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PubMed2000

Transgenic animal models for virus-induced autoimmune diseases.

In the pathogenesis of autoimmune diseases, tolerance against self-determinants is lost and autoreactive lymphocytes are activated leading to pathological damage of single or multiple organs. Viral and other microbial infections have been implicated in these processes. Viruses may induce immunopathological damage by maintaining a chronic immune response against the locally persisting infectious agent. Alternatively, viruses may help to initiate anti-self immunoreactivity, e.g. by induction of an inflammatory milieu needed to overcome tolerance against self-antigens. Presentation of viral antigens and/or previously immunologically ignored self-antigens in secondary lymphoid organs is most probably the key event in the initiation of autoimmune diseases. Translocation of antigens to secondary lymphoid organs and primary induction of T cell responses is primarily mediated by dendritic cells (DCs). We discuss here two transgenic models of autoimmune diseases where DC-mediated antigen transport initiated autoimmune responses against microbial neoself antigens. In the first model, dose and timing of antigen delivery by DCs and turnover of antigenic peptides presented by DCs are the main parameters regulating the outcome of autoimmune diabetes. In the second model, chronic stimulation of organ-specific immune responses via DCs leads to severe cardiovascular immunopathology with arteritis, myocarditis and eventually dilated cardiomyopathy. Taken together, transgenic mouse models are valuable tools for delineating basic pathogenic mechanisms and evaluating therapeutic strategies to interfere with early detrimental processes that lead to manifest autoimmune diseases.

Animals↗

PubMed2002

Familial association in autoimmune liver disease.

The occurrence of autoimmune liver disease in members of the same family is hardly a frequent observation in clinical practice. In a group of 204 cases of primary biliary cirrhosis (PBC) (196 women) and 219 of type 1 autoimmune hepatitis (AIH) (183 women), seen from 1985 to 2000, family occurrence of autoimmune liver disease was investigated. Diagnosis of both entities was based on clinical criteria, immunological studies and liver biopsy. Six families were identified with 2 members each presenting with autoimmune liver disease. In 4 of them the index case had an AIH. This association was observed between mother and daughter in 3 instances. In the remaining AIH index case the association found was with a PBC in her sister. In the other two families the index cases were PBC. In one of them, PBC and AIH association were observed in sisters. Lastly, in another case, an antimitochondrial (AMA) negative variant of PBC was detected in mother and her daughter. The low frequency of family association observed in this cohort could be due to the fact that only symptomatic cases were included. Concurrent autoimmune manifestations were confirmed in 5 members of 6 families (42%). Our results, given the concurrence of both liver diseases in the same family, suggest a link among diverse entities of the autoimmune lineage. The frequency of AIH family association seems to be more prominent in this series than that of PBC. It is also shown that family association in the case of an AMA-negative variant of PBC is feasible, thus confirming that no substantial differences exist between the latter and AMA-positive PBC.

Adult↗

PubMed2005

[B cells as key contributors in determining the level of immune responses -B-cell-targeted therapy in patients with autoimmune diseases].

The levels and types of immune responses are determined dependent on the extent of pathogen invasion, reactions to antigens mediated by macrophage-dendritic cells, T cells and antibodies. Recently, accumulating evidence suggests that B cells also play an important role in the regulation of immune responses. Here we have made a review to present a role of B cells in determining the level of immune responses and discussed about the clinical significance of B cell-targeted therapy in patients with autoimmune diseases. Type 1 diabetes is a T cell-mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells. We and other groups have elucidated that B cells play a critical role in the development of insulitis and diabetes, as B-cell-deficient NOD mice are protected from developing type 1 diabetes. B cells are essential for the T cell receptor clonotype spreading of islet-infiltrating T cells, indicating that B cells may play a role in determining the level of immune responses by antigen presentation to antigen specific T cells. There are now numerous case reports and small series of clinical trials regarding rituximab therapy in autoimmune diseases, such as refractory autoimmune hemolytic anemia, IgM antibody-associated polyneuropathy, systemic lupus erythematosus and rheumatoid arthritis. Rituximab is a genetically engineered chimeric anti-CD 20 monoclonal antibody that is approved for the treatment of lymphoma. CD20 is a B-cell surface antigen that is expressed only on pre- B and mature B cells. Thus, rituximab causes a selective transient depletion of the CD20+ B -cell subpopulation. Rationale and strategy for targeting B cells in the treatment of autoimmune diseases consist of the inhibition of antigen-presentation and co-stimulation that induces T cell expansion and activation. Further careful mechanistic studies are required to develop therapies in patients with autoimmune diseases.

Animals↗

PubMed1992

Interleukin-2, a pro-autoimmune lymphokine that interferes with post-deletional tolerance.

Various complementary mechanisms arranged in a fail-safe hierarchy impede the immune system from launching auto-aggressive attacks, namely intrathymic or post-thymic clonal deletion, anergy, and immunosuppression. Both epidemiological and clinical evidence demonstrates that interleukin-2 (IL-2) may exert a pro-autoimmune effect. Thus, IL-2 reverses immunological tolerance in determined in vitro or in vivo circumstances, is produced at abnormally high levels in certain autoimmune diseases, and induces organ-specific autoimmune lesions when administered to patients. To unravel the molecule and cellular mechanisms responsible for the pro-autoimmune nature of IL-2, our group has employed a recombinant hIL-2 vaccinia virus construct (IL-2. VV) as a self-replicating IL-2-releasing device that may be administered as a source of exogenous IL-2 to experimentally manipulated mice. IL-2 does not interfere with clonal deletion of potentially autoreactive T cells in the thymus since application of IL-2. VV to young mice fails to augment the frequency of T cells bearing 'forbidden' T cell receptor (TCR) V beta gene products (i.e. T cells that recognize endogenous retroviral superantigens). Along the same line, IL-2. VV does not reverse the clonal deletion in male mice bearing a male-specific transgenic alpha/beta TCR that undergo depletion of CD4+ CD8+ thymocytes, nor does it abolish post-thymic clonal deletion of V beta 8+ T cells reactive with the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB). In contrast with its incapability to abolish intra- and post-thymic elimination of T cells with unwarranted specificities, IL-2 abrogates anergy of T cells. Non-deleted, 'forbidden' T cells from congenitally athymic or neonatally thymectomized mice, under normal circumstances anergic, become responsive to TCR-triggering and mediate a systemic autoimmune syndrome upon IL-2. VV treatment. Thus, IL-2 appears to interfere with T cell tolerance at a post-deletional stage, reversing functional non-responsiveness and enabling non-deleted T cells that bear a potentially autoreactive TCR repertoire to cause manifest autoimmunity.

Animals↗

PubMed2006

[Chronic autoimmune thyroiditis and connective tissue system diseases].

Autoimmune thyroiditis is often related to non-specific autoimmune organ diseases such as Rheumatoid Arthritis, Sjögren's syndrome, systemic sclerosis, Systemic Lupus Erythematosus or polymyalgia rheumatica. Etiology of autoimmune diseases has not been clearly discovered yet. In many aspects, mechanisms leading to organ-specific autoimmune diseases are identic with mechanisms causing organ-nonspecific autoimmune disease. In many cases genetic disposal combined with specific antigens can be seen. Another possible factor in terms of endogenesis is genus. External factors are important too, such as undergoing infection, stress situations, exposion to ultraviolet radiation. Authors of this work summarize facts about chronic autoimmune thyroiditis and system connective tissue disease. The most literature supports more frequent appearance of these diseases, while the thyroiditis can appear both in clinical form with typical symptoms and in subclinical form.

Autoimmune Diseases↗

PubMed1990

Autoantibodies and autoimmune diseases in young diabetics.

Another autoimmune disease was found to accompany insulin dependent diabetes mellitus (IDDM) in 14% of the young diabetics (n = 14) studied. Thyroid autoimmune disease was the most common of the accompanying autoimmune diseases, and was detected in 11% (n = 15) of the patients. Two thirds of the IDDM patients with autoimmune thyroiditis were hypothyroid, one was hyperthyroid, and 20% lacked detectable thyroid antibodies when thyroid disease was diagnosed. Coeliac disease was found in 2% of the patients, and one had Addison's disease. Autoantibodies were found in one third of the patients. Thyroid microsomal antibodies were detected in 22% of the patients, IgA anti-gliadin in 11%, gastric parietal cell antibodies in 3% and rheumatoid factor in 7%. Autoimmune disease and the relevant autoantibodies coexisted in 11% of the patients. Autoimmune disorders and autoantibodies were not associated to any particular HLA type. The distribution of the HLA-types in the patients was unusual in that the frequency of HLA-DR3 was not increased. The value of autoantibody tests in the diagnosis of functional disorders of the thyroid and of coeliac disease are discussed.

Adult↗

PubMed1994

Differences in non-MHC alloantigens promote tissue rejection but fail to mediate allogeneic co-operation and autoimmunity in mice neonatally injected with semi-allogeneic F1 B cells.

Mice injected at birth with semi-allogeneic lymphoid cells develop a lupus-like autoimmune syndrome in which donor B cells are polyclonally activated by host alloreactive CD4+ T cells, producing autoantibodies and immune complex-mediated glomerulonephritis. It has been demonstrated that the recognition of major histocompatibility complex (MHC) class II alloantigens triggers the development of a complete disease. But differences in either MHC class I molecules or Mls-1 antigens are not sufficient to induce production of autoantibodies. Here we have investigated whether differences in other non-MHC alloantigens could induce a similar autoimmune disease and whether the maternal environment could modulate the T-B allogeneic co-operation in this model. For this purpose (BALB/c x BC20)F1 hybrid females were backcrossed with BC20 males. R2 mice obtained in this backcross were neonatally injected with 10(8) (C57BL/6 x BALB.Igb)F1 spleen cells and the tolerance against maternal derived BALB/c alloantigens as well as the development of autoimmune manifestations were subsequently evaluated. In contrast to R2 mice injected at birth with (C57BL/6 x BALB.Igb)F1 cells, control R2 mice rejected skin grafts from BALB/c mice and B cells from (C57BL/6 x BALB.Igb)F1 mice, independently of their H-2 haplotype (H-2b/d or H-2b/b). Nevertheless, after neonatal injection of (C57BL/6 x BALB.Igb)F1 cells, none of 19 H-2b/d R2 injected mice presented autoimmune manifestations, in contrast with the typical autoimmune disease observed in all neonatally injected H-2b/b R2 mice (26 mice). These results support that the development of autoimmunity in this model depends exclusively upon differences in MHC class II alloantigens and that the relationship between mother and fetus, through the pregnancy or the breast suckling, is not sufficient to inhibit cytolytic and allo-helper responses against non-inherited maternal-derived alloantigens.

Animals↗

PubMed2004

Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide.

Class I and class II MHC-restricted T cells specific for proteins present in myelin have been shown to be involved in autoimmunity in the central nervous system (CNS). It is not yet known whether CD1d-restricted T cells reactive to myelin-derived lipids are present in the CNS and might be targeted to influence the course of autoimmune demyelination. Using specific glycolipid-CD1d tetramers and cloned T cells we have characterized a T cell population reactive to a myelin-derived glycolipid, sulfatide, presented by CD1d. This population is distinct from the invariant Valpha14+ NK T cells, and a panel of Valpha3/Valpha8+ CD1d-restricted NK T cell hybridomas is unable to recognize sulfatide in the presence of CD1d+ antigen-presenting cells. Interestingly, during experimental autoimmune encephalomyelitis a model for human multiple sclerosis, sulfatide-reactive T cells but not invariant NK T cells are increased severalfold in CNS tissue. Moreover, treatment of mice with sulfatide prevents antigen-induced experimental autoimmune encephalomyelitis in wild-type but not in CD1d-deficient mice. Disease prevention correlates with the ability of sulfatide to suppress both interferon-gamma and interleukin-4 production by pathogenic myelin oligodendrocyte glycoprotein-reactive T cells. Since recognition of sulfatide by CD1d-restricted T cells has now been shown both in mice and humans, study of murine myelin lipid-reactive T cells may form a basis for the development of intervention strategies in human autoimmune demyelinating diseases.

Animals↗

PubMed1996

Generation of autonomously pathogenic neo-autoreactive Th1 cells during the development of the determinant spreading cascade in murine autoimmune encephalomyelitis.

Chronic progression of autoimmune disease is accompanied by the acquisition of autoreactivity to new self-determinants. Recent evidence indicates that this process, commonly referred to as determinant spreading, may be pathogenic for chronicity. Our studies on experimental autoimmune encephalomyelitis (EAE), a murine model widely used in multiple sclerosis (MS) studies, have shown that determinant spreading develops as a predictable sequential cascade of neo-autoimmunity during progression to chronic disease. By 7-8 weeks after immunization of (SWR x SJL)F1 mice with the immunodominant myelin proteolipid protein determinant (PLP 139-151), splenocytes consistently respond to the immunodominant myelin basic protein determinant (MBP 87-99). In the present study, we directly address the pathogenicity of neo-autoimmunity resulting from endogenous self-priming during the course of disease. Our results indicate that T cells responding to the spreading MBP 87-99 determinant produce a proinflammatory cytokine profile consistent with type 1 helper T cells (Th1) cells. In addition, splenocytes activated to the spreading MBP 87-99 determinant consistently transfer acute EAE in naive recipients even when T cells reactive to the priming PLP 139-151 immunogen are eliminated by bromodeoxyuridine (BUdR)-mediated photolysis. Our data indicate that endogenous neo-autoantigen priming during chronic autoimmune disease generates type 1 helper T cells (Th1) cells that are autonomously pathogenic. These results provide further evidence supporting the view that determinant spreading is a pathogenic process that leads to chronic progression of autoimmune disease.

Adoptive Transfer↗

PubMed1999

Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes.

We recently evidenced a dramatic enrichment for T cells reactive against Epstein-Barr virus (EBV) within inflamed joints of two rheumatoid arthritis patients. To assess the generality of this phenomenon and its relevance to autoimmunity, we studied the responses of CD8 T cells from patients with either acute or chronic inflammatory diseases (rheumatoid arthritis: n = 18, ankylosing spondylitis: n = 5, psoriatic arthritis: n = 4, Reiter's syndrome: n = 3, arthrosis: n = 2, uveitis: n = 2, multiple sclerosis: n = 2, encephalitis: n = 1) against viral proteins derived from EBV and another common herpes virus, human cytomegalovirus (CMV). T cell responses against EBV and/or CMV epitopes were frequently observed within CD8 T cells derived from chronic inflammatory lesions, irrespective of their location (knee, eye, brain) and autoimmune features. In most cases, CD8 T cells derived from affected organs yielded stronger anti-viral T cell responses than CD8 T cells derived from patients' PBL, even in chronic inflammatory diseases devoid of autoimmune features or induced by defined bacterial agents. Taken together, these results suggest that the presence of virus-specific T cells within inflamed lesions of patients suffering from autoimmune diseases is a general phenomenon associated with chronic inflammation rather than the initiating cause of the autoimmune process. Since this phenomenon was sometimes associated with long-term T repertoire biases within inflamed lesions, the physiopathological significance of T cell clonal expansions found in a recurrent fashion within chronically inflamed autoimmune lesions should be interpreted with caution.

Adult↗

PubMed2001

A novel role for interleukin-18 in human natural killer cell death: high serum levels and low natural killer cell numbers in patients with systemic autoimmune diseases.

OBJECTIVE: Patients with systemic autoimmune diseases have been reported to have reduced numbers of peripheral blood natural killer (NK) cells compared with healthy subjects. The ability of selected cytokines to trigger NK cell death prompted us to compare the levels of peripheral blood cytokines with the numbers of NK cells in patients with various systemic autoimmune diseases. METHODS: We used enzyme-linked immunosorbent assays to measure the concentration of selected cytokines (interleukin-18 [IL-18], IL-15, IL-12, IL-2, interferon-gamma [IFNgamma], and tumor necrosis factor alpha [TNFalpha]) in sera from 58 patients with systemic autoimmune diseases and 33 healthy controls. The absolute number of T cells and NK cells in the peripheral blood was measured in parallel using flow cytometry. The ability of selected cytokines to induce NK cell death was then measured using 3,3'-dihexyloxacarbocyanine iodide dye, propidium iodide staining, and caspase 3 activity. RESULTS: Levels of IL-18, IL-15, IFNgamma, and TNFalpha were elevated in sera from patients with systemic autoimmune diseases compared with normal controls. The percentage of NK cells and natural killer T cells were significantly decreased in the peripheral blood of patients with systemic autoimmune diseases compared with normal controls. Serum concentrations of IL-18, IL-15, and TNFalpha were inversely related to the number of NK cells in both patients and healthy controls. The combination of IL-18 and IL-15 or IL-18 and IL-12 induced NK cell death in vitro. The combination of IL-18 and IL-15 or IL-18 and IL-12 enhanced IFNgamma and TNFalpha production by NK cells in vitro. Cytokine-induced NK cell death is caspase-dependent and is partially blocked by neutralizing antibodies against TNFalpha. CONCLUSION: High levels of IL-18 and IL-15 are associated with the decreased number of NK cells that is observed in patients with systemic autoimmune diseases.

Adolescent↗

PubMed1995

Silica exposure and autoimmune diseases.

There have long been case reports linking silica exposure to a variety of autoimmune diseases (systemic sclerosis, rheumatoid arthritis, lupus, chronic renal disease). Evidence of this association in larger epidemiologic studies has been increasing in the last decade. We summarize this evidence here, and present some plausible mechanisms which have been discussed in the literature. The link between silica exposure and autoimmune disease may have been missed in cohort mortality studies because autoimmune diseases are rarely underlying causes of death. Similarly, case-control studies of autoimmune diseases have often failed to consider occupational exposure to silica. Further research is needed in occupationally exposed populations to verify this association. The link between respirable silica exposure and autoimmune disease may have some bearing on the possible association between silicone breast implants and autoimmune disease, although the nature of the silica involved is quite different in the two situations.

Autoimmune Diseases↗

PubMed1989

Autoimmune thyroid phenomena are not evidence for human lymphocyte antigen-genetic heterogeneity in insulin-dependent diabetes.

It is well established that there is genetic heterogeneity between a human lymphocyte antigen (HLA)-DR3-associated allele and an HLA-DR4-associated allele in insulin-dependent diabetes mellitus (IDDM). Equally well established are the association of DR3 with Graves' disease and other autoimmune disorders in nondiabetics and the increased prevalence of autoimmune thyroid disease in IDDM. Perhaps in large part because of these facts, it has been postulated that there are two major forms of classical IDDM--one form characterized by coexistent autoimmune disease, such as autoimmune thyroid disease which is associated with DR3, and another form not associated with additional autoimmune disorders, which is associated with DR4. Several studies have repudiated the idea of specific clinical findings in IDDM being associated exclusively with DR4. However, the DR3-thyroid association in IDDM has not been investigated carefully. Therefore, in order to study this putative association, we divided a group of diabetic children into overlapping subgroups based on thyroid enlargement, antithyroid microsomal antibodies, acquired hypothyroidism, and no evidence of thyroid disease. The distributions of HLA-DR3 and -DR4 among these subgroups did not differ from each other; nor did the distribution of the HLA alleles differ from those of randomly selected IDDM individuals. These results suggest that thyroid autoimmunity in IDDM is part of the IDDM "syndrome" and is associated with DR3 and DR4 to the same extent that IDDM without thyroid disease is associated with these two antigens. Thus, although genetic studies are consistent with the heterogeneity between DR3 and DR4 in IDDM, there is no HLA-thyroid disease association to support this heterogeneity.

Diabetes Mellitus, Type 1↗

PubMedDate not supplied

Gender differences in GAD antibody-positive diabetes mellitus in relation to age at onset, C-peptide and other endocrine autoimmune diseases.

BACKGROUND: Females have an increased incidence of autoimmune diseases. However, no gender difference in the incidence of type 1 diabetes is found. The frequency of antibodies against glutamic acid decarboxylase (GADA) in diabetes mellitus depends on age at diagnosis and also gender. Several studies have shown that high GADA levels can predict future beta-cell failure and need for insulin treatment. The aim of this study was to investigate possible gender differences in relation to GADA levels, fasting plasma C-peptide levels and frequency of other autoimmune endocrine diseases in GADA-positive patients with different age at diabetes diagnosis. METHODS: GADA were screened in 4974 patients from a local diabetes registry, and plasma C-peptide was measured and a history of other autoimmune endocrine diseases was recorded. Of these patients, 822 were GADA positive and were further divided into four groups depending on the age at diagnosis of diabetes; Group 1: <20 years, Group 2: 20-39 years, Group 3: 40-59 years and Group 4: > or =60 years. RESULTS: Female patients in Group 3 had lower fasting plasma C-peptide levels (median 0.21[0.00-0-56] vs. 0.41[0.00-0.73] nmol/L, p=0.02), higher GADA levels (median 7 [4-9] vs. 5 [2-7] Arbitrary Unit (AU), p=0.0003) and higher frequency of other autoimmune endocrine diseases (22.4 vs. 5.3%, p=0.0001) than male patients. In a stepwise logistic regression analysis, diabetes duration (p<0.000001), high GADA levels (Exp (B) 3.68 CI 1.69-7.98, p=0.001) and low BMI (p=0.00002) were associated with total beta-cell failure in Group 3. CONCLUSIONS: GADA-positive female diabetic patients with an age at diagnosis between 40 and 59 years have higher GADA levels and a more severe loss of beta-cell function than male patients with the same age at diagnosis. This could be due to the effect of sex steroids and/or GnRH on the regulation of the immune system. Female patients with high GADA levels also had a high prevalence of other autoimmune endocrine diseases, especially autoimmune thyroid disease, which further emphasises the need for screening of thyroid function in female patients with high GADA levels.

Adolescent↗

PubMed1983

In vitro correction of the interleukin 2 defect of autoimmune mice.

The effect of concanavalin A (Con A) and/or phorbol myristate acetate (PMA) on interleukin 2 (IL 2) production and tritiated thymidine incorporation was measured in young (6 weeks) and old (16-24 weeks) autoimmune mice by pulsing 5 X 10(6) unfractionated spleen cells with 5 micrograms of Con A and/or 5 ng of PMA for variable periods of time. The apparent deficiency in Con A-stimulated IL 2 production manifested by mice prone to the development of autoimmune disease was repaired by the addition of PMA. PMA did not enhance interleukin 1 (IL 1) secretion in autoimmune MRL-lpr mice either alone or in combination with Con A. The addition of purified IL 1 to Con A-pulsed autoimmune cells did not increase IL 2 production. Freeze-thaw experiments suggested that PMA does not promote IL 2 synthesis. Con A-pulsed cells plus PMA-pulsed cells do not syngergize. These data indicate that autoimmune-prone mice are capable of producing IL 2 and of proliferating in response to Con A provided the comitogen PMA is present. It can be argued that the failure to produce IL 2 or to respond to proliferative signals is not fundamental to the development of the disease sustained by autoimmune-prone mice.

Animals↗

PubMed1986

Requirement of H-2 heterozygosity for autoimmunity in (NZB X NZW)F1 hybrid mice.

In the F1 hybrid of autoimmune New Zealand Black (NZB) and phenotypically normal New Zealand White (NZW) mice, there occurs a severe systemic lupus erythematosus (SLE)-like autoimmune disease more fulminant than that found in the parental NZB mice. To determine the role of the H-2 complex in the pathogenesis of autoimmune disease of the (NZB X NZW)F1 hybrid, we developed H-2-congenic NZB (NZB.H-2z) and NZW (NZW.H-2d) strains, and compared the degree of autoimmune features between congenic H-2d/H-2d and H-2z/H-2z homozygous F1 hybrids and the original H-2d/H-2z heterozygous (NZB X NZW)F1 hybrid. We found that autoimmune features such as productions of IgG class anti-DNA antibodies and retroviral gp70 immune complexes and the development of renal disease were to a great extent reduced in both H-2 homozygous F1 hybrids, as compared with the H-2 heterozygous (NZB X NZW)F1 hybrid. It would thus appear that the heterozygosity of H-2d haplotype derived from NZB and H-2z from NZW is essential for the autoimmune disease characteristic of the (NZB X NZW)F1 hybrid.

Animals↗

PubMed1988

Autoantibody production is associated with polyclonal B cell activation in autoimmune mice which express the lpr or gld genes.

Systemic autoimmune disease in humans and mice is characterized by hypergammaglobulinemia and abnormally high levels of serum autoantibodies. The presence of certain genes, such as the lpr and gld genes, induces otherwise normal mice to spontaneously develop systemic autoimmunity. To better understand the effect of these genes on the development of hypergammaglobulinemia, we quantitated the absolute number of splenic B cells producing antibodies reactive with each of four autoantigens and two conventional antigens and compared this to the total number of Ig-secreting spleen cells present in these mice. Whereas autoimmune mice had significantly greater numbers of autoantibody-secreting spleen cells than normal mice, they also had significantly greater numbers producing antibodies of conventional specificity. When expressed as a proportion of the total repertoire, no bias towards autoantibody production was present when autoimmune lpr and gld animals were compared to their congenic nonautoimmune C57BL/6 and C3H/HeJ counterparts. We also examined the B cell repertoires of recombinant inbred mice derived by mating autoimmune NZB with normal NFS mice. Some recombinant inbred (RI) lines developed hypergammaglobulinemia and produced large quantities of autoantibody. While evidence for specific (auto)antigenic stimulation was present in some RI lines, hypergammaglobulinemia was commonly associated with polyclonal B cell activation in these autoimmune mice as well.

Animals↗

PubMed1990

Correlations of autoimmunity with H-2 and T cell receptor beta chain genotypes in (NZB X NZW) F2 mice.

Accelerated autoimmunity as expressed by the classical autoimmune strain mouse (NZB x NZW)F1 is thought to be the result of major histocompatibility complex (MHC)-associated NZW genes acting on a genetic predisposition for autoimmunity as expressed by the NZB mouse. To evaluate more accurately both H-2 and T cell receptor (TcR) beta chain involvement in F1 disease, we studied the segregation of NZB (H-2d, TcRB) and NZW (H-2z, TcRW) haplotypes of these genetic elements and the development of autoimmunity in (NZB x NZW)F2 generation mice. F2 mice with the H-2d/z genotype lived shorter average life-spans and expressed elevated levels of antibodies to gp70, ssDNA and dsDNA, while those with the TcRW/W genotype (homozgous for the NZW TcR deletion) expressed elevated levels of autoantibodies but had relatively long life-spans. On the other hand, mice with the TcRB/B genotype (homozygous for the NZB TcR) produced consistently low levels of autoantibodies but died at an early age. The most severely affected F2 population were the mice carrying both the TcRB/B and H-2d/z alleles. These mice died on an average within the first 5 months of life, but produced the lowest levels of antibodies to gp70, single-stranded DNA and double-stranded DNA. These data confirm the contribution of NZW H-2-linked genes to accelerated autoimmunity in the F1 hybrid and, furthermore, define NZB TcR-linked components as primary developers of this phenomenon. They also suggest a limited, if any, contribution of both the NZW TcR deletion and traditional autoantibodies to F1 accelerated autoimmunity.

Animals↗