmussen's encephalitis, and narcolepsy neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and stroke and the secondary neurodegeneration associated with spinal cord injury (3-10)....

Additional observations

The use of interferon-alfa appears to predispose to autoimmune disease and serologic phenomena, particularly thyroid abnormalities. With its use in the treatment of Kaposi's sarcoma and as an antiretroviral agent, we might expect an increase in these features as patients live longer.

Roberta D Laredo RD CDE

Type 1 diabetes is an autoimmune disease in which the beta cells of the pancreas eventually produce little or no insulin. Type I diabetes generally occurs in children and young adults. The body's immune system attacks and destroys the beta cells of the pancreas. Initial therapy involves medical management to correct the hyperglycemia. glycosuria, and ketonuria responsible for symptoms. including polydipsia, polyuria, dehydration, and weight loss. Management of type I diabetes requires insulin replacement v ia daily insulin injections and consistent timing and composition of meals and snacks.

Epidemiology and Classification of Uveitis

Uveitis is responsible for over 2.8 of blindness in the United States. Each year, 17.6 of active uveitis patients experience a transient or permanent loss of vision, with 12.5 developing glaucoma 4 . The incidence and prevalence of uveitis has been difficult to determine because the disease is not reportable to the health authorities and is treated in an ambulatory setting. More recently, the epidemiology of the disease in the US has been affected by the aging of the population, racial diversity and an increasing incidence of autoimmune disease. Historically, an incidence rate of 17 100,000 person-years and a prevalence ratio of 204 100,000 over a 10-year period has been reported 5 . However, a recent report from the Northern California Epidemiology of Uveitis Study 6 suggested a higher disease rate for the older population, particularly women, with a higher incidence of chronic disease. Recurrence rates after an initial episode of uveitis in Great Britain showed that 11.3 of patients...

Autoimmune Anterior Uveitis

EAAU is an organ-specific autoimmune disease of the eye, which serves as an animal model of idiopathic human AAU 3, 28-38 . It was originally described by Broekhuyse et al. 28 in 1991. Bora et al. 33 have extensively characterized this model and have shown that severe inflammation occurs in the anterior segment of the eye of Lewis rats after the foot pad injection of the antigen isolated from bovine iris and CB 3, 33, 34, 36-38 . In EAAU there is no damage to the retina. Thus, EAAU is representative of human AAU in contrast to EAU. EAAU is characterized histologically by lymphocytic infiltration in the iris and CB. Antigen-specific CD4+ T cells can adoptively transfer disease into na ve syngeneic recipients and are the predominant inflammatory cells within the uvea 3, 37 . Study of the cytokine profile of the host during EAAU Recently, the pathogenic antigen in EAAU has been purified to homogeneity by Bora et al. 3 . The uveitogenic antigen is a 22-kDa fragment of bovine type I...

Polyclonal BCell Activation

Nonspecific proliferation of B cells has been implicated as a cause of autoimmune diseases. Although it is accepted that autoreactive B cells or anergic B cells can be activated by mitogenic stimulation by endotoxins or superantigens, it is unlikely that polyclonal B-cell activation plays a role in autoimmune diseases (Friedman et al., 1993). Multiple data sets have shown that (1) tissue damage induced in autoimmune diseases is related to high-affinity IgG and polyclonal activation produces low-affinity IgM, (2) most animal models for autoimmune diseases involve T-cell-dependent production of antibody, (3) a genetic predisposition is necessary to evoke the pathology of the disease in the presence of high amounts of antibody, and (4) endotoxins may exacerbate or result in disease processes but they cannot in themselves initiate the disease process (Theofilopoulos, 1995).

Hazard Identification

The presence of autoantibodies directed toward host tissue is a hallmark of an autoimmune response. Immunofluorescence assays can be used to detect the presence of autoantibodies. Data from these assays must be interpreted with caution, as antibody titers may decrease with time (Rose and Bhatia, 1995). Tissue-specific, autoreactive T cells should also be demonstrable in an autoimmune response. Proliferation of T cells following exposure to tissue antigens can be used as an in vitro correlate of Thl autoimmunity.

The Antigenic Specificity of Autoreactive T Cells

Several self-antigens have been associated with autoimmune diabetes, but three appear to be most relevant, both in NOD and in human T1D (pro)insulin, GAD, and the tyrosine phosphatase-like islet antigen IA-2. Accumulating evidence favours a role for proinsulin as a key autoantigen in diabetes. The proinsulin insulin molecules have a sequence that is a primary target of the autoimmunity NOD mice knock-out for insulin 1 and insulin 2 genes and expressing a mutated proinsulin transgene (in which residue 16 on the P chain was changed to alanine) do not develop insulin autoantibodies, insulitis or

Tissue Stress in Glaucoma

What seems to be the most important parameter for the modulation of the immune system in glaucoma is that the retina and optic nerve head are under widespread and long-term tissue stress in glaucomatous eyes. In addition to the clinical evidence of elevated intraocular pressure in glaucoma patients, there is also evidence of hypoxic 30 and oxidative tissue stress 31 in glaucomatous eyes. The tissue stress in glaucoma is best represented by increased expression of stress proteins, including heat shock proteins, in the retina and optic nerve head 32 . While heat shock proteins function as endogenous protectants of retinal neurons in response to a variety of stressors, including those associated with glaucoma 24, 33 , they also have the ability to elicit an activated immune response. For example, heat shock proteins are known to be highly antigenic, and immune responses to heat shock proteins are implicated in the development of a number of human autoimmune diseases as a consequence of...

Pathogenic and Protective T Cells

Distinguishing CD4+CD25+ cells from recently activated CD4+ T cells is Foxp3, a transcription factor that is required for CD4+CD25+ cell development and is sufficient for their suppressive function (102-104). Foxp3+ CD4+CD25+ cells play an important role in preventing the induction of several autoimmune diseases, such as the autoimmune syndrome induced by day-3 thymectomy in genetically susceptible mice (100), inflammatory bowel disease (105), T1D in thymectomized rats (106), and in NOD mice (9,107). CD4+CD25+ cells are reduced in NOD compared to other mouse strains and this reduction could be a factor in their susceptibility to T1D (9,10). Mice with a defect in Foxp3, required for the generation and activity of regulatory T cells, exhibit massive lymphoproliferation and severe inflammatory infiltration of multiple organs, in particular the lungs, liver, and skin (103). This phenotype is influenced by an additional defect in central tolerance induction, generated by either crossing in...

Faulty Termination of Immune Responses in the Pathogenesis of T1D

In the pathogenesis of autoimmune diseases, emphasis is usually placed on inductive steps and on the breaking of mechanisms that control tolerance to self antigens. Although these are certainly important, emerging evidence suggests that a key feature of T1D, and possibly of other autoimmune diseases, is the failure of mechanisms that normally terminate immune responses. The main pathways for the termination of immune responses appear to be defective in the NOD mouse (Table 3). Intriguingly, the autoimmune diabetes susceptibility locus idd3 has been mapped to a 0.35-cM interval containing the IL-2 gene (124). The NOD IL-2 gene appears to be an allelic variant resulting in a serine-to-proline substitution at position 6 of the mature IL-2 protein, which is, nevertheless, functional (124). IL-2 or IL-2 receptor-deficient mice develop severe autoimmune diseases, probably due to the non-redundant function of IL-2 in tolerance to self via two major pathways homeostasis of CD4+CD25+...

The Future What Is Required for the Development of New and Safer Treatments for Sight Threatening Posterior and

Has received approval from national or supranational regulatory authorities for use in uveitis, and most drugs are administered 'off label'. In an attempt to develop a minimal set of diagnostic characteristics for uveitis, a consensus paper from a group of experts has been published, setting out a range of clinical symptoms and signs which might form the basis for outcome measures for new drug therapies 72 . In practice, it has been found that direct, robust control of inflammatory sight-threatening disease using an ever increasing range of immunosuppressives, singly or in combination, to minimize side effects has proved highly beneficial in the management of most cases of non-infectious uveitis. There is considerable promise that some of the newer approaches to control of inflammation using 'biologics' will prove valuable. In the meantime, investigation of basic immunological mechanisms both in the experimental models and in patients will shed light on the mechanism of autoimmunity...

Thyroid dysfunction causes goiter

Goiter occurs when the production of thyroglobulin is far above normal and the follicles become greatly enlarged. Hy-perthyroid goiter results when the negative feedback mechanism fails to turn off the follicle cells even though blood levels of thyroxine are high. The most common cause of hyperthyroidism is an autoimmune disease in which an antibody to the TSH receptor is produced. This antibody can bind to the TSH receptor on the follicle cells, causing them to produce and release thyroxine. Even though blood levels of TSH may be quite low because of the negative feedback from high levels of thyroxine, the thyroid remains maximally stimulated, and it grows bigger. Hyperthyroid patients have high metabolic rates, are jumpy and nervous, usually feel hot, and may have a buildup of fat behind the eyeballs, causing their eyes to bulge.

Degenerative Diseases

Multiple sclerosis (MS) commonly attacks people in their 20s or 30s and progresses at intervals and at varying rates. It involves patchy loss of myelin with hardening (sclerosis) of tissue in the CNS. The symptoms include vision problems, tingling or numbness in the arms and legs, urinary incontinence, tremor, and stiff gait. MS is thought to be an autoimmune disorder, but the exact cause is not known.

Selective Deficiencies Of Immunoglobulin Classes

A number of immunodeficiency states are characterized by significantly lowered amounts of specific immunoglobulin isotypes. Of these, IgA deficiency is by far the most common. There are family-association data showing that IgA deficiency prevails in the same families as CVI, suggesting a relationship between these conditions. The spectrum of clinical symptoms of IgA deficiency is broad many of those affected are asymptomatic, while others suffer from an assortment of serious problems. Recurrent respiratory and genitourinary tract infections resulting from lack of secreted IgA on mu-cosal surfaces are common. In addition, problems such as intestinal malabsorption, allergic disease, and autoimmune disorders may also be associated with low IgA levels. The reasons for this variability in the clinical profile of IgA deficiency are not clear but may relate to the ability of some, but not all, patients to substitute IgM for IgA as a mucosal antibody. The defect in IgA deficiency is related...

Chemotherapeutic agents that may induce rheumaticlike disorders are the following

Granulocyte colony-stimulating factor (G-CSF) may be associated with Sweet's syndrome. Interleukins and interferons have been associated with the development of signs and symptoms of autoimmune disease or auto-antibodies. Treatment with interferon-alfa is associated with Raynaud's syndrome and SLE-like illness. The manifestations vary depending on the underlying disease being treated. When used to treat myeloproliferative disorders, interferon-alfa can induce formation of antinuclear antibodies and rheumatoid factor, polyarthritis, or polyarthralgia. The incidence for these complications appears to be much lower in patients treated for carcinoid or viral hepatitis. Ongoing clinical trials of Il-4, IL-10, IL-1ra, and other biologic response modifiers should continue to monitor for any increase in auto-antibodies or autoimmune complications. O. Bone marrow transplantation may be associated with chronic graft-versus-host disease that includes scleroderma-like skin changes, alopecia,...

Spermspecific antigens

Since tolerisation to spermatozoa does not normally occur, vasectomy may lead to exposure of the immune system to sperm-associated antigens and the development of autoimmune disease. An association has been demonstrated between the expression of HLA-A28 and the development of anti-sperm antibodies in vasectomised men. These antibodies have been shown to form circulating immune complexes which, in monkeys, have been implicated in the rapid onset of atherosclerosis.

T Cell Tolerance and Antitumor Responses

Immunological tolerance ensures control of self-reactive lymphocytes and prevention of autoimmune disease, while generating a competent immune repertoire capable of responding to a myriad of foreign antigens. Central tolerance occurs in the thymus and eliminates T cells with strong self-reactivity (negative selection) and promotes maturation of T cells capable of responding to foreign antigens (positive selection). Most TAAs are self- or altered self-antigens and as such may be expressed in the thymus during T cell development. Therefore, the majority of high-affinity, potentially tumor-reactive T cells may be deleted from the T cell repertoire prior to leaving the thymus (Mathis and Benoist 2004). Potentially self-reactive T cells that exit the thymus tend to have low-affinity T cell receptors (TCRs) and are further subjected to peripheral tolerance mechanisms.

Overcoming Tolerance Leads to Tumor Immunity

Generating antitumor immune responses can be a double-edged sword. Antitumor therapy is aimed at eliciting an immune response to cells derived from self-tissue. As such, inducing tumor immunity that modulates tolerance to self-antigens may result in autoimmunity. Several studies have shown that enhancing immune responsiveness to tumors can also result in autoimmune reactions. In both cancer patients and murine models of melanoma, immunotherapy for melanoma often results in an autoimmune depigmentation, referred to as vitiligo (Naftzger et al. 1996 Overwijk et al. 1999 Hurwitz and Ji 2004), in which T cells with antigenic specificity for pigmentation antigens destroy normal melanocytes. Rosenberg et al. have reported that treating melanoma patients with an mAb against CTLA-4 can results in clinical regression of the tumor. However, autoimmunity including colitis, dermatitis, hepatitis, hypophysitis, and uveitis can also occur with this treatment (Attia et al. 2005b). Despite these...

TCell Vaccination Is a Possible Therapy

The basis for T-cell vaccination as a therapy for some autoimmune diseases came from experiments with the EAE animal model. When rats were injected with low doses (< 10-4) of cloned T cells specific for MBP, they did not develop Some experimental agents for immunointervention in autoimmune disease.

Clinical Focus Box 341

Adrenal insufficiency may be caused by destruction of the adrenal cortex (primary adrenal insufficiency), low pituitary ACTH secretion (secondary adrenal insufficiency), or deficient hypothalamic release of CRH (tertiary adrenal insufficiency). Addison's disease (primary adrenal insufficiency) results from the destruction of the adrenal gland by microorganisms or autoimmune disease. When Addison's first described primary adrenal insufficiency in the mid-1800s, bilateral adrenal destruction by tuberculosis was the most common cause of the disease. Today, autoimmune destruction accounts for 70 to 90 of all cases, with the remainder the resulting from infection, cancer, or adrenal hemorrhage. The prevalence of primary adrenal insufficiency is about 40 to 110 cases per 1 million adults, with an incidence of about 6 cases per 1 million adults per year.

Tolerance in the Mucosal Immune System

The immune system requires a mechanism for generating antigen specific tolerance to maintain immune homeostasis and control the harmful effects of auto-antigen reactive T lymphocytes. Several mechanisms have been proposed to allow the immune system to suppress the activity of certain T cell clones including clonal deletion, the induction of anergy and antigen specific suppression (reviewed in ref. 23). Recent experiments both in vitro and in animal models of autoimmune disease have characterised different populations of regulatory T lymphocytes that suppress antigen specific lymphocyte responses by the release of cytokines and also by cell cell interactions.

Autoantibodies To Ion Channels

A number of autoimmune disorders are caused when the body produces antibodies to its own ion channels. Of these, myasthenia gravis is the most common. It is one of the best characterised of autoimmune diseases and is produced by autoantibodies to the nicotinic acetylcholine receptor. Autoantibodies to the P Q-type of voltage-gated Ca2+ channels give rise to Lambert-Eaton myasthenic syndrome, antibodies to voltage-gated K+ channels are responsible for acquired neuromyotonia, and Rasmussen's syndrome is associated with antibodies to the GluR3 glutamate receptor subunit. In this chapter, we consider how these autoantibodies produce disease. A brief introduction to immunology is also provided for those unfamiliar with the subject. When circulating immunoglobulins encounter their specific epitope on an antigen, they bind to it via one of their Fab arms. The strength of this interaction is determined by the snugness with which the epitope fits into the antigen-binding site. The binding of...

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