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PubMed1994

A study of mast cells in autoimmune mice: the proliferative response of autoimmune mast cells to cytokines.

To investigate the mechanisms underlying the increased number of mast cells in autoimmune mice, the proliferative response of autoimmune mast cells to cytokines was examined. Bone marrow cells from autoimmune NZB mice produced scarcely any bone marrow derived mast cells (BMMCs) in the presence of interleukin 3 (IL-3), but were able to generate BMMCs when cultured with pokeweed mitogen-stimulated spleen cell conditioned medium (PWM-SCM). In contrast, NZB BMMCs showed very little proliferation in the presence of PWM-SCM, but proliferated strongly when cultured with stem cell factor (SCF). Non-autoimmune NZW BMMCs showed a strong proliferative response to both IL-3 and PWM-SCM, but proliferated weakly in culture with SCF. Autoimmune NZB x NZW F1 (B/W) BMMCs shared the proliferative activities of both NZB and NZW BMMCs, showing strong proliferation in response to IL-3, PWM-SCM and SCF. All strains (including other non-autoimmune strains) except for NZW demonstrated synergism between PWM-SCM and SCF. This study suggests that the strong proliferative response of autoimmune mast cells to SCF plays a major role in, and that other cytokines are partially responsible for, increasing the number of mast cells in autoimmune mice. These mechanisms are discussed in relation to both constitutive and inducible hematopoiesis.

Animals↗

PubMed2002

Coexistence of four autoimmune diseases in one patient: the kaleidoscope of autoimmunity.

Genetic, immune, hormonal, and environmental factors are associated with the multifactorial origin of autoimmunity. When one or more of these factors are altered, a "switch" from one autoimmune condition to another can occur, developing the so called "kaleidoscope phenomenon" of autoimmunity. We present the case of a 30-year-old woman with myasthenia gravis and hypothyroidism probably resulting from autoimmune thyroiditis. A thymectomy was performed, and 1 year later, rheumatoid arthritis was diagnosed based on clinical, radiological, and serological features. Nine years after thymectomy, systemic lupus erythematosus was diagnosed based on skin, renal, hematologic, and immunologic manifestations. We suggest that the immune system function was modified when thymectomy was performed, playing an important role in the development of the new autoimmune conditions. Thymectomy increases the risk of developing a new autoimmune disease because it modifies, by mechanisms not well defined, the equilibrium and normal function of the immune system. This patient presents the infrequent association of four autoimmune conditions. When a patient has one autoimmune disease, she is at risk for another.

Journal Article↗

PubMed1995

Autoimmunity to steroid-producing cells and familial polyendocrine autoimmunity.

New insights into the autoimmune basis for Addison's disease have come from identification of at least three P450 cytochrome enzymes as autoantigens, each having distinct associations with Addison's disease as part of the APS type 1 or 2 syndrome. Enzymes are tissue-restricted proteins which are the frequent targets of autoimmunity in other organ-specific diseases (Editorial, 1992), and it seems likely that further P450 enzymes could be involved in the pathogenesis of other components of these syndromes. How adrenal damage is initiated remains unclear. Adrenal autoantibodies may have a pathogenic role, as yet obscure, or could arise secondary to T cell-mediated tissue damage, although it seems highly likely that the same autoantigen provokes cell-mediated and humoral autoimmunity. Sharing of autoantigens between ovary and adrenal glands, particularly the side-chain cleavage enzyme, is one explanation for the close association of ovarian failure and Addison's disease, but other, more common forms of ovarian autoimmune disease exist. Their further definition will come from identification of the autoantigens involved. By analogy with animal models, T cell-mediated injury is likely to be central to pathogenesis. The evidence for antibodies blocking hormone receptors in premature ovarian failure is meagre at present, but the availability of recombinant LH and FSH receptors should clarify this issue. HLA-DR3 is associated with almost all autoimmune endocrinopathies, and this is particularly striking in APS type 2. However, there is no such association with APS type 1; the most likely genetic candidate in this condition is at a locus controlling T cell development. Although the adrenal and ovarian autoimmune processes in APS type 1 and 2 may be distinct, the characterization of the gene involved in APS type 1 will have major implications for our understanding of autoimmune endocrine disease.

Addison Disease↗

PubMed2001

Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Graves' disease.

Autoantibodies directed against human CD38 (an enzyme catalysing the interconversion of NAD(+) and cyclic ADP-ribose) have been demonstrated recently in patients with type 2 diabetes. We tested 220 consecutive Caucasian patients with autoimmune chronic thyroiditis, 104 patients with Graves' disease, 220 subjects from the general population (control I) and 78 healthy control subjects not affected by thyroid autoimmune disorders (control II) for the presence of anti-CD38 autoimmunity. Using Western blot analysis and optical densitometry, a specific band corresponding to human recombinant CD38 was identified in the serum of several subjects. By defining anti-CD38 positivity as a standardized optical reading > 3 s.d. higher than the mean value of control I, 10.4% of patients with thyroiditis and 7.7% of Graves' patients were anti-CD38 positive (P = 0.0009 versus 1.8% of control I). Similarly, 13.1% of patients with thyroiditis and 10.5% of Graves' patients had a standardized optical reading > 3 s.d. higher than the mean value of the subjects not affected by thyroid autoimmune disorders (P = 0.002 versus 1.2% of control II). Anti-CD38 autoimmunity did not differ between euthyroid, hyperthyroid or hypothyroid patients or between patients with or without thyroid hypoechogenicity. Anti-CD38 autoantibodies were associated with higher levels of circulating antithyroid-peroxidase antibodies (P = 0.03) and they were more frequent in Graves' patients with ophthalmopathy (P < 0.05). Anti-CD38 autoantibodies are a new autoimmune marker in chronic autoimmune thyroiditis and Graves' disease. The specific role of CD38 and its autoantibodies in the modulation of thyroid cell function or growth remains to be investigated.

ADP-ribosyl Cyclase↗

PubMed2006

Impaired caspase-3 expression by peripheral T cells in chronic autoimmune thyroiditis and in autoimmune polyendocrine syndrome-2.

CONTEXT: Activation-induced cell death (AICD) is a major mechanism in the regulation of peripheral tolerance, and caspase-3 represents its major executioner. AICD impairment contributes to the persistence of autoreactive T cells, and defective AICD has been reported in autoimmune thyroiditis as well as in type 1 diabetes mellitus. OBJECTIVE: The objective of this study was to evaluate the involvement of caspase-3 in the regulation of AICD resistance in thyroid and polyendocrine autoimmunity. DESIGN/SETTINGS/PATIENTS/INTERVENTION: Caspase-3 expression was analyzed in peripheral blood lymphocytes from 26 adults (A-AT) and 25 children (Y-AT) affected by autoimmune thyroiditis and 13 individuals affected by chronic autoimmune thyroiditis plus Addison's disease [autoimmune polyendocrine syndrome-2 (APS-2)] in comparison with 32 age-matched normal control subjects (NC). OUTCOME MEASURES: Caspase-3 mRNA expression in peripheral T cells was evaluated by quantitative real-time PCR; protein expression of both procaspase-3 and activated caspase-3 by Western blot analysis was followed by scanning densitometry. RESULTS: Caspase-3 mRNA expression was significantly reduced in resting lymphocytes from both A-AT (P = 0.001) and Y-AT (P = 0.016) compared with NC. After lymphocyte activation, protein levels of caspase-3 active form were significantly reduced in A-AT (P = 0.023) and Y-AT (P = 0.001) compared with NC. The APS-2 group displayed characteristics similar to the A-AT group because both caspase-3 mRNA and protein active form levels were significantly reduced compared with NC (P = 0.004 and 0.002, respectively). CONCLUSION: Our data show that peripheral lymphocytes of subjects affected by thyroid autoimmunity or APS-2 show defective expression of the major executioner of AICD, thus potentially contributing to AICD resistance and to the development of autoimmunity.

Adolescent↗

PubMed1996

Although DR3-DQB10201 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB10302 haplotype is implicated only in beta-cell autoimmunity.

Human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles were analyzed using a PCR-based sequence-specific priming technique in 16 patients with autoimmune polyglandular syndrome type I (APS-I), 31 patients with APS-II, and 110 patients with component diseases of APS-II, including 9 patients with isolated Addison's disease, 43 patients with Hashimoto's thyroiditis, 22 patients with Graves' disease, and 36 patients with vitiligo. No significant associations was observed between HLA and APS-I patients in our data set, nor was sharing of HLA haplotypes by sibling pairs affected by APS I significantly different from the random expectation. Thus, HLA-DRB1 and -DQB1 genes are probably not involved in APS-I. To delineate the associations between HLA-DRB1, DQB1, and APS-II, we analyzed APS-II patients with or without beta-cell autoimmunity [i.e. insulin-dependent diabetes (IDD) and/or islet cell or glutamic acid decarboxylase autoantibodies]. Our results suggest that the association between DR4-DQB1*0302 and APS-II was entirely due to the presence of pancreatic beta-cell autoimmunity, since this haplotype was otherwise not significantly associated with APS-II or with any other of its component diseases. In contrast, the DR3-DQB1*0201 haplotype was associated not only with IDD, but also with APS-II in the absence of pancreatic beta-cell autoimmunity, as were several its component diseases, including isolated Addison's disease, Graves' disease, and Hashimoto's thyroiditis. Interestingly, the frequency of DQB1*0602, a dominantly protective allele against IDD, was not significantly decreased in the APS-II patients with IDD or beta-cell autoimmunity, albeit the patient numbers were small. This phenomenon may suggest that the development of autoimmunity to nonpancreatic endocrine glands may predispose autoimmunity to the pancreatic beta-cells and involve genes other than those of the MHC.

Adolescent↗

PubMed2000

A heterozygous deletion of the autoimmune regulator (AIRE1) gene, autoimmune thyroid disease, and type 1 diabetes: no evidence for association.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autoimmune disease with endocrine components including type 1 diabetes, adrenal failure, and thyroid dysfunction, with major autoantibodies directed against adrenal, pancreas, and thyroid tissue. A 13-bp deletion in exon 8 of the autoimmune regulator (AIRE1) gene on chromosome 21q22.3 accounts for more than 70% of mutant alleles in United Kingdom subjects with APECED. To determine whether this polymorphism contributes to disease susceptibility in subjects with autoimmune disease in general, we screened 302 patients with Graves' disease, 154 patients with autoimmune hypothyroidism, 235 patients with type 1 diabetes, and 318 control subjects for the 13-bp deletion of the AIRE1 gene. The mutation was present in only 1 (0.33%) patient with Graves' disease, 1 patient with autoimmune hypothyroidism (0.6%), and 1 (0.315) of the control subjects. No patients with type 1 diabetes were found to carry the mutation. We conclude, therefore, that the 13-bp deletion of the AIRE1 gene is not a susceptibility locus for the more common autoimmune endocrinopathies in the United Kingdom.

Chromosomes, Human, Pair 21↗

PubMed2003

A case of autoimmune hepatitis and autoimmune hemolytic anemia following hepatitis A infection.

UNLABELLED: Hepatitis A infection is known to induce autoimmune hepatitis and autoimmune hemolytic anemia. Here we present a case with autoimmune hepatitis type I and autoimmune hemolytic anemia following hepatitis A virus (HAV) infection. CASE: M.A., a male patient, was brought to the hospital with complaints of jaundice and malaise. Physical examination revealed paleness and icterus. The liver was palpable 5 cm below the costal margin in the midclavicular line; the spleen was palpable 2 cm from the costal margin. Laboratory examination revealed severe anemia, reticulocytosis and direct Coombs' IgG positivity. Liver enzymes, total and conjugated bilirubin and alkaline phosphates levels, total protein and immunglobulin levels were high and prothrombin time elongated. Hepatitis A IgM antibody was found positive, while other hepatitis serologic markers were negative. Anti-smooth muscle antibody (ASMA) was positive in 1/80 titer. With these laboratory findings, the case was diagnosed as autoimmune hepatitis and autoimmune hemolytic anemia induced by hepatitis A infection. Liver histology also supported the diagnosis. Steroid therapy resulted in clinical and laboratory remission. In conclusion, it is important to vaccinate children against hepatitis A infection to protect them from its complications and also from autoimmune diseases induced by this infection.

Anemia, Hemolytic, Autoimmune↗

PubMed2005

Diagnosing autoimmune hepatitis in nonalcoholic fatty liver disease: is the International Autoimmune Hepatitis Group scoring system useful?

BACKGROUND: There are no surrogate serum markers for autoimmune hepatitis (AIH) and nonalcoholic fatty liver disease (NAFLD). An AIH scoring system was reported by the International Autoimmune Hepatitis Group; however, the criteria did not focus on making the distinction between AIH and NAFLD. We examined the effectiveness of using the AIH score for diagnosing AIH in NAFLD patients. We also identified the prevalence of autoimmune phenomena, in terms of various auto-antibodies, including antinuclear antibodies (ANA), to determine whether these markers had any clinicopathological significance, and whether they were related to the patients' clinical courses. METHODS: We studied 212 patients (103 males and 109 females) with biopsy-proven NAFLD. The AIH score of each patient was calculated without including the liver biopsy results. The patients were divided into three groups based on their clinicopathological features: the overlap group (those with clinical and histological features of both NAFLD and AIH), the systemic group (those with systemic autoimmune disease other than AIH), and the "other" group (patients with no autoimmune disease). To evaluate the clinicopathological significance of ANA in NAFLD patients, those without autoimmune diseases (the "others" group) were classified according to their ANA positivity and ANA titer. RESULTS: Seventy patients (33.0%) were positive for ANA. Among the female patients, 106 patients (97.2%) had an AIH score of 10 or more. Of the 103 male patients, 21 (20.4%) had an AIH score of 10 or more. However, after liver biopsy, only 1 patient (0.5%) could be classified as "definite AIH." In the NAFLD patients without autoimmune diseases ("other" group), multivariate logistic regression analysis found that female sex was an independent predictor of the presence of ANA (P = 0.029). In contrast, multivariate logistic regression analysis found that severe obesity (body mass index [BMI], >or=30 kg/m2) was the only independent predictor of the presence of an ANA titer of 1 : 80 or more (P = 0.026). CONCLUSIONS: The AIH score without liver biopsy findings was not useful for diagnosing AIH in NAFLD patients. In patients with elevated ANA titers and risk factors for NAFLD, it is very important to perform a liver biopsy to make a definitive diagnosis before treatment.

Antibodies, Antinuclear↗

PubMed1994

Autoimmune cholangiopathy: the result of consecutive primary biliary cirrhosis and autoimmune hepatitis?

Autoimmune cholangiopathy is a recently proposed entity that describes a specific group of patients presenting overlapping features of primary biliary cirrhosis and autoimmune hepatitis, i.e., clinical and/or biochemical cholestasis, high titer antinuclear antibody, negative antimitochondrial antibody, and elevated immunoglobulin G. Liver histology shows primary biliary cirrhosis coexisting with varying degrees of parenchymal inflammation. In addition, these patients achieve remission on corticosteroid therapy. The patient in this report fulfilled the above criteria. However, preceding the autoimmune cholangitis stage, a typical antimitochondrial antibody-positive primary biliary cirrhosis was documented with favorable response to ursodeoxycholic acid treatment. Twenty months later, the patient developed autoimmune hepatitis with elevated aspartate aminotransferase and immunoglobulin G and high titer antinuclear antibody as well as corticosteroid dependency, whereas the antimitochondrial antibody disappeared. The patient's sera initially showed reactivity to three mitochondrial proteins, the 74-, 64-, and 56-kilodalton autoantigens of the 2-oxo acid dehydrogenase complexes, which was characteristic of primary biliary cirrhosis. After developing autoimmune hepatitis, reactivity to the 74- and 64-kilodalton antigens disappeared, whereas reactivity to the 56-kilodalton antigen decreased to low levels. Autoimmune cholangitis and probably other forms of the overlap syndrome may result from the association of two diseases: primary biliary cirrhosis and autoimmune hepatitis.

Antibodies, Antinuclear↗

PubMed2003

Prospective study of enteroviral infections and development of beta-cell autoimmunity. Diabetes autoimmunity study in the young (DAISY).

OBJECTIVE: To determine whether there is association between infection with enteroviruses and beta-cell autoimmunity in children at elevated risk of developing type 1 diabetes. BACKGROUND: Recent prospective and case-control studies of children who are at high risk of developing type 1 diabetes have suggested that enterovirus (EV) infections are a risk factor for beta-cell autoimmunity and type 1 diabetes. METHODS: A nested matched case-control study of incident cases of beta-cell autoimmunity within two prospective cohorts of genetically high-risk children (cases=26, controls=39). EV infection was detected by PCR of serum, saliva and rectal swab samples. RESULTS: Prior to autoimmunity conversion (or the equivalent age in controls), 11.5% of cases and 17.9% of controls were positive for EV infection. EV was detected in 19.5% of cases and 25.6% of controls over the whole follow-up period. Conditional logistic regression gave no evidence that the frequency of EV infection was associated with beta-cell autoimmunity. There was a trend for the mean number of EV infections found in EV-positive cases (2.2/case) to be higher than in EV-positive controls (1.2/control, P=0.08). However, there were no multiple infections prior to conversion in either cases or controls. CONCLUSIONS: There is no evidence from this study that EV infection is a risk factor for development of beta-cell autoimmunity. Further study is needed to assess whether persistent or repeated EV infections occur frequently in individuals with beta-cell autoimmunity.

Autoantibodies↗

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↗

PubMed1986

Cyclosporine-induced autoimmunity. Conditions for expressing disease, requirement for intact thymus, and potency estimates of autoimmune lymphocytes in drug-treated rats.

These studies explore the phenomenon of cyclosporine-induced autoimmunity in irradiated Lewis rats. We show that (a) the presence of a thymus is required, and autoimmune precursors develop in and exit from this organ to the peripheral lymphocyte pool within a 2-wk period after the initiation of cyclosporine treatment; (b) adoptive transfers of drug-induced autoimmunity to irradiated secondary recipients can be accomplished with relatively few cells of the Th subset, and these transfers of autoimmunity can be blocked by cotransfer of normal lymphoid cells; and (c) potency estimates, using popliteal lymph node assays in syngeneic and F1 recipients indicate similar levels of auto- and alloreactivity by cells from drug-induced autoimmune donors. These various findings indicate that this particular animal model may be useful for studies of the onset and control of autoimmunity, and they raise the possibility that the lack of autoimmunity in normal animals and its induction with cyclosporine may involve similar cellular mechanism as have been found to be operative in GVH reactions and specifically induced immunologic resistance to GVHD.

Animals↗

PubMed1990

Lack of high avidity IgM anti-ssDNA antibodies in cells from autoimmune-prone and autoimmune mice.

Non-autoimmune prone CBA mice were compared with autoimmune prone NZB, NZW, and (NZB x NZW)F1 mice for the ability of their splenic cells to produce anti-ssDNA-forming cells spontaneously in vitro, measured in the plaque forming cell assay. The number of antibody forming cells was measured and the relative avidity of antibody produced determined using a plaque inhibition assay. Splenic lymphocytes from young animals of a non-autoimmune strain (CBA/J) were shown to be capable of generating anti-ssDNA IgM antibody-forming cells in culture which displayed a higher avidity for antigen than that from autoimmune-prone or frankly autoimmune mice. Since an increased switching from IgM to IgG autoantibody production and defects in Fc-mediated signalling by IgG antibody have been identified in autoimmunity, we suggest that the metabolic block, normally in force in non-autoimmune-prone animals, accounts for this elevated avidity of IgM autoantibody.

Aging↗

PubMed1984

Atypical lymphoplasmacytic and immunoblastic proliferation in lymph nodes of patients with autoimmune disease (autoimmune-disease-associated lymphadenopathy).

This study is based on an analysis of the morphologic, clinical, and laboratory findings in 26 patients whose pretherapy lymph node biopsies showed some, but not all, of the diagnostic features of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Partial or complete effacement of nodal architecture by a diffuse lymphoplasmacytic and immunoblastic proliferation was a constant histologic finding. In contrast to the findings in AILD, lymphocytic depletion and pronounced arborizing vascular proliferation were often lacking. Clinically, many of the patients had fever, sweats, weight loss, skin rashes, generalized lymphadenopathy, hepatosplenomegaly, and, in some cases, pulmonary infiltrates. Of the 26 patients, 23 had clinical and/or laboratory evidence of autoimmune disease or immune complex disease. In 12 patients (Group I--idiopathic), various autoantibodies or immune complexes were demonstrable, but these patients did not manifest a well-defined immunologic disease or syndrome. In 11 patients (Group II--secondary), the lymphadenopathy occurred secondary to a well-defined, clinically recognized immunologic disease. Three patients (Group III) had neither a well-defined autoimmune disease nor demonstrable autoantibodies, but two of them had a history of exposure to antibiotics. We suggest that patients whose lymph nodes have the morphologic features described here frequently have an autoimmune disorder, and that the pathogenesis of this clinicopathologic picture is probably related to a deficiency in suppressor T-cell function which results in an unopposed proliferation of B cells with autoantibody formation and polyclonal gammopathy. Our observations should stimulate clinicians to consider the possibility of an autoimmune pathogenesis for a lymphadenopathy in which a florid lymphoplasmacytic and immunoblastic proliferation similar to that observed in AILD is demonstrated, even though the sections may not meet all the histologic criteria reported for the diagnosis of AILD. Clinical and laboratory investigations necessary to confirm the presence of autoimmunity are indicated in these cases. Moreover, since there is evidence of genetic factors predisposing to autoimmune disease (17, 43), it would be important to investigate close relatives of patients whose lymph nodes showed the histologic changes described in this paper in prospective studies which include suppressor T-cell function, autoantibodies, HLA type of blood lymphocytes and chromosomal analysis. The median survival of the 23 patients with stigmata of autoimmune disease or immune complex disease was 36 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

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↗

PubMed1985

Effects of L-canavanine on immune function in normal and autoimmune mice: disordered B-cell function by a dietary amino acid in the immunoregulation of autoimmune disease.

This study reports the effects in vitro and in vivo of L-canavanine (LCN), an amino acid found in commonly consumed legumes, on immune function in normal and autoimmune mice. L-Canavanine in high doses effectively blocks all DNA synthesis in vitro within 24 h. At lower doses, LCN affects B-cell function of autoimmune New Zealand Black/New Zealand White (NZB/NZW)F1 mice, inhibiting [3H]thymidine incorporation in response to B-cell mitogens, and pokeweed-induced intracytoplasmic immunoglobulin synthesis. LCN stimulates intracytoplasmic immunoglobulin (IgG greater than IgM). T-cell functions such as lymphoproliferation in response to concanavalin A or phytohemagglutinin and T-cell cytotoxicity are not affected. Suppression of the lipopolysaccharide response by LCN is removed by the addition of fresh B cells. Addition of the amino acid to mouse diet resulted in a decrease in the life-span of the autoimmune NZB and (NZB X NZW)F1 mice and abolished the protective effect of male sex on their survival. The decrease in survival in LCN-treated autoimmune mice correlated with an increase in spontaneous immunoglobulin-secreting cells (IgG greater than IgM) and antinuclear and double-stranded DNA antibodies. The histopathological analyses revealed increased glomerular damage and immunoglobulin deposition in the kidneys of the LCN-treated autoimmune and normal (DBA/2) mice. Ten percent of normal mice developed high titers of autoantibodies after 24 weeks of the diet. These data suggest a dietary amino acid, L-canavanine, affects B-cell function resulting in autoimmune phenomena and providing a new animal model of autoimmunity, a diet-induced systemic lupus erythematosus.

Animals↗

PubMed2002

The role of autoimmunity in islet allograft destruction: major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade.

Although it has often been assumed that transplanted allogeneic islets can be destroyed by recurrent autoimmunity in recipients with type 1 diabetes, definitive evidence is lacking and the settings in which this may occur have not been defined. To address these issues, we compared the survival of islet transplants (subject to tissue-specific autoimmunity) with cardiac transplants (not subject to tissue-specific autoimmunity) from various major histocompatibility complex (MHC)-matched and -mismatched donors transplanted into autoimmune NOD recipients. We found that when recipients were treated with combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with better MHC matching, whereas islets survived worst when the donor and recipient shared MHC class II antigens. In the absence of full or MHC class II matching, there was no difference in the survival of islet and cardiac allografts. We also found that the tendency of NOD mice to resist tolerance induction by costimulation blockade is mediated by both CD4+ and CD8+ T-cells, not directly linked to the presence of autoimmunity, and conferred by non-MHC background genes. These findings have clinical importance because they suggest that under some circumstances, avoiding MHC class II sharing may provide better islet allograft survival in recipients with autoimmune diabetes, since mismatched allogeneic islets may be resistant to recurrent autoimmunity. Our results may have implications for the design of future clinical trials in islet transplantation.

Animals↗