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PubMed1997

Thymic expression of autoantigens correlates with resistance to autoimmune disease.

Experimental autoimmune uveoretinitis (EAU), an animal model for human intraocular inflammation (uveitis), is induced by immunization with retinal proteins such as S-Ag or interphotoreceptor retinoid binding protein. Marked differences exist among different animal species and strains in their susceptibility to EAU induction, but the cause of these differences is not completely clear. Here we show for the first time a correlation between constitutive expression of ocular autoantigens in the thymus (mRNA and protein) and resistance to EAU. This correlation was noted both at the species (mice vs rats or monkeys) and the subspecies (differences among strains) level. The data thus provide a novel mechanistic explanation for the differences in susceptibility to autoimmune diseases, suggesting that resistance to an organ-specific autoimmune disease may be regulated at least in part by capacity to establish central tolerance to the relevant autoantigen.

Animals↗
PubMed2006

Drug exposure, pregnancy outcome and fetal and childhood development occurring in the offspring of mothers with systemic lupus erythematosus and other chronic autoimmune diseases.

Most autoimmune diseases occur more commonly in females and many of these young women wish to become mothers. For pregnancy to proceed successfully immunomodulation and physiological changes preparing the reproductive system need to occur. Pregnancy occurring in a chronically ill mother who requires medications in order to maintain her own health and who may have already incurred significant organ pathology gives rise to several problems and so four questions arise: 1) What will be the effect of the pregnancy on the underlying disease? 2) What will be the effect of the disease on the outcome of pregnancy? 3) How to manage the disease, just prior to, throughout and immediately after the pregnancy? 4) The long term fetal and childhood effects of maternal disease and its management. This paper reviews the current literature pertaining to these questions in patients with systemic lupus erythematosus (SLE) and other chronic rheumatic and autoimmune diseases.

Adrenal Cortex Hormones↗
PubMed2005

Shared gene expression profiles in individuals with autoimmune disease and unaffected first-degree relatives of individuals with autoimmune disease.

Patients with autoimmune disorders exhibit highly reproducible gene expression profiles in their peripheral blood mononuclear cells. These signatures may result from chronic inflammation, other disease manifestations, or may reflect family resemblance. To test the latter hypothesis, we determined gene expression profiles in unaffected first-degree relatives of individuals with autoimmune disease. Gene expression profiles in unaffected first-degree relatives resembled the profiles found in individuals with autoimmune diseases. A high percentage of differentially expressed genes in unaffected first-degree relatives were previously identified as autoimmune signature genes. Examination of the linear regression relationship of gene transcript levels between parent-offspring pairs revealed that autoimmune signature genes display high levels of family resemblance. Taken together, these results support the hypothesis that these variations in gene transcript levels are associated with family resemblance rather than clinical manifestations of disease.

Autoimmune Diseases↗
PubMed1996

Manipulation of the Th1/Th2 balance in autoimmune disease.

Many autoimmune diseases are caused by autopathogenic Th1 cells. Because in vitro Th1 and Th2 cells cross-regulate each other, it is likely that the induction of self-antigen-specific Th2 cells can prevent autoimmune disease. In the past year, investigators have further defined the role of Th1 and Th2 cytokines in the induction and regulation of autoimmunity. Furthermore, the role of MHC-antigen-T-cell avidity (strength of signal) in inducing such protective immune responses has been elucidated.

Animals↗
PubMed2000

Prospects of stem cell transplantation in autoimmune diseases.

Severe autoimmune diseases are not cured by current conventional treatments. Preclinical studies of treatments requiring stem cell transplantation have shown sustained remissions in some models of autoimmune diseases. Both autologous stem cell transplantation after high-dose immunoablative therapy and allogeneic stem cell transplantation have a profound effect on the recipient's immunological system. Pilot clinical studies of autologous stem cell transplantation are being conducted. Sustained remissions will require the induction of tolerance to autoantigens during recovery. In a group of patients highly selected to minimize transplant-related mortality, allogeneic stem cell transplantation should be tested to determine if elimination of the autoreactive immunological system will achieve sustained remissions. These are promising therapies which will require long-term follow-up of patients to evaluate efficacy.

Autoimmune Diseases↗
PubMed1985

Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease.

Organ-specific autoimmune diseases such as oophoritis, gastritis, thyroiditis, and orchitis were induced in female or male nude (nu/nu) mice by the transfer of nu/+spleen cells from which particular Lyt T cell subset(s) had been removed: nu/+spleen cells treated with anti-Lyt-1 plus complement (C) caused disease in recipient nude mice; anti-Lyt-2 plus C-treated spleen cells, in contrast, did not. The cells responsible for disease induction are believed to be Thy-1+, Lyt-1-, 2,3- (Thy-1, Lyt-1, 2,3), since spleen cells treated with mixed antisera, including anti-Lyt-1 and anti-Lyt-2, plus C, could induce the disease with almost the same incidence as anti-Lyt-1 plus C-treated cells (oophoritis 50%, gastritis 25%, thyroiditis 10-20%, and orchitis 40%). Cells treated with mixed antisera of anti-Thy-1, anti-Lyt-1, and anti-Lyt-2, plus C, could not induce autoimmune disease. Each induced autoimmune disease could be adoptively transferred to other nude mice via spleen cells, with resulting histological lesion of corresponding organs and development of specific circulating autoantibodies. Since anti-Thy-1 plus C treatment of donor spleen cells abrogated the capacity to transfer the disease, we conclude that T cells are required as effector cells, and that these may develop from Lyt-1-, 2,3- cells. Lyt-1+, 2,3- cells were demonstrated to have suppressive activity upon the development of the diseases; induction of autoimmunity was completely inhibited by the cotransfer of Lyt-1+, 2,3- cells with Lyt-1-, 2,3- cells. When anti-Lyt-2 plus C-treated cells (i.e., Lyt-1+, 2,3- and Lyt-1-, 2,3- cells) were mixed with anti-Lyt-1 and anti-Lyt-2 plus C-treated cells (i.e., Lyt-1-, 2,3- cells) in various ratios, then transferred to nude mice, the development of each autoimmune disease was clearly inhibited, even by small doses of Lyt-1+, 2,3- cells. The autoimmune disease we were able to induce was quite similar to human organ-specific autoimmune disease in terms of the spectrum of organs involved, histopathological features, and the development of autoantibodies to corresponding organ components (oocytes, parietal cells, thyroid colloid, including thyroglobulin, and sperm).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

The coexistence of systemic lupus erythematosus with other autoimmune diseases: the kaleidoscope of autoimmunity.

Patients with systemic lupus erythematosis (SLE) often manifest features of other autoimmune diseases. In this review, we provide a detailed compendium of features of SLE that overlap with other conditions. This compendium is important because a critical feature in our understanding of autoimmunity has been the clustering of coexisting/different autoimmune diseases both within an affected patient and within a pedigree. Indeed, autoimmune disorders share a variety of similar clinical and serological defects. For example, all autoimmune disorders are associated with the elaboration of autoantibodies and/or the production of self-reactive mononuclear cell populations; many have high levels of immune complexes and defects in cell-mediated immunity. Several diseases share similar genetic backgrounds, as reflected by study of loci within the major histocompatibility complex. In part the coassociation is due to common genetic tendencies with different environmental precipitating agents (trigger mechanisms). It is likely that many factors can modulate the immune system to autoimmunity in the presence of an appropriate genetic background, eg, drugs, viral infections, UV irradiation, and toxins, ie, toxic oil syndrome and L-tryptophan-induced eosinophilic myalgia. The coexistence of SLE with other autoimmune diseases is an excellent venue to understand these events, and we believe that the presence of other autoimmune diseases in patients with SLE can be called the kaleidoscope of autoimmunity.

Autoimmune Diseases↗
PubMed1996

Virus-induced autoimmune disease: transgenic approach to mimic insulin-dependent diabetes mellitus and other autoimmune diseases.

The technology of cloning viral genes and expressing them in vivo under cell-specific promoters allows to dissect the role of viruses, host self proteins, host genetics and immune responses in the complex etiology of autoimmune disease. Expression of a viral transgene, that is really a marker for a host "self" protein per se in beta cells of the islets of Langerhans, need not cause disease. In our model, expression of a viral gene was not associated with disease over the lifetime of the animal. However, when the host becomes infected with a virus encoding the same gene as the transgene or one closely related to it, a resultant immune response directed against the virus also recognizes the transgene leading to progressive T-cell-mediated response and destruction of the tissue expressing the viral ("self") gene, leading to autoimmune disease. This multifactorial process is influenced by whether the viral transgene is expressed in the thymus as well as in the disease-related cell or target tissue. Thymic expression influences negative selection of responder lymphocytes and thus delays the onset of the autoimmune disorder. Further, the MHC haplotype or other background genes of an individual undergoing autoimmune dysfunction play a role in the affinity of binding of the transgene products to the MHC molecule and influence the degree of negative selection that occurs, thereby influencing the vigor of the resulting immune response. The current ability to express host or viral genes in unique cell populations, and to make double- or triple-tg mice in which various cytokine genes or lymphocyte activation genes can be expressed along with the viral gene, offers a unique possibility for molecular dissection of autoimmunity. With the information on hand, approaches to the prevention and treatment of human autoimmune disease are likely to be uncovered. Finally, animal models are available in which the onset, progression and control of molecular mimicry can be evaluated. Future studies should define roles played by cytokines, bystander and immune-specific cross-reactivity to viruses and other microbes in several autoimmune diseases.

Animals↗
PubMed1996

Short term treatment with soluble neuroantigen and anti-CD11a (LFA-1) protects rats against autoimmune encephalomyelitis: treatment abrogates autoimmune disease but not autoimmunity.

Resistance to autoimmune encephalomyelitis was induced by s.c. infusion of myelin basic protein (MBP) in saline in combination with i.p. injections of anti-CD11a (LFA-1) mAbs. This treatment induces resistance to EAE induction, which appears early and persists for at least one month after treatment. Some MBP-CFA-challenged resistant rats showed minimal inflammation in the central nervous system, which was, however, confined to the meninges of the lower spinal cord. Examination of the immune status of MBP-anti-LFA-1 treated rats before encephalitogenic challenge failed to reveal any priming when assessed by Ag driven proliferation and cytokine production by lymphoid cells, and by circulating Ab production. Following challenge of protected rats, lymph node cell proliferation to MBP was unaltered, indicating that reactive cells had not been deleted or energized. Resistance could not be transferred with lymphoid cells from treated rats nor abrogated by cyclophosphamide treatment. In treated rats following challenge, there was a shift in the isotype of anti-MBP Ab produced, from an IgG2a:IgG1 ratio of 2:1 to 1:1, due to an increase in IgG1 production, indicating a possible bias towards a nonpathogenic Th2 CD4+ T cell response. The IgG1 Ab was detected early after challenge suggesting that pretreatment had indeed primed the animals, and had primed them to go down the Th2 pathway following encephalitogenic challenge. The ability to divert immune reactivity from a destructive to a nondestructive response could have important therapeutic implications for autoimmune disease.

Adoptive Transfer↗
PubMed1989

Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease.

Cyclosporin A (CsA), a potent immunosuppressive drug, caused organ-specific autoimmune disease, such as gastritis with anti-parietal cell autoantibodies or oophoritis with anti-oocyte autoantibodies, in BALB/c mice when the drug was administered daily for 1 wk to newborns. Administration to adult mice did not. CsA abrogated the production of L3T4+ T cells and Lyt-2+ T cells in the thymus. Consequently, these T cells were substantially depleted from the peripheral lymphoid organs, especially when the drug was administered from the day of birth. Autoimmune disease was prevented when CsA-treated newborn mice were inoculated with splenic T cells from normal syngeneic mice. However, removal of the thymus immediately after neonatal CsA treatment produced autoimmune disease with a higher incidence and in a wider spectrum of organs, i.e., thyroiditis, sialoadenitis of the salivary gland, gastritis, insulitis of the endocrine pancreas, adrenalitis, oophoritis, or orchitis. Each autoimmune disease was accompanied by the development of circulating autoantibodies specific for the corresponding organ Ag. Immunopathology of these autoimmune diseases was quite similar to that of human organ-specific autoimmune diseases.

Animals↗
PubMed1993

Autoimmune diseases in humans, e.g. autoimmune rheumatic diseases.

In spite of increasing evidence that viruses and especially retroviruses could act as etiologic factors in autoimmune and especially autoimmune rheumatic diseases, clear-cut evidence for an involvement of these agents is still missing. Findings, which, for example, indirectly support the hypothesis that retroviruses might play a part, are the demonstration of antibodies to the gp24 in SLE and Sjögren's patients as well as the description of retroviral antigens in the inflamed synovium of rheumatoid arthritis patients. Furthermore, evidence comes from animal models that viruses, such as the Visna or Caprine arthritis encephalitis virus, induced chronic inflammatory diseases in sheep and goats. More recently, a mouse model for rheumatoid arthritis and Sjögren's syndrome was reported in mice transgenic for HTLV-1tax. It is hoped that, especially from the experimental animal models, the possible role of retroviruses as etiological factors in autoimmune rheumatic diseases can be clarified.

Animals↗
PubMed2006

Autoantibodies against the replication protein A complex in systemic lupus erythematosus and other autoimmune diseases.

Replication protein A (RPA), a heterotrimer with subunits of molecular masses 70, 32, and 14 kDa, is a single-stranded-DNA-binding factor involved in DNA replication, repair, and recombination. There have been only three reported cases of anti-RPA in systemic lupus erythematosus (SLE) and Sjögren syndrome (SjS). This study sought to clarify the clinical significance of autoantibodies against RPA. Sera from 1,119 patients enrolled during the period 2000 to 2005 were screened by immunoprecipitation (IP) of 35S-labeled K562 cell extract. Antigen-capture ELISA with anti-RPA32 mAb, immunofluorescent antinuclear antibodies (ANA) and western blot analysis with purified RPA were also performed. Our results show that nine sera immunoprecipitated the RPA70-RPA32-RPA14 complex and all were strongly positive by ELISA (titers 1:62,500 to 1:312,500). No additional sera were positive by ELISA and subsequently confirmed by IP or western blotting. All sera showed fine speckled/homogeneous nuclear staining. Anti-RPA was found in 1.4% (4/276) of SLE and 2.5% (1/40) of SjS sera, but not in rheumatoid arthritis (0/35), systemic sclerosis (0/47), or polymyositis/dermatomyositis (0/43). Eight of nine patients were female and there was no racial predilection. Other positive patients had interstitial lung disease, autoimmune thyroiditis/hepatitis C virus/pernicious anemia, or an unknown diagnosis. Autoantibody specificities found in up to 40% of SLE and other diseases, such as anti-nRNP, anti-Sm, anti-Ro, and anti-La, were unusual in anti-RPA-positive sera. Only one of nine had anti-Ro, and zero of nine had anti-nRNP, anti-Sm, anti-La, or anti-ribosomal P antibodies. In summary, high titers of anti-RPA antibodies were found in nine patients (1.4% of SLE and other diseases). Other autoantibodies found in SLE were rare in this subset, suggesting that patients with anti-RPA may form a unique clinical and immunological subset.

Antibodies, Antinuclear↗
PubMed1998

Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases.

Human autoimmune diseases are thought to develop through a complex combination of genetic and environmental factors. Genome-wide linkage searches of autoimmune and inflammatory/immune disorders have identified a large number of non-major histocompatibility complex loci that collectively contribute to disease susceptibility. A comparison was made of the linkage results from 23 published autoimmune or immune-mediated disease genome-wide scans. Human diseases included multiple sclerosis, Crohn's disease, familial psoriasis, asthma, and type-I diabetes (IDDM). Experimental animal disease studies included murine experimental autoimmune encephalomyelitis, rat inflammatory arthritis, rat and murine IDDM, histamine sensitization, immunity to exogenous antigens, and murine lupus (systemic lupus erythematosus; SLE). A majority (approximately 65%) of the human positive linkages map nonrandomly into 18 distinct clusters. Overlapping of susceptibility loci occurs between different human immune diseases and by comparing conserved regions with experimental autoimmune/immune disease models. This nonrandom clustering supports a hypothesis that, in some cases, clinically distinct autoimmune diseases may be controlled by a common set of susceptibility genes.

Animals↗