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The Autoimmunity Bible & Norton Protocol

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Methods of experimentally inducing autoimmunity

Induction of autoimmunity by immunization ('immunization models') Table 1 Induction of experimental autoimmunity by immunization with autoantigens Autoimmune uveitis Autoimmune tubulointerstitial nephritis Autoimmune glomerulonephritis Rheumatoid arthritis Chronic active hepatitis Autoimmune orchitis Autoimmune myocarditis Idiopathic thrombocytopenia Autoimmune hemolytic anemia Myasthenia gravis One major disadvantage of this procedure is that the pathological effects induced are often transient in nature, presumably due to the imposition of autoimmunity on the normal animal with intact immuno-regulatory feedbacks. As a consequence, overt clinical disease is not observed in many immunization models, even though short-term tissue infiltration is readily apparent histologically. However, EAE is a notable exception in that severe nervous signs can be readily induced by immunization of susceptible animals with myelin basic protein or its peptide derivatives. Clearly, the nervous system is...

Modulating factors in autoimmune disease

In discussing factors or conditions that can modify the severity and course of autoimmune disease a clear distinction between etiology and pathogenesis becomes often difficult. This is due to the fact that autoimmune diseases have a multifactorial etiology requiring both genetic features and environmental conditions to occur. The question as to whether a given genetic or epi genetic factor is permissive to an autoimmune disease or only modifying the pathogenesis is open in most cases. The first evidence for an involvement of certain genes in the development of autoimmune diseases came from clinical experiences in humans revealing familial incidence of certain autoimmune diseases. This was confirmed by the observations that certain strains of experimental animals spontaneously exhibit enhanced frequencies of certain autoimmune disorders, and that selective breeding for the autoimmune phenotype resulted in further enhanced incidence and severity. The best-established animal models for...

Autoimmune Disease Spontaneous Animal Models

Autoimmune diseases can be experimentally induced by immunization of normal animals with the respective antigens combined with appropriate adjuvants. By this means organ-specific experimental autoimmune diseases can be produced in animals of many different strains and in nearly every organ. There is no doubt that such experimentally induced autoimmune diseases, e.g. experimental allergic encephalomyelitis (EAE) or experimental autoimmune thyroiditis (EAT), have contributed considerably to our understanding of the pathogenesis of autoimmune diseases in general and these models in particular. It is, however, also clear that most of these artificially produced autoimmune diseases often do not parallel their human counterparts with respect to all essential characteristics. Fortunately, there are several animal strains available that - based on many years of selective breeding - develop certain organ-specific or systemic autoimmune diseases spontaneously, i.e. without any experimental...

Genetic factors in autoimmune disease

The genetic make-up of the host may be a major determinant in the onset and development of autoimmune disease. Particularly relevant in this respect are those genes that control the size and type of immune response to an antigen, i.e. the MHC and antigen receptor genes. It is well documented that organ-specific autoimmune diseases can show a familial association. However, within a family, the type of disease manifested may vary from one member to another. Recent evidence suggests that as little as a single mutation of one particular gene may switch the susceptibility for disease from one organ to another. Several autoimmune diseases have been shown to be associated (at least loosely) with the expression of particular MHC and immunoglobulin allotypic genes. Individuals with seropositive rheumatoid arthritis (RA+) commonly express the product of the Class II gene DR4 whilst systemic lupus erythematosus (SLE) is associated with DR2 and DR3. Although these diseases Modern developments in...

Viruses in autoimmune disease

Viruses have been found to be associated with the presence of autoimmune disease in humans and other animals. They may cause autoimmune disease by a number of different mechanisms including polyclonal activation of lymphocytes (e.g. Epstein-Barr virus), release of intracellular organelles due to destruction of Figure 5.5 The role of antigen mimicry in autoimmune disease Figure 5.5 The role of antigen mimicry in autoimmune disease Role of Epstein-Barr virus in autoimmune disease Epstein-Barr virus (EBV) infects B cells and directly causes their activation. Although some autoreactive B cells escape elimination in the bone marrow, they are usually prevented from producing autoreactive antibody either by a lack of antigen-stimulated T cell help or by T cell-mediated suppression. However, if a potentially autoreactive B cell is infected by EBV it can proliferate and differentiate into a plasma cell without the help of T cells. Infected cells from both healthy individuals and patients with...

Dendritic cells in autoimmune disease

There is a considerable body of evidence implicating dendritic cells in the pathology of autoimmune disease. Their number is elevated both in the serum and synovial fluid of patients with rheumatoid arthritis. Also, patients with multiple sclerosis have raised levels of circulating dendritic cells secreting proinflammatory cytokines. In diabetes, dendritic cells from people at high risk of the disease expressed low levels of co-stimulatory molecules affecting T cell responses. Dendritic cells present antigen most effectively to na ve T cells. When dendritic cells are matured in the presence of proinflammatory cytokines, they are able to stimulate a Thrtype response through the release of IL-12. If inflammatory conditions do not prevail, dendritic cells are able to tolerise T cells or prime Th2-type responses. In autoimmune disease the balance between Thj and Th2 cells and between effector and regulatory T cells may influence disease progression. In addition to presentation, processing...

Lack of CD137CD137L Interaction Prevents Autoimmune Diseases

The same group (Seo et al., 2004) also tested the effect of CD137 CD137L pathway blockade on the development of collagen-induced arthritis (CIA), an experimental mouse model for the study of human rheumatoid arthritis (RA), which is a chronic and debilitating inflammatory autoimmune disease of joint (Feldmann et al., 1996). Type-II collagen (CII) is recognized as a prominent target of autoimmune destruction in RA and is the arthritogenic antigen in CIA (Luross and Williams, 2001 Myers et al., 1997). CIA is induced in genetically predisposed mice such as DBA 1 mice by immunization with bovine collagen II (bCII) emulsified in CFA. CD4+ T cells seem to play a central role in disease induction in arthritis (Ranges et al., 1985).

Organ Specific Autoimmune Diseases

In an organ-specific autoimmune disease, the immune response is directed to a target antigen unique to a single organ or gland, so that the manifestations are largely limited to that organ. The cells of the target organs may be damaged di- Some autoimmune diseases in humans Some autoimmune diseases in humans ORGAN-SPECIFIC AUTOIMMUNE DISEASES Myasthenia gravis SYSTEMIC AUTOIMMUNE DISEASES SYSTEMIC AUTOIMMUNE DISEASES

Mercuric Chloride Induced Autoimmunity

In genetically predisposed individuals, nontoxic amounts of mercuric chloride (HgCl2), a compound that was once used therapeutically and that is ubiquitous as a pollutant, provoke the appearance of immunologically mediated glomerulopathies. Gold salts, which are used in the treatment of rheumatoid arthritis, also induce immune glomerulopathies in 10 of patients. Experimental models have been developed mainly in rats. Brown Norway (BN) rats and to a lesser degree H-2s mice develop HgCl2- or gold-salt-induced autoimmunity, while LEW rats and DBA 2 mice (for example) are resistant. In BN rats HgCl2 provokes a B cell polyclonal activation that is under the control of CD4+ TH2-like cells. This activation is responsible for an impressive increase in serum IgE and IgG1 concentration. HgCl2 induces antibodies, mainly of IgG1 isotype, directed against both self antigens (e.g., DNA, laminin, type II collagen) and haptens (trinitrophenol). Kinetics assessment of the antibody response shows that...

Links between mycobacteria and autoimmunity

There are several aspects of the mycobacteria which lead to the possibility that these organisms, or antigens cross-reactive with them, are involved in autoimmune disease. In view of the fact that mycobacteria are ubiquitous in soil and water, but absent from the commensal microbial flora, there is the tantalizing possibility that variable exposure to mycobacteria in different geographical environments plays a role in the regulation of susceptibility to certain autoimmune diseases. See also Autoimmunity Bacteria, immunity to Bacterial cell walls BCG Delayed-type hypersensitivity Glycosylation of immune system molecules Granuloma Hypersensitivity reactions Stress proteins T cell vaccination.

Treatment of Autoimmune Disease with Agonistic AntiCD137

Various costimulatory molecules seems to be an attractive therapeutic approach for the treatment of T cell-dependent autoimmune diseases. However, these strategies appear to be prophylactic rather than therapeutic, since naive T cell activation are more dependent on costimulatory signaling while the function of preexisting autoreactive T cells are less costimulation-dependent. Another shortcoming of this approach is its requirement of repeated long-lasting treatments, which is costly. Promisingly, recent studies showed that costimulatory agonists of CD137 could prevent and have therapeutic effects on CD4+ T cell-mediated organ-specific autoimmune disease such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveitis (EAU) (Shao et al., 2005 Sun et al., 2002b), and both CD4+ T cell and autoantibody-involved systemic autoimmune diseases such as systemic lupus erythematosus (SLE), collagen type II-induced arthritis (CIA) and chronic graft-versus-host disease...

Association of IL10 Production with Autoimmune Diseases

A number of studies of both mouse and human models of autoimmune diseases have documented altered IL-10 serum levels, suggesting a direct link between IL-10 levels and disease.1'2 Evidence from mouse models suggest that IL-10 production may play a protective role in organ-specific autoimmune disease and alter the balance between pathogenic Th1 cells and protective anti-inflammatory Th2 cells.2 However, while some studies show that administration of IL-10 could result in improvement of the disease phenotype, other studies have shown that IL-10-deficient mice fail to develop an autoimmune syndrome, and the expression of an IL-10 transgene resulted in earlier disease onset or exacerbated disease rather than in protection.2 High serum levels of IL-10 have been documented in human autoimmune diseases. In systemic lupus erythematosus (SLE) patients, high IL-10 levels have been shown to correlate with disease activity,9,10 and studies indicate that cultured PBMC from lupus patients...

Treatment of autoimmune diseases in humans

Gut for autoantigen-specific TGFfJ-secreting cells in a human autoimmune disease simply by oral administration of the autoantigen. Furthermore, it also appears that continuous oral administration of oral antigen is required as MS patients had worsening of disability over a 3-year observation when they were not taking oral myelin.

Soluble CD137 and Autoimmune Diseases

The elevated levels of sCD137 have been observed in sera of patients with multiple autoimmune disorders such as rheumatoid arthritis (Jung et al., 2004 Michel etal., 1998), multiple sclerosis (Sharief, 2002), systemic lupus erythematosus (SLE) and Behcet's disease (BD) (Jung et al., 2004). Michel et al. (1998) first observed dramatic increased levels of sCD137 in sera of patients with rheumatoid arthritis. Later studies (Jung et al., 2004) showed that both sCD137 and sCD137L serum levels were significantly higher in RA patients compared with healthy controls, and their concentration correlated with rheumatoid factor (RF) values and the disease severity. Moreover, the levels were markedly decreased at the quiescent stage following immunosuppressive therapy, compared with patients at disease onset (Jung et al., 2004). Sharief observed significantly higher levels of sCD137 in serum and the intrathecal compartment of patients with clinically active multiple sclerosis (MS), which is a...

Role of T cells in autoimmune disease

The thymus plays a vital role in the development of self-tolerance and thus abnormalities affecting the development or functioning of the thymus may contribute to the development of autoimmune diseases. For example, a variety of thymic abnormalities have been reported in systemic lupus erythematosus but it is unclear whether these are causative, or sequelae of the disease. The TCR repertoire in autoimmune diseases Evidence suggests that autoimmune disease is associated with restricted usage of particular TCR V region genes. In rheumatoid arthritis, studies have indicated that restriction of the TCR gene repertoire is limited to the genes of the junctional region of the TCR on CD8+ cells. In myasthenia gravis, patients have increased expression of the Vb5.1 (variable region gene 5.1 on the beta chain) and Vb8 genes in the peripheral blood and on mature thymocytes but not on precursor thymic cells. This suggests that these patients may exhibit an altered thymic selection process. T...

Gene Therapy for Autoimmune Diseases

Autoimmune disease is a pathogenic condition in which one's immune system mistakenly targets and attacks person's own cells, tissues, and organs. Inflammation is a prevalent symptom for this disease caused by the excessive presence of large number of immune cells and molecules in the target site of the body. Against autoimmune diseases or other inflammatory conditions, the delivery of cytokines or cytokine inhibitors through gene therapy is proved very effective. Interferon y (IFN-y), in-terleukin-1 (IL-1, a or 3), IL-12, and tumor necrosis factor a (TNFa) are the most frequently addressed inflammatory cytokines in illness related to autoimmune inflammatory diseases. Other than these cytokines, transforming growth factor j3 (TGF (3) is also a key regulatory cytokine (53), because TGF )3 inhibits T- and B-cell responses, dysregulation of which lead to elevation of autoimmune disease conditions. In animal models, pDNA constructs with the encoding anti-inflammatory cytokine genes for...

Superantigens and Autoimmunity

Owing to their mode of action, superantigens have been identified as a possible candidate for one of the causative agents of autoimmune disease (2,61). Because autoreactive T and B cells can easily be isolated from the peripheral blood of healthy individuals (62,63), superantigens could stimulate auto-reactive T cells both locally and systemically, since they do not discriminate between autoimmune and normal lymphocytes (64). Thus the delicate balance of tolerance could be broken. Although superantigens are yet to be directly implicated in human autoimmune disease, there is growing evidence to suggest their involvement. For example, SED and SED-reactive T cell lines have been shown to stimulate auto-antibody production by B cells in vitro (65). It has been shown that Staphylococcus aureus strain AB-1 is responsible for the spontaneous outbreak of staphylococcal arthritis in a colony of rats (66). When this strain was isolated from a swollen joint and injected intravenously into...

C A Wider Role for Hsp 60 in Autoimmunity

The expression of hsp 60 is increased under conditions of stress in many tissues. It has been proposed that a physiological function of this stress protein may be to alert the immune system to the presence of damaged cells and to function as a target for their removal (55). In autoimmune disease, the initial insult against the target cell may activate a population of cross-reactive T cells, which are then able to react with the homologous sequences on the tissue-spe-cific antigens. As the potential epitopes exhibit a variety of motifs, it would be expected that different MHC alleles would present alternative hsp 60 epitopes in the target cells, and thus susceptibility to specific autoimmune diseases would be associated with the expression of distinct MHC haplotypes. In the specific case of IDDM, the amino acid similarity between hsp 60 and the tissue-specific Myasthenia gravis

Hematopoietic Stem Cell Transplantation For Autoimmune Diseases

Historically, HSCT was used to rescue hematopoiesis after myeloablative therapy for the treatment of nonresectable tumors and malignancies. Subsequently, improvements in induction and immunosuppressive therapies have allowed the use of myeloablative therapy as a supportive platform for replacement of defective hematopoietic stem cells in patients with congenital diseases. In the context of HSCT therapies, autoimmune diseases share aspects of both congenital diseases and malignancies, in that both immunosuppressive therapy and replacement of defective hematopoietic stem cells may be directly therapeutic. Recently, observed therapeutic resolution of coincidental autoimmune diseases in patients receiving HSCT for primary malignancies or hematopoietic failure suggested the possible application of HSCT in the treatment of primary autoimmune diseases (reviewed in ref. 1). Autoimmune diseases encompass a broad range of diseases with unique pathogeneses and manifestations. Criteria for...

B Antibodies Specific for Chaperonins in Autoimmune Disease

These antibodies are found in a wide range of autoimmune diseases and in healthy controls (reviewed in Winfield and Jarjour, 1991). Anti-human chaperonin antibodies have been described in children with juvenile chronic arthritis, systemic lupus erythematosus, and cystic fibrosis (de Graeff-Meeder et al., 1993), in patients with Kawasaki disease (Yokota etal., 1993), and in patients with atherosclerosis (Xu et al., 1993), polymyositis, dermatomyositis, psoriatic arthritis, inflammatory bowel disease, epidermolysis bullosa aquisita, and bullous pemphigoid (Winfield and Jarjour, 1991). However, anti-human chaperonin autoantibodies were not found by other workers in the rheumatoid arthritis, Sjogren's syndrome, or Reiter's disease (Worthington et al., 1993 Winfield and Jarjour, 1991). In addition, there are numerous reports of anti-bacterial chaperonin antibodies in many autoimmune diseases (reviewed in Winfield and Jarjour, 1991 Kaufmann, 1994). There is no evidence from animal models...

The Rationale For The Use Of alloBmt For The Treatment Of Autoimmune Disorders

Allogeneic bone marrow transplantation which normally follows myeloablative conditioning can also eliminate spontaneous autoimmunity, as has been shown in (NZBxNZW)Fl, BxSB, (NZBxNZW)Fl females and MRL lpr mice 13 , and more recently in clinical practice 19-22 , most likely by a combination of elimination of self-reactive lymphocytes of hostorigin and replacement of genetically susceptible stem cells with normal stem cells of donor origin. Successful elimination of manifestations of autoimmune disease were documented in patients with RA, SLE, hyperthyroidism, dermatitis, vasculitis and Crohn's disease 13-22 . Successful treatment of MS was also reported in a patient with chronic myeloid leukemia following alloBMT, with subjective improvement in symptoms and objective improvement of neurological manifestations of disease and stabilization of MRI 14 . We have also treated one patient with CML with severe psoriasis accompanied by severe psoriatic arthritis and another patient with acute...

Genetic Evidence Supporting Autoimmunity In Ms

Epidemiologic data strongly support a genetic predisposition to MS. Other putative autoimmune diseases such as SLE and rheumatoid arthritis are well documented to occur at a higher frequency within families of affected patients than in the general population (41). Twenty percent of patients with MS report a positive family history for MS (42,43). Approximately 30 of monozygotic twins are concordant when one of the twins has MS, while among other siblings the risk is 2 to 5 , and among half-siblings the risk is 1.1 to 1.4 (44). Among adopted siblings and the general U.S. and Canadian populations, the risk is 0.1 (45,46). The familial predisposition to MS has prompted investigations into immune-response genes to explain this enhanced susceptibility. MHC-II molecules are expressed on the surface of antigen-presenting cells and present processed antigen to CD4+ T-cells (47). The CD4+ T-cell, in turn, is the primary mediator of the animal model for MS, EAE (48), and is strongly implicated...

HLA the major genetic locus in autoimmunity

The first recognition of a role for a specific gene for determining autoimmune susceptibility came from the identification in 1973 that the vast majority of patients with ankylosing spondilitis, a disorder of axial joints, possessed HLA B-27 (Brewerton et al., 1973). This observation was made utilizing HLA antisera rather than DNA-based genetic methodology and has led to the transformation in our understanding of the genetics of autoimmunity and of the functional role of HLA antigens themselves. This initial report was shortly followed by similar observations in a range of other autoimmune diseases. In the case of diabetes, investigators identified a role for HLA B8 in the juvenile form of disease, distinguishing a subtype of diabetes, now known as Type 1 diabetes, from other more common adult forms of the disease (Cudworth and Woodrow, 1976). As the tools for typing HLA variants became better and incorporated both cellular and humoral reagents, it became clear that the exact nature...

Candidate Autoimmune Diseases 609241 Amyotrophic lateral sclerosis

Atrophy, and die of respiratory failure. Over 90 of ALS cases are sporadic of the familial cases of ALS, a fraction is caused by mutations in the gene for the free-radical scavenger superoxide dismutase (SOD)-1. It has been hypothesized that sporadic ALS is an autoimmune disease.

Autoimmunity andor Infection

The thymus negatively selects T cells with autoantigen-specific surface receptors. This negative selection process requires the presence of peripheral autoantigen in the thymus. Although this review will not focus on the thymic selection process, it is noteworthy that the transcription factor AIRE has been proposed to assure thymic expression of peripheral antigens 3 . AIRE was identified as the mutated gene in humans with Autoimmune Dystrophy (APECED), a familiar polyendocrine autoimmune disease 4 . To study central tolerance and peripheral autoimmunity, several T cell receptor transgenic mice specific for relevant extralymphatic peripheral autoantigens have been developed during the past decade 5 . Interestingly, central tolerance appeared to be more the exception than the rule. These findings implicate that naive autoantigen-specific T cells are probably common, much more than widely believed. However, most T cell receptor transgenic autoimmune mouse models fail to induce disease...

The Role of Autoimmunity in Uveitis

Although it has been recognised for a long time that bacterial and viral infection can account for some cases of uveitis, it has also been recognised that the majority of cases fail to show any evidence of this. Furthermore, in many instances the eye disease may be associated with known autoimmune disease elsewhere in the body. There are several different ways in which the uvea might be expected to become the focus of an antigen-antibody reaction. A foreign agent such as a virus might reside in the uvea and cause an antibody response, which coincidentally involves uveal tissue, or, on the other hand, a foreign agent might react with a

Mechanisms Contributing to Autoimmune Diseases

In the course of autoimmune diseases, the immune system, upon reacting to bacteria, viruses, and other exogenous pathogens, also can attack self-antigens and tissues. Numerous autoimmune diseases are known, each of them exhibiting a distinct general etiopathology and affecting a limited number of defined self-antigens and tissues. Some autoimmune diseases are clinically heterogeneous and merely defined by common clinical criteria. These diseases may resemble a collection of genuinely distinct autoimmune disorders that share only distinct features. Examples include such widespread autoimmune disorders as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Frequently, these diseases initially present with mild symptoms but then become chronic and progressive, eventually resulting in severe and irreversible obstructions. Autoimmune diseases affecting humans and animals are genetically complex 1,2 . Multiple gene defects contributing to the development of lupus in the NZB W...

Definition of Autoimmune Disease Physiology Versus Pathology

Identification of genes controlling autoimmune diseases requires that we have a clear definition of what an autoimmune disease is. Over the years, this definition has been shifting and also varies depending on whether it is seen from a clinical point of view or from a basic science point of view. has emerged as one of the major driving factors, for example, psoriasis and atherosclerosis. It is obvious that from this perspective autoimmune diseases compose a highly heterogeneous group, even within each disease classification, as there are not yet means to link diagnosis with disease mechanisms. Rather we are bound to description of the more obvious pathologic end-result, such as the lack of insulin in T1D or the neurological deficit in MS. From the basic science standpoint, autoimmune recognition is often the phenomenon of interest for definition of autoimmune diseases. It stems from a tradition of viewing autoimmunity as forbidden self or horror autotoxi-cus, as Burnett described it....

LTi Cells and Ectopic Lymphoid Follicles in Autoimmunity

Several autoimmune diseases, including Crohn's disease, rheumatoid arthritis, and type I diabetes, are marked by formation of ectopic lymphoid organlike structures within the affected tissues. The contribution of such ectopic follicles to disease pathogenesis remains unexplored. The role of LTi cells or related inducer cells (such as those found in CPs) in these lesions has yet to be explored. Forced expression of CXCL13 BLC in pancreatic islet cells resulted in the local formation of lymphoid follicles, but this was independent of LTi cells, because follicles were also observed in RORY- -mice ( 66 and unpublished collaborative result). However, CXCL13 expression by stromal cells is induced by LT0R signaling. As LTi-like cells are the producers of LTap, this system may bypass the requirement for the cells. In autoimmune diseases, inflammatory stimuli may result in activation of LTi or CP-like cells, particularly in the intestine, and this could induce excessive follicle formation....

Mechanisms controlling autoimmunity

Cell Bypass Theory

Because pathogenic autoimmunity is the exception rather than the rule, mechanisms must exist which normally prevent the development of autoimmune disease. In this respect the immune system is able to distinguish self from nonself and, ultimately, becomes 'tolerant' towards most self antigens. However, as alluded to above, many of the tolerance mechanisms controlling autoimmunity may be less concerned with repression of all self reactive lymphocytes than with preventing the development of pathogenic T cells and autoantibodies. Indeed, there is evidence from studies in transgenic mice to suggest that, in situations in which high-affinity antiself B cells are anergized, low-affinity antiself B cells escape this tolerization process. Although evidence for several different tolerance mechanisms exists, the relative role of each of these in controlling autoimmunity remains to be firmly established. For a long time it was thought that many self antigens were sequestered in 'privileged sites'...

Autoimmunity Can Be Induced Experimentally in Animals

Autoimmune dysfunctions similar to certain human autoimmune diseases can be induced experimentally in some animals (see Table 20-2). One of the first such animal models was discovered serendipitously in 1973 when rabbits were immunized with acetylcholine receptors purified from electric eels. The animals soon developed muscular weakness similar to that seen in myasthenia gravis. This experimental autoimmune myasthenia gravis (EAMG) was shown to result when antibodies to the acetylcholine receptor blocked muscle stimulation by acetylcholine in the synapse. Within a year, this animal model had proved its value with the discovery that auto-antibodies to the acetylcholine receptor were the cause of myasthenia gravis in humans. Experimental autoimmune encephalomyelitis (EAE) is another animal model that has greatly improved understanding of autoimmunity. This is one of the best-studied models of autoimmune disease. EAE is mediated solely by T cells and can be induced in a variety of...

Genetic Analysis in Autoimmunity

Genome Scans and Linkage Analysis in Autoimmune Diseases During the last 10 years, several groups have collected multiplex families of the various autoimmune diseases for genome screening with microsatellites and linkage analysis. The very first report of linkage analysis came from the field of type 1 diabetes (T1D) mellitus (Davies et al., 1994) followed by multiple sclerosis (MS) (Ebers etal., 1996), rheumatoid arthritis (RA) (Cornelis etal., 1998), and systemic lupus erythematosus (SLE) (Gaffney et al., 1998 Moser et al., 1998). I limit this review to these diseases, adding only Crohn's disease (CD) and ulcerative colitis (UC). Just as with T1D, full-genome scans have been performed for MS (Ebers et al., 1996). In the initial genome scan, possible loci were detected on chromosome 6p21 and 5p and evidence was later provided on 5p with 21 Finnish MS families (Kuokkanen et al., 1996). A full-genome scan also performed in the Finnish families identified a region in chromosome...

TGF0 and experimental autoimmune diseases

The influence of TGFp on EAE as a prototype of organ-specific CD4+ T cell-mediated autoimmune disease has been extensively studied. TGFp strongly inhibits in vitro activation of T cells from Lewis rats with EAE. During recovery from EAE, CD4+ spleen cells produce TGFp and thereby regulate both the production of IFNy and the encephalitogenicity of effector cells. Systemic administration of TGFp reduces the incidence and severity of EAE induced in the SJL mouse, without generalized immunosuppression. This observation is in line with the known resistance of resting lymphocytes, but increased susceptibility of activated T lymphocytes, to suppression. In vivo administration of antibody to TGFp worsened the clinical signs of monophasic EAE. Taken together, these observations suggest that endogenous TGFp has an important role in the natural recovery from E1AE. The mechanisms of how TGFp acts in EAE are not yet fully understood but it can be assumed that the disease-limiting effects are at...

Rationales of B Cell Targeted Therapy in Autoimmune Diseases

A signal of infection initiating B cell activation. In humans, the expression of TLR9 appears to be relatively restricted to B cells and CD123+ dendritic cells. After ligation of CpG motifs to TLR9, B cells are induced to proliferate and secrete Ig, and DCs secrete a wide array of cytokines, interferons and chemokines that activate TH1 cells. Bacterial DNA or CpG motifs co-stimulate B cell activation through cell membrane Ig and thereby promote an early antigen-specific response. This study (Leadbetter et al. 2002) found that immune complexes containing self-DNA activate rheumatoid factor-specific B cells as a result of two distinct signals (a) engagement of the B cell antigen receptor (BCR) and (b) activation of TLR9 through the histone DNA portion of the immune complex. Although the implications of these findings for certain autoimmune diseases need further studies, the evidence that TLR9 activation co-stimulates autoreactive B cells provides a mechanism of action for an established...

Hsp 60 Autoimmune Diseases

In addition to the nonspecific adjuvant and regulatory effects of natural hsp 60 autoimmunity, it is clear that certain autoimmune diseases can be caused by specific hsp 60 autoimmunity. The development of type I diabetes in the NOD mouse seems to fulfill the criteria for assigning such a causal relationship anti-hsp 60 T cells can transfer diabetes (12), active immunization to the p277 epitope of hsp 60 can induce diabetes, even in mice that are not prone to dia betes (15), and the p277 peptide can be used to downregulate hsp 60 autoimmunity and cure diabetes (13). Another example of the causal relationship between hsp 60 autoimmunity and a specific disease seems to be a form of uveitis (19). The relationship between hsp 60 autoimmunity and arthritis is less clear (30) mimicry between an epitope of a bacterial specific hsp 60 sequence and a cartilage proteoglycan may be involved (31). Thus, adjuvant arthritis may combine bacteria-hsp 60 mimicry of a joint-specific molecule, along...

Consequences of autoimmunity

Autoimmunity is defined as an immune response leading to reaction with self antigen, i.e. any molecule that is a normal body constituent of the animal mounting the response. Self reactivity can arise either and although these antibodies are present at higher titers in about 70 of Hashimoto's disease patients, it is autoantibodies to another thyroid component, thyroid peroxidase, which show a stronger correlation with histopathological lesions. These autoantibodies occur in 95 of patients with Hashimoto's disease and, unlike most thyroglobulin autoantibodies, are complement fixing and therefore potentially cytotoxic to thyroid epithelial cells. Another example underlining the distinction between autoimmunity and disease is seen in patients treated for longer than 1 year with the drug procainamide (used to control cardiac arrhythmia). Over 90 of these patients develop IgM antibodies reactive with a broad spectrum of self histones but it is only in the 10-20 of patients who develop high...

Immunological Memory and Chronic Autoimmune Diseases

Though most autoimmune diseases become chronic, spontaneous remission occurs in a small, but considerable proportion of patients suffering from various autoimmune diseases 18, 19 . Complete remission is common among autoimmune diseases that had been induced by an exogenous stimulus in individuals bearing an otherwise intact immune system. This applies for most animal models, where autoreactivity is induced in animals that otherwise would not develop that autoimmune disorder such as experimental autoimmune encephalomyelitis (EAE) 20 . Similarly, drug-induced human SLE usually undergoes remission in patients no longer receiving this drug 21 . These observations suggest that the factors that induce acute autoreactivity and autoimmune tissue destruction are not necessarily sufficient to make immunopathology and inflammation chronic. Clear evidence that induction and chronicity of an autoimmune disease could be driven by distinct mechanisms is provided by genetic approaches in animal...

Malignant Transformation In Autoimmune Diseases

Malignant tumors specifically lymphoid malignancies are diagnosed with increasing frequency in various autoimmune diseases. The cancer may appear during the diagnosis of the autoimmune disease or many years later. This association has important clinical and therapeutic implications. First, it may imply that in certain autoimmune diseases screening tests for malignancies should be performed routinely. Moreover, it has to be determined if the treatment given to these autoimmune diseases contributed to the malignant transformation or whether the malignancies appear independent of the treatment.

Causes of autoimmunity

Every day, the body is exposed to a number of factors, which alone, or in combination, under the correct conditions may initiate the development of an autoimmune disease. In addition, it is also a normal consequence of ageing and may be induced by certain drugs or microorganisms (especially viruses). The exact cause of most autoimmune diseases is largely unknown as are the factors that control the severity of the disease, the range of autoantigens or the target organs involved. However, a number of parameters are known to be generally Table 5.5 Factors affecting the development of autoimmune disease Effects associated autoimmune disease Oestrogen aggravates autoimmune disease androgens are immunosuppressive Neurochemicals and hormones are involved in rapid onset of autoimmune disease in response to these agents Autoimmune thyroid disease Autoimmune haemolytic disease Myasthenia gravis, pemphigus, autoimmune thyroid disease, autoimmune haemolytic anaemia Autoimmune haemolytic anaemia,...

Autoimmunity

The association of autoimmune disease and CLL is well known but misunderstood. There is no general tendency for patients with CLL to develop autoimmune disease. The only autoimmune conditions seen in CLL with any frequency are autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). A few other rare conditions occur in CLL more commonly than would be expected, but the common autoimmune diseases, such as rheumatoid arthritis, Other types of autoimmune disease The idea that CLL was regularly associated with all types of autoimmune disease was reinforced by reviews by Miller86 and Dameshek.87 However, in an elderly population, autoantibodies are recognized quite commonly. Hamblin et al.65 found that 21.5 of a control population of individuals over 60 years of age had tissue-specific autoantibodies detected by immunofluorescence. In an age-matched series of 195 patients with CLL, the prevalence of autoantibodies was exactly the same. Duhrsen et al.75 confirmed this. However,...

Autoimmune disorders

Some autoimmune diseases are now identified as infection-triggered, such as Crohn's disease (CD), which is an intestine autoimmune disease that causes chronic inflammation. Recently, it was shown that inflammation induced by bacterial infection triggers chronic inflammation, and mutation of NOD2 increases disease susceptibility 75, 76 . Extensive concentration of bacteria such as Mycobacterium paratuberculosis and Listeria monocytogenes has been observed by biopsy of CD patients using 16S rDNA PCR and DNA hybridization analysis 77 . Such infection-triggered autoimmune disorders are not specific to Crohn's disease reflecting the inherent fragility of the immune system where antigen patterns presented for immune reaction are sufficiently similar to the host's own signature, causing the immune system to react against the self 78 . The MHC antigen presentation and receptor system is the core of the bow-tie architecture, and so a breach in this system seriously affects its functionality....

AID in Autoimmunity

There is compelling evidence that B cells play a critical role in the pathogenesis of many of the organ-specific and systemic autoimmune diseases. Systemic autoimmune disorders with a known B cell component include systemic lupus erythematosus (SLE), rheumatoid arthritis, mixed connective tissue disorder and scleroderma, among others. Many of the hallmark antibodies associated with these disorders are against nuclear components such as DNA, ribonuclear proteins and DNA repair proteins, antigens not readily exposed to the cells of the immune system. It is not understood why antinuclear antibodies develop but defective apoptosis, defective clearance of apoptotic material, excess necrosis from ongoing chronic damage, defects in toll receptor signaling and a breakdown in B and T cell tolerance mechanisms have been suggested as potential culprits. Ultimately, these autoantibodies can trigger an autoimmune cascade characterized by inflammation and tissue destruction. One way B cells...

Myasthenia gravis

Myasthenia gravis is associated with painless weakness which is worse after exertion with deterioration during stress, infection or trauma. Tendon reflexes are normal. It is an autoimmune disease associated with acetylcholine receptor and, rarely, anti-striated muscle antibodies. There is also an association with other autoimmune diseases (e.g. thyroid disease, SLE, rheumatoid arthritis).

Autoimmune Diseases

Autoimmune inflammation of the inner ear may occur in isolation as an organ-specific process or may be part of a systemic autoimmune syndrome (20). Evidence is mounting to support the existence of an organ-specific cochlear autoimmune disease. The presence of antibodies to cochlear antigens, such as the 68 kD inner-ear antigen, as well as an impressive response to immunosuppressive medications, implicate autoimmunity as the underlying pathologic process in some patients with idiopathic sensorineural hearing loss. These patients with autoimmune inner-ear disease (more accurately termed immune-mediated inner-ear disease, since proof for autoimmunity is still lacking) have a fluctuating progressive sensorineural hearing loss, often associated with vertigo and tinnitus. Generally, hearing loss progresses rapidly, within a period of weeks and months, to an irreversible end-stage disease. While at any given moment, one ear may be more significantly affected, the process eventually affects...

Autoimmune disease

The therapeutic application of DAB389IL-2 is not limited to the treatment of T-cell derived malignant disease. DAB389IL-2 is a potential therapeutic for any disease where the underlying etiology is mediated by activated T cells, such as many autoimmune diseases. To date, the clinical studies conducted to evaluate the efficacy of Ontak for the treatment of autoimmune disease have been limited to psoriasis and rheumatoid arthritis (RA). Common examples of other T lymphocyte mediated diseases include chronic inflammatory diseases such as atopic eczema, lichen planus, alopecia areata, multiple sclerosis, systemic lupus erthematosus (SLE), myasthenia gravis, Grave's disease, and graft versus host disease (Livolsi et al., 1994). Taken in aggregate, autoimmune disease is the most prevalent human disease (Murphy and vanderSpek, 2000). The presentation of autoimmune disease ranges from mild to severe and from manageable to refractory. While most autoimmune diseases are not life threatening,...

Comparison of Common Tests

The most commonly performed test to measure autoantibodies in clinical laboratories is IIF to screen for the presence of ANAs 1 (Fig. 8.3). Almost all patients with systemic lupus erythematosus (SLE) are ANA positive, so a negative result on this test virtually rules out SLE 13 . Patients with many other systemic autoimmune diseases, as well as some healthy individuals, are also positive for ANAs 14 . Thus, a positive result is suggestive that the person has an autoimmune disease, but it is not diagnostic. Originally, the ANA IIF test was performed on thin sections of tissue such as mouse kidney. Because of the relatively small size and random orientation of the cells, only a few staining patterns could be observed on this substrate. Also, antibodies to one of the more common autoantigens, SS-A Ro, were not detected on mouse kidney slides 15 . A significant improvement to screening for ANAs occurred when cells that grow in a monolayer in culture, like HEp-2 cells, were used as the...

Role of Autoantibodies in Tissuespecific Organ Damage

Autoimmune diseases affect 3-5 of the population, but they attract medical attention only when they become sustained and cause lasting tissue damage 1 . Depending on the affected organ, the clinical presentation of autoimmune diseases can be very heterogeneous and specific, or unspecific features can predominate. A common characteristic of autoimmune diseases is the presence of autoantibodies that are produced by autoreactive lymphocytes and that may be the direct cause of some of these disorders. For instance, in Graves' disease, autoantibodies bind to and stimulate the receptor for thyrotropin, resulting in unrestrained thyrocyte growth, excessive thyroid hormone production, and diffuse hyperplasia of the thyroid gland 2, 3 . In Hashimoto's thyroiditis, antibodies against thyroglobulin, thyroid peroxidase, and the thyrotropin receptor have been suggested to play a role in the progressive destruction of thyroid follicular cells 4, 5 . In pemphigus vulgaris, autoantibodies against the...

Stanford L Peng Summary

Murine models of systemic lupus erythematosus provide fertile research systems for the pathogenesis and therapy of systemic autoimmune disease. Their phenotypes span the broad range of clinical manifestations of human lupus and consist of both spontaneous and experimentally induced disease in both inbred and targeted mutant animals. This chapter contrasts the clinical characteristics of these various models, providing an outline for the use and analysis of these in vivo autoimmune systems. Keywords Arthritis autoantibodies autoimmune diseases glomerulonephritis hemolytic anemia lupus inbred mice knockout mice mutant mice transgenic mice.

Other Target Antigens

Antibodies to insulin, GAD65 and IA-2 are well established as distinct and important markers for diabetes diagnosis and prediction and the latter two antigens contribute to ICA reactivity on frozen sections of pancreas 103 . However it is clear that diabetic patients have increased immune reactivity to several other components of pancreatic islets, including proteins and glycolipids (Table 15.1). There is evidence that the sialo-ganglioside GM2-1 may represent a major component of ICA 104 and that antibodies to the glycolipid are associated with progression to diabetes in relatives with ICA. Sulfatides have also been shown to be reactive with antibodies in a high proportion of diabetic patients at disease onset 105 . Other protein antigens, such as ICA69 106 and Glima 38 107 , have shown some promise as predictive markers for diabetes, but difficulties in establishing reproducible assays for these antibodies have prevented their widespread use in large-scale screening studies. Some...

The Carcinogenicity Of

The use of immunosuppressive drugs bears intrinsically the risk of tumor formation with two basic mechanisms a genetic one, consisting of a direct effect of the drug on DNA replication and an epigenetic mechanism, including indirect effects on immunological, hormonal, metabolic control of multiple cellular regulatory events 16 . CyA does not seem to be geno-toxic 15 several experimental data have excluded any mutagenic properties 17, 18 . The association of CyA to carcinogenesis is mainly related to its immunosuppressive capacity. It is well known that severe immunosuppression leads to an increased incidence of malignancy, especially virus-related a minor immune surveillance for transformed cells is associated to the development of a microenviroment more permissive towards chronic oncogenic viral infection 19 . Viral infections are common among immunodeficient patients, first of all Epstein Barr virus (EBV), papilloma and herpes virus 20, 21 , EBV induces B-cell proliferation and,...

Introducation About Lupus In Immune Disease Summary

Autoimmunity should be defined in the strict sense as an immune response by the host to a self-antigen, at either the humoral or cellular level or both. This definition distinguishes the autoimmune response per se from autoimmune disease where the humoral and or cellular consequences of the immune response have resulted in pathophysiological abnormalities. In this sense, autoimmunity as a phenomenon is not uncommon, but the follow-through to autoimmune disease has been less common. This observation begs the question of whether there are autoimmune responses that are physiological and others that are pathological. In this chapter, I will describe the unique features of the auto-antibody-defined epitope, or the antigenic determinant on the self-antigen, and how perhaps this knowledge might be useful in the context of designing reagents for immunotherapy. One of the hallmarks of many autoimmune diseases is the production of au-toantibodies to specific cassettes of cellular autoantigens....

Discussion and Conclusions

A common feature of all autoimmune diseases is the presence of autoantibodies. Some autoantibodies are specific for the site of the disease process, as exemplified by thyroid diseases, pemphigus vulgaris, or autoimmune gastritis. However, even in instances in which the autoantibodies are not believed to be the causative agents, they always make an important contribution to the diagnosis of autoimmune diseases. Subdifferentiation of the pattern of autoantibodies allows us to distinguish not only different autoimmune types but also different subsets of autoimmune diseases. For instance, antinuclear antibodies are the most commonly detected autoantibodies in AIH type 1, but they are also frequently (50 ) detected in PBC. Subclassification of ANAs shows that in PBC In a number of autoimmune diseases, it is still unknown whether the autoantibodies highlight the responsible pathogenic process, thereby directly contributing to organ-specific autoimmunity and injury, or whether this is...

Study Design

When applying these methods to study other signaling molecules, it is important to design the study to analyze various forms and fractions of the molecules by using antibodies that can bind to multiple forms rather than one structural epitope. Normal T cells or autoimmune disease controls such as rheumatoid arthritis, Sjogren's syndrome, Still's disease, limited systemic sclerosis, mixed connective tissue disorder, antiphospholipid syndrome, and dermatositis can

Lupus Erythematosus What Is Lupus Erythematosus

Lupus erythematosus is an autoimmune disease, meaning that the inflammation-causing immune cells attack the body's own tissues. It can affect different parts of the body, such as the skin, joints, kidneys, lungs, and cardiovascular system, and cause a wide variety of symptoms. Some cases are very mild, whereas others may be disabling or fatal. Ninety percent of people with lupus experience inflammation of their connective tissue, with symptoms often similar to rheumatoid arthritis, another autoimmune disease. Other common symptoms include rashes, sensitivity to sunlight, and kidney disorders.

Effector mechanisms of Thmediated immunity

Th1 cells appear to be critical in effecting an antigen-specific phagocytic-mediated defence against microorganisms, principally bacteria, fungi and some parasites. If, however, Thl-biased immunity is directed against self-antigens, extensive tissue destruction and autoimmune disease may ensue. Common autoimmune diseases resulting from inappropriate Th1 responses include autoimmune haemolytic anaemia, autoimmune thrombocytopenic purpura, Goodpasture's syndrome, type I insulin-dependent diabetes mellitus, rheumatoid arthritis and multiple sclerosis. Disease may also ensue if a Thl-biased immune response is inappropriately directed against innocuous antigens, such as occurs in coeliac disease.

Link Between Genetics And Immunology

Disruption in the mechanisms of antigen presentation can result in either immune deficiency or autoimmunity, depending on the specific abnormalities present. For example, it has been observed that the amino acid at position 57 on the HLA-DQ beta chain is associated with either risk for or protection from autoimmune diabetes (44). Specifically, when aspartic acid (Asp57P) is present at position HLA-DQA1+0102 DQB1+0602 (DR2), then the risk of developing autoimmune disease is low. On the other hand, lack of aspartic acid at this position is observed for HLA DQB1 molecules associated with diabetes risk, such as HLA-DQB1+0201 (DR3-DQ2) and HLA-DQB1+0302 (DR4-DQ8). Variations in the MHC class II molecules have been linked not only to diabetes, but also to various other chronic autoimmune conditions, such as multiple sclerosis, celiac disease, rheumatoid arthritis, and narcolepsy. Although not entirely clear at this time, it appears that the polymorphisms encountered in the beta chain of HLA...

Oxidation and Disease an Overview

Even when other primary mechanisms appear to be involved, such as autoimmunity in rheumatoid arthritis and lupus, it is the unrelenting generation of free radicals that causes the damage we associate with these diseases. Which disease will develop depends on the site of the free-radical attack. For example, in rheumatoid arthritis free-radical injury occurs within the joints. You must also appreciate that, even though the primary attack is within the joints, free radicals spill out into the blood stream causing damage to other far-removed tissues, including the brain, muscles, nerves, heart, and kidneys. In lupus, injury is concentrated primarily in the connective tissues of the body. The reason the symptoms associated with lupus are so widespread and varied is that connective tissue exists throughout the body, and in all the organs. The brain and peripheral nerves are commonly affected in lupus for this same reason. This universal free-radical attack makes lupus an especially...

Natural and diseaseassociated lymphocytespecific antibodies

In the blood of normal individuals one finds lympho-cyte-specific antibodies which, under certain conditions, may be cytotoxic to all, or to subpopulations of, lymphocytes. These antibodies are part of the natural antibodies found in nonimmunized individuals. The significance of these antibodies is not clear, but their presence may induce acute rejection of a transplanted tissue. Autologous antibodies against lymphocytes seem to be induced by virus infections. They also occur in increased frequency in autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis), cancer, and in patients exposed to alloantigen, such as multiple transplanted uremic patients, multiparous dialysis patients, hemophiliacs and male homosexuals. A large percentage of patients with Behcet's syndrome have lymphocytotoxic antibodies, as do some of their healthy children. The presence of lymphocyte-

Detection identification and clinical significance of ANAs

The IFT is generally used as a screening assay for the presence of ANAs. The method is highly sensitive and detects almost all ANA specificities. Most laboratories now use cultured cells as substrate instead of tissue sections. Sera from patients with generalized autoimmune diseases mostly have several distinct ANAs at the same time. Since the titers of these antibodies differ, titration of the serum can reveal the strongest ANAs giving a certain pattern of nuclear fluorescence. Homogeneous patterns are frequently observed in patients with SLE or rheumatoid arthritis (RA), speckled or granular patterns in sera from patients with Sjogren's syndrome or scleroderma. Nucleolar fluorescence is often seen in patients with progressive systemic sclerosis (PSS). These associations, however, are of limited value to the clinician. Nearly all patients with SLE have ANAs, mostly in high titers. In RA, Sjogren's syndrome, PSS, MCTD, myasthenia gravis and chronic active hepatitis the frequency of...

Clinical examples of free radical antioxidant and immune function interactions

Rheumatoid arthritis (RA), an autoimmune disease of unknown cause, is characterized by a chronic inappropriate immune response in articular joints, resulting in inflammation and destruction of joint tissues. At some point, the initial insult and inflammation becomes a chronic process. Infiltration of the fluid-filled joint space (synovium) with inflammatory neutrophils occurs and structural changes appear in the synovium, forming an inflamed layer called a pannus. Oxidative products reduce the viscosity of the synovial fluid, thus hindering joint movement further. The cumulative effects of free radical damage throughout the lifespan are seen in the pigmented age spots of the elderly, which are a consequence of lipid oxidation. The overall increased oxidative stress associated with aging also adversely affects many aspects of immune responses. The consequences of suboptimal immune responses are particularly detrimental in the elderly who have an increased risk of infections as well as...

The Good the Bad and the Promising

Role of IFN in Autoimmune Diseases Constitutive production of IFN has been associated with the pathogenesis of some autoimmune diseases, whereas while in others, IFN treatment seems to be beneficiary. There is a preponderance of evidence for an association of IFN with the pathogenesis of systemic lupus erythematosus (SLE) and that of insulin-dependent diabetes mellitus (IDDM). In both diseases, serum levels of IFN are increased, but no initial inducer, be it endogenous or exogenous, has been identified so far. In addition, either disease may appear as an unintended consequence of IFN treatment for an unrelated condition (Devendra and Eisenbarth 2004). The use of IFNP in the treatment of multiple sclerosis (MS) is well established, although its mechanism of its action is mostly unknown. The beneficial effects of IFNP in preventing relapsing episodes may be due to a combination of anti-inflammatory, antiproliferative, and pro-apoptotic responses (Hafler 2004). Both experimental...

Suggested Reading

D. (1999). Molecular mimicry and autoimmunity. N. Engl. J. Med. 341, 2068-2074. Kuchroo, V. K., Das, M. P., Brown, J. A., Ranger, A. M., Zamvil, S. S., Sobel, R. A., Weiner, H. L., Nabavi, N., and Glimcher, L. H. (1995). B7-1 and B7-2 costimulatory molecules activate differentially the Th1 Th2 developmental pathways Application to autoimmune disease therapy. Cell 80, 707-718. Racadot, E., Rumbach, L., Bataillard, M., Galmiche, J., Henlin, J. L., Truttmann, M., Herve, P., andWijdenes, J. (1993). Treatment of multiple sclerosis with anti-CD4 monoclonal antibody. A preliminary report on B-F5 in 21 patients. J. Autoimmunity 6, 771-786. Weiner, H. L., Friedman, A., Miller, A., Khoury, S. J., al-Sabbagh, A., Santos, L., Sayegh, M., Nussenblatt, R. B., Trentham, D. E., and Hafler, D. A. (1994). Oral tolerance Immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu. Rev. Immunol. 12,...

Morbidity Associated With Klinefelters Syndrome

Data from large population-based studies of chromosome abnormalities at birth have demonstrated that the KS occurs in approx 1 in 400-600 male births (30-32). In adults, overall age-matched mortality is roughly doubled (33,34). Most of this increase is from non-neoplastic diseases of the cardiovascular, respiratory, and digestive systems, and diabetes however, the incidence of breast cancer and autoimmune disease is also increased (35). There may be an increased risk for autoimmune disease in individuals with KS. Systemic lupus erythematosis, rheumatoid arthritis, ankylosing spondylitis, and even rare vascular disorders, such as Takaysu's arteritis, have been reported in patients with KS, although the true relative increase in risk is difficult to calculate because of the small number of affected individuals (38-40). It has been speculated that this possible increased risk of autoimmune disease results from an increase in the estrogen to testosterone ratio, because it is believed that...

Jo HM Berden Karel JM Assmann

Renal involvement in systemic lupus erythematosus (SLE), dysproteinemias, and certain rheumatic diseases, namely rheumatoid arthritis, Sjogren's syndrome, and scleroderma (systemic sclerosis), is discussed. SLE is a systemic autoimmune disease that can lead to disease manifestations in almost every organ. SLE is characterized by the formation of a wide array of autoantibodies mainly directed against nuclear autoantigens, of which antibodies against double-stranded DNA (dsDNA) are the most prominent. Although the cause is still obscure, considerable progress has been made recently by identification of the nucleosome as the major driving autoantigen in SLE and the possible role of disturbances in apoptosis in disease development. The section on SLE reviews the major clinical and serologic features of the disease, the serologic analysis, new insights into the pathophysiology of lupus nephritis, and the histologic assessment of kidney biopsies. The therapeutic options for treatment of...

The Repertoire and Regulatory Perspective 41 Avoiding Immunoregulation

To reiterate a point made at the outset of this chapter, one route to escape from negative selection involves the avoidance of regulatory influences at any of several points. One of these is in the thymus, where the AIRE gene regulates the transcription of many autoantigens (see Subheading 3.6.). In the periphery, there are many sites at which regulation can fail and any one of these may abrogate control of otherwise forbidden clones. Three other examples will follow, one describing how failure to process a regulatory determinant leads to arthritis, another showing how the lack of control over determinant spreading can lead to an autoimmune disease state, and a third describing effects arising from the frequency of regulatory components. In a mouse strain such as the nonobese diabetic mouse, where there appear to be several general failures in overall regulation (for example, in the appropriate timing and extent of apoptosis 21,22 ),

Translational Studies

The explosion in the use of 'biologics' in therapy of many human diseases from cancer to aging disorders and autoimmune disease has had significant impact on the treatment of intraocular inflammation uveitis. Early studies with T cell-depleting drugs, e.g. anti-CD3 and anti-CD52 (Campath 1h), proved to be effective in several conditions, including ocular inflammation 66 , but particularly in the latter case, profound effects on marrow function have restricted its use.

Systemic Lupus Erythematosus

SLE, or lupus, is the classic example of an autoimmune disease in which the immune system attacks not a specific tissue or organ in the body, but rather a wide range of self tissues. Like most autoimmune diseases of this type, lupus is seen most frequently in females, almost always setting in during the peak reproductive years. Lupus is 10 times more common in women than men, and more common in people of color than in Caucasians. The erythematosus in SLE refers to a rash that often breaks out on the face, particularly around the nose. This so-called butterfly rash is one manifestation of the general sensitivity of lupus patients to ultraviolet light, including sunlight. Other symptoms include fever, weakness, pleurisy, anemia, and heart and kidney problems. Joint pain from arthritis is a common concomitant of lupus throughout all its stages. No one really knows what causes it, but it is often associated with recurrent Epstein-Barr virus infections and certain prescription medications....

Induction of Transplantation Tolerance With MAb

Induction of Tolerance With MAb in Autoimmunity 1. Animals the use of MAb to restore the state of dominant regulation has been tested in several animal models of autoimmune and immune-inflammatory disease. Some of the most common examples are listed in Table 2. Such animal models can be divided into three broad categories (1) animals developing the disease spontaneously, (2) animals where the disease is induced experimentally, and (3) TCR-transgenic animals where most or all the T cells are specific for a self-antigen. It should be noted that some animals, initially described as developing an autoimmune disease spontaneously, were later found to develop the disease following an environmental challenge. This is the case for SKG mice, carrying a mutation of the ZAP-70 gene, that develop chronic autoimmune arthritis with features closely resembling rheumatoid arthritis (RA) (48). In spite of initial reports suggesting that autoimmune arthritis was spontaneous, it was recently shown...

Nicole R Bianco Seon Hee Kim Adrian E Morelli and Paul D Robbins

Initial studies in our laboratory were focused on the use of dendritic cells (DC) genetically modified to express Th2-derived cytokines (i.e., interleukin IL -4 and IL-10) or apoptotic proteins (i.e., Fas Ligand FasL ) to reduce inflammation in a mouse model of experimentally induced arthritis. Exosomes are nano-sized vesicles (40-100 nm diameter) released by different cell types, including DC, that contain many of the proteins thought to be involved in regulating the immune response. We have demonstrated that exosomes derived from immature DC treated with immunomodulatory cytokines (i.e., IL-10, IL-4) are able to inhibit inflammation in a murine footpad model of delayed-type hypersensitivity (DTH) and reduce the severity of established collagen-induced arthritis (CIA). In fact, the exosomes were as therapeutic as the parental DC. Because purified DC-derived exosomes are very stable vesicles, they may be a better approach for future treatment of arthritis and other autoimmune...

Retinopathy Associated with Other Forms of Human Cancer

In the sera of patients with CAR, heat shock protein (HSP) 70 has been detected in addition to recoverin (Ohguro et al. 1999). The involvement of bacterial HSPs in the induction of autoimmunity has been recognised with the demonstration that HSP65 from the tubercle bacillus mycobacterium can induce autoimmune disease in certain animal tumour models. Certain peptides derived from mycobacterial HSP65 and their homologous peptide obtained from patients with Behcet's uveitis or iridocyclitis induce uveitis in Lewis rats. High antibody titres against these peptides are found in rats that developed uveitis as compared with those that had not (Uchio et al. 1998). This suggests that HSPs do function as autoantigens. Therefore, the detection of HSP70, together with recoverin, might suggest that both these antigens stimulate humoral autoimmunity in the pathogenesis of CAR. This view would be in line with the implication of HSPs in other autoimmune diseases such as rheumatoid arthritis (RA)...

Miscarriage and Endometriosis Is There a Connection

Women who don't have endometriosis but do have an autoimmune disease (like lupus or rheumatoid arthritis) also have an increased risk of miscarriage and failed implantation. So, given the possible association of the immune system and endometriosis, it's understandable that women with endometrio-sis are also more likely to have a miscarriage.

Guide To Further Reading

Albert L J, Inman R D1999 Molecular mimicry and autoimmunity. New England Journal of Medicine 341 2068-2074 Broe M E, Elseviers M M 1998 Analgesic nephropathy. England Journal of Medicine, 334 445-451 Fitzgerald G A, Patrono C 2001 The coxibs, selective inhibitors of cyclooxygenase-2. New England Journal of Medicine 345 433 42 Goodnow C C 2001 Pathways for self-tolerance and the treatment of autoimmune disease. Lancet 357 2115-2121

Nase I in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects over one million people in the United States alone 140 . SLE is characterized by the presence of antinuclear antibodies (ANA) directed against naked DNA and nucleosomes. The resulting immune complexes are deposited in the kidney, joints, and blood vessels, causing glomerulonephritis, arthritis, and vasculitis, respectively. The underlying cause of this disease is linked with deficiencies in serum amyloid P (SAP) component 141 , certain complement proteins 142,143 , and a decreased serum DNase I activity 144-146 . These proteins are all known to be involved in the clearance of apoptotic bodies in extracellular fluids like serum. The decreased activity of DNase I in SLE has originally been associated with increased concentrations of actin in serum of SLE patients 146 . Later on, however, a mutation of the gene encoding DNase I 147 and antiDNase I antibodies were found in certain SLE patients 148,149 . Considering...

Autoimmune Effects Of Ifna

Infections are cytokines with both antiviral and antiproliferative properties. IFN-a increases the expression of human lymphocyte antigen (HLA) class I and II, which results in a magnified activity of both helper and cytotoxic lymphocytes, and subsequent upregulation of the immune system. This, in turn, can lead to the induction of a new autoimmune disease, or to the exacerbation of an existing autoimmune disease. Shortly after IFN-a2b was Food and Drug Administration-approved for the therapy of hepatitis C, came reports that showed a worsening of amino-transferase levels in HCV patients during therapy, with an autoimmune

Breakdown of autotolerance

Induce tolerance against any given foreign antigen. With regard to autoimmunity the interest has focused primarily on T lymphocytes, because of the central regulatory role of T helper cells in the immune response against protein antigens, and in view of the well-known association of autoimmune diseases with major histocompatibility complex (MHC) alleles differing in effectivity of antigen presentation to T cells. According to the aforementioned concepts a breakdown in autotolerance can occur due to failures in thymic selection, and any factors that influence the survival of thymic lymphocytes could principally be expected to result in shifts in the peripheral T cell repertoire. As MHC molecules play an important role in the presentation of thymic autoantigens, changes in thymic selection may be one mechanism by which genes of the MHC influence autoimmune diseases. Nevertheless, it has to be stated that experimental data directly proving the occurrence of autoimmune reactions as a...

Hashimoto Thyroiditis

Chronic lymphocytic thyroiditis (Hashimoto) is an autoimmune disease closely related to Graves disease 49 . It was first described by Hashimoto 50 HT, a typical organ-specific autoimmune disease, is characterized histologically by lymphocytic infiltration of the thyroid. There is infiltration of lymphocytes and plasma cells between follicles and atrophy and fibrosis of the follicles are present. HT is seen more frequently with type 1 DM, celiac disease, Addison, autoimmune atrophic gastritis, chronic candidiasis and hypoparathyroidism, and juvenile chronic arthritis 59-61 . HT is also associated with certain chromosomal aberrations, in particular Turner, Down and Klinefelter syndromes 51, 53 . Progressive dementia and Hashimoto-related encephalopathy has been reported in some HT patients 62, 63 .

Eureka Theres Gold in MS Drugs

A key immune system protein, thus making the protein inactive. The protein MHCII normally holds pieces of invading bacteria and virus to the cell surface. When the cell recognizes that these invaders are present, it starts a normal immune response. In an autoimmune disease, this response goes awry and the body turns on itself causing diseases like type I diabetes, lupus, or rheumatoid arthritis.

Roles in disease and therapeutic applications

Several studies investigated the consequences of an aberrant expression of IFN7 in transgenic mice. Overexpression of murine IFN7 led to increased class I and II MHC expression, localized inflammation and tissue destruction. In a recent study aberrant expression of IFN7 in the neuromuscular junctions produced myasthenia gravis-like symptoms. In view of its stimulatory action on MHC expression and antigen presentation IFN7 has long been suspected to play a role as a mediator of autoimmunity. However, it appears that the role of IFN7 in autoimmune disease may vary depending on the stage of the disease process or site of action. McDev-itt and coworkers showed that in complete Freund's adjuvant (CFA)-induced arthritis in rats, administration of IFN7 24 h before CFA caused an enhancement of arthritis, whereas injection of IFN7 24-48 h after CFA suppressed the disease. In collagen-induced arthritis in mice, locally injected IFN7 promoted arthritis whereas systemically administered IFN7 was...

Common abnormalities

The skin may feature in a wide variety of specific skin disorders such as contact dermatitis (see Fig. 2.I9D, p. 42), Skin changes may also occur as the dermatological manifestation of systemic disease (Fig. 2.27B). Likewise v itiligo may be restricted to Ihe hands or face or widespread (Fig. 2,28). I(s presence may indicate underlying autoimmune disease.

Polyclonal Hypergammaglobulinemia Causes

Cause of the IgE increase is not known. Hyper-IgD syndrome has also been described. These patients may present with constitutional symptoms including fever and headaches, and they may have lymphaden-opathy. Still another group of patients may have hyper-IgG syndrome. This is a familial disorder. There is no underlying infectious or inflammatory condition, and there is no evidence of an autoimmune disease or lymphatic neoplasm. The class restriction has been linked to class-specific regulatory T cell clones. Autoimmune disorders commonly manifest polyclonal hypergammaglobulinemia. Among these, rheumatoid arthritis and Sj grens syndrome cause the most profound polyclonal increase in gamma globulin. In systemic lupus erythematosus, the increase in polyclonal immunoglobulin is usually modest but many different autoantibodies may be present, such as antinuclear antibody, rheumatoid factor, cardiolipin antibodies and antibodies against red blood cells, neutrophils and platelets. The...

Systemic Lupus Erythematosus Attacks Many Tissues

Myasthenia Gravis Antibodies

One of the best examples of a systemic autoimmune disease is systemic lupus erythematosus (SLE), which typically appears in women between 20 and 40 years of age the ratio of female to male patients is 10 1. SLE is characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction (Figure 20-6). Lupus is more frequent in African-American and Hispanic women than in Caucasians, although it is not known why this is so. Affected individuals may produce auto-antibodies to a vast array of tissue antigens, such as DNA, his-tones, RBCs, platelets, leukocytes, and clotting factors interaction of these auto-antibodies with their specific antigens produces various symptoms. Auto-antibody specific for RBCs and platelets, for example, can lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively. When immune complexes of auto-antibodies with various nuclear antigens are deposited along the walls of BLOCKING AUTO-ANTIBODIES...

An antigen that does not normally circulate in the blood may become exposed to the immune system

Antibodies may be produced that are directed against other antibodies. Such interactions may be necessary for the prevention of autoimmunity, but imbalances may actually cause autoimmune diseases. Rheumatoid arthritis, for example, is an autoimmune disease associated with the abnormal production of one group of antibodies (of the IgM type) that attack other antibodies (of the IgG type). This contributes to an inflammation reaction of the joints characteristic of the disease. Table 15.10 Some Examples of Autoimmune Diseases Myasthenia gravis 4. Antibodies produced against foreign antigens may cross-react with self-antigens. Autoimmune diseases of this sort can occur, for example, as a result of Streptococcus bacterial infections. Antibodies produced in response to antigens in this bacterium may cross-react with self-antigens in the heart and kidneys. The inflammation induced by such autoantibodies can produce heart damage (including the valve defects characteristic of rheumatic fever)...

IL10 Promoter Polymorphisms and Automimmune Disease

Genome wide scans have shown linkage of disease susceptibility to the region on chromosome 1 that encompasses the IL-10 locus. The IL-10 gene has been localized at 1q31-1q32 region, and several genome scans have identified regions ofchromosome 1 (1q21-23, 1q31-32, 1q42-44) which may contain susceptibility loci for SLE and other autoimmune diseases.45-51 Using case-control approaches to look at the distribution of promoter SNP or STRP alleles, several studies have found an association between IL-10 promoter polymorphisms and autoimmune disease susceptibility or disease manifestations (Tables 2 and 3).19,37,38,41,43,52-65,74 In each autoimmune disease examined, some studies have failed to find associations between promoter polymorphisms and susceptibility or manifestations.37,43,61,63-73 For example, Lazarus et al (1997) have found an association between -1082G, -1082G-containing haplotypes and the presence of anti-Ro autoantibodies and nephritis in Caucasian SLE.53 A study by Crawley...

Pathology caused by nitric oxide

Self-recognition and the induction of autoimmune aggression may cause the production of NO which causes damage to cells within the inflammatory focus. NO has been implicated in the tissue damage observed in several models of autoimmune disease, including autoimmune diabetes and rheumatoid arthritis. In addition, intestinal enteropathy associated with graft-versus-host disease, which involves

Immune Complex Diseases

Immune complex disease can also result from the formation of complexes between self-antigens and autoantibodies. This produces systemic autoimmune disease, where the inflammation and tissue damage is not limited to a particular location. Two examples of this are the autoimmune diseases rheumatoid arthritis and systemic lupus erythematosus (SLE).

Initial Laboratory Evaluation

For the patient with risk factors for HCV, who not infrequently has an elevated alanine aminotransferase (ALT), the screening HCV antibody test (enzyme-linked immunosorbent assay or enzyme immunoassay EIA ) is adequate in making the serologic diagnosis of hepatitis C. The second-generation EIA blood test, developed in 1992, is 97 sensitive, inexpensive, and generally used as the screening antibody test for making the diagnosis of HCV (8). A positive EIA does not distinguish acute, chronic, or resolved hepatitis C infection, and does not indicate viremia. False-negatives can occur in immunosuppressed patients, such as the patient with chronic renal failure, or the transplant patient. Much more frequently, the clinician is faced with a false-positive EIA, which typically occurs in an individual with no risk factors and normal serum ATs. A false-positive EIA may occur in individuals with autoimmune disease or hypergammaglobulinemia of any cause. Immunologic Autoimmune diseases, document...

KIR Effects in Autoimmune and Inflammatory Diseases

Historically, the most robust disease associations with the highly polymorphic HLA class I class II loci have been autoimmune in nature, and only very few infectious diseases have shown strong, consistent HLA associations (Cooke and Hill 2001 Gao et al. 2001). It would not be surprising if the strongest effects of KIR variation were also observed in autoimmune diseases. Some previously determined HLA associations with autoimmune diseases might actually be explained by synergistic interactions between KIR and alleles encoding their HLA class I ligands. An obvious hypothesis in this regard is that KIR genotypes expected to confer relatively strong activation to effector cells increase the risk of autoimmune disease. On the other hand, NK cell activation may be protective against some autoimmune disorders by suppressing or eliminating dendritic cells and monocytes (Shah et al. 1985 Gilbertson et al. 1986 Djeu and Blanchard 1988 Chambers et al. 1996 Geldhof et al. 1998 Carbone et al....

MHC and Disease Susceptibility

Some HLA alleles occur at a much higher frequency in those suffering from certain diseases than in the general population. The diseases associated with particular MHC alleles include autoimmune disorders, certain viral diseases, disorders of the complement system, some neurologic disorders, and several different allergies. The association between HLA alleles and a given disease may be quantified by determining the frequency of the HLA alleles expressed by individuals afflicted with the disease, then comparing these data with the frequency of the same alleles in the general population. Such a comparison allows calculation of relative risk (see Table 7-4). A relative risk value of 1 means that the HLA allele is expressed with the same frequency in the patient and general populations, indicating that the allele confers no increased risk for the disease. A relative risk value substantially Myasthenia gravis above 1 indicates an association between the HLA allele and the disease. As Table...

Clinical Features

An associated internal malignancy including carcinomas of internal organs, multiple myeloma, melanoma, and lymphomas is found in about 15-25 of patients (4-6). In most cases, the diagnosis of MR precedes that of the neoplasm. In approximately 15 of cases, MR is accompanied by an autoimmune disease such as Sjogren syndrome or systemic lupus erythematosus (7,8).

Pathogenesisinvolvement in disease

Autoimmune disease In addition to the 'autoimmune' mechanisms found in immunodeficiency and wasting disorders discussed earlier, murine leukemia viruses are thought to exacerbate the autoimmune disease of (NZB > NZW)F1 mice that resembles human systemic lupus erythematosus (SLE), as well as the necrotizing

Iron and Inflammation

It has been well documented that the anaemia of chronic disease, ACD, results in a lowering of various haematological parameters. Several mediators are involved, among them histamine, serotonin, bradykinin, prostaglandins and, as found more recently, cytokines and nitric oxide. ACD is a parameter of systemic autoimmune disorders. The severe inflammatory stimuli lead to several systemic changes, mediated by inflammation-associated cytokines, e.g. IL-6, IL-1 TNFa, TGF beta that regulate hepatic synthesis of the acute phase proteins. In rheumatoid arthritis iron accumulates in the joints, specifically the synovium, and this was reputed to exacerbate joint injury by the production of ROS. Later studies indicated that ischaemia reperfusion injury, associated with increased iron loading, might be more relevant to the joint damage. Circulating levels of TNFa and IL-1b serum levels are significantly increased in RA with ACD. RA patients treated with TNFa antibodies show disease improvement...

Allelic spectrum in lupus

Overall, ANAs are much more common than lupus. ANAs may represent a general tendency towards autoimmunity. Almost all lupus patients have ANAs, but ANA alone has a low positive predictive value for the diagnosis of lupus. On the basis of evidence from mouse and human studies, the ANA phenotype appears to have a large genetic footprint. Furthermore, many autoimmunity alleles are associated with more than one autoimmune disease (e.g. PTPN22 RA, SLE, T1D autoimmune thyroid disease Bottini et al 2004 FCRL3 RA, SLE, thyroiditis Kochi et al 2005 , Table 1), and therefore cannot easily account for either the relative specificity of the autoantibody spectrum, or the end-organ pathology that distinguishes lupus from other autoantibody-mediated diseases (e.g. myasthenia gravis, Goodpasture's syndrome). What remains to be determined is whether overall, the allelic spectrum of the general tendency towards autoimmunity, including the production of ANAs, is similar to that of specific end-organ...

Immediate Questions

Heart failure) may cause pseudoanemia. In the setting of increased plasma volume, anemia may be made more apparent. History or family history of anemia, splenomegaly, jaundice, thalassemia, sickle cell anemia, or G6PD deficiency Patients with hereditary disorders of RBCs usually present nonacutely. History of autoimmune disease or immunodeficiency May be associated with direct Coombs-positive hemolytic anemias or anemia of chronic disease.

Organs and Systems Cardiovascular

Although interferon gamma is mainly used for its immu-noregulatory properties, the possibility of clinical immune adverse consequences has been addressed in a limited number of prospective studies. In two studies involving patients with chronic hepatitis B treated for 4-6 months, most developed a new autoantibody (20,21), but none developed clinical evidence of autoimmune disease. However, other reports suggested that interferon gamma can either improve or aggravate immune or inflammatory conditions. Although no change in antinuclear antibodies

Implementation Of Protein Microarrays

Using this approach, pro-survival checkpoints were determined showing the transition for histologically normal to neoplastic prostate tissue associated with a change in phosphorylation status of signal subpopulations. Similarly, protein microarrays can be incubated with patient serum and used to detect autoantibody binding to specific proteins of autoimmune disease, such as systemic lupus erythe-matosus and rheumatoid arthritis 30 . This new area of research is limited by the availability of the capture proteins and antibodies.

Clinical Implications

What about cell-mediated immunity against pathogenic stress proteins Most bacterial and parasitic agents appear to induce such an immune response, but in some cases, rather than protecting the host, the response tends to exacerbate or contribute to the disease. For example, T-cell response to chlamydial GroEL has been associated with infection of the female reproductive tract as well as the respiratory system (50). Similarly, T cells that recognize GroEL from Borrel-ia burgdorferi, the etiological agent of Lyme disease, line the synovium of joints affected by the arthritic component of the disease (51). These types of observations have raised the question of whether these T cells were part of a general inflammatory response in these illnesses, or instead directly caused damage, perhaps by cross reacting with self-stress proteins. If the latter were true, it would imply that the well-conserved stress proteins contribute in some way to autoimmune diseases. The idea that stress proteins...

Australia See oceania

Autoantibody An antibody produced by b cells in response to an altered self antigen on one type of the body's own cells, that attacks and destroys these cells an antibody to self-antigens (autoantigens). Autoantibodies are the basis for autoimmune diseases. autoimmune disease An ailment caused by an immune response against an individual's own tissues or cells. Among many such diseases are rheumatoid arthritis, diabetes mellitus, multiple sclerosis, and lupus. autoimmune mechanism The response that produces autoimmunity, in which the body recognizes itself as foreign and forms antibodies against its own tissues. See antibody. autoimmunity Immunity to self-anti gens (autoantigens) the loss of normal tolerance by the immune system of self-antigens on the surface of the body's own cells. b cells are activated

Hsp 60 In Autoimmune Responses

According to the molecular mimicry theory (2,3), it is possible that antibodies and or T lymphocytes made in the immune response to a specific epitope found on a component of the pathogen may also bind to a structurally similar host determinant, thereby leading to autoimmune damage. This mimicry may be due to the presence of a common epitope in homologous proteins, such as the host and pathogen members of the hsp 60 family. Because of their high degree of homology across the broad stretches of phylogeny and their ubiquity, heat shock proteins represent a logical protein family in which to seek examples of molecular mimicry. As previously reviewed (4), it has been hypothesized that molecular mimicry between host and pathogen heat shock proteins constitutes an important physiological element of the protective immune response, which for unknown reasons may go awry in some individuals and may contribute to autoimmune disease. Another possibility, presented below, is molecular mimicry...

Cell Surface Expression of Stress Proteins

The issue of cell surface expression of hsp 90 on PBMCs from patients with SLE or other autoimmune diseases has been approached by Erkeller-Yuksel and colleagues (15). Using AC88, an IgGl monoclonal antibody raised against hsp 90 isolated from Achyla ambisexualis that recognizes human hsp 90, and flow cytometry, 2 of PBMCs from 62 patients with SLE exhibited immunofluo-rescent staining, a significantly higher value than the 0.4 staining seen with PBMCs from 42 control subjects. Anti-hsp 90 surface staining was particularly prominent in patients with active SLE, but it was not linked to expression of lymphocyte activation markers. Disease control patients with Sjogren's syndrome, systemic sclerosis, rheumatoid arthritis, and polymyositis dermato-myositis were only occasionally positive in this investigation. Excluding molecules with structural characteristics of integral membrane proteins (16,17), stress proteins (or peptides thereof) could be expressed on the cell surface by three...

Antibodies to Microbial Stress Proteins

Antibodies to microbial hsp 60 and or hsp 70 have been demonstrated in patients with various rheumatic and autoimmune diseases, including rheumatoid anti-stress protein autoantibodies, that, like rheumatoid factor, may be present in essentially all human sera. In any case, it is clear that patients with autoimmune disease do not develop high-affmity high-titer autoantibodies to stress proteins of the kind that are commonly seen to DNA and certain other nuclear antigens in SLE.