Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice.

The influence of oestrogen on the lupus disease in MRL/l mice has been investigated. Adult, castrated male and female MRL/l mice were administered with s.c. injections of 3.2 micrograms of 17 beta-oestradiol twice a week. The results clearly demonstrate that a relatively small dose of oestrogen is a potent accelerator of the lupus disease in this mouse strain. Thus, administration of oestrogen accelerates glomerulonephritis, lymphoproliferation and mortality. Our results also indicate that oestrogen exerts a dual effect on the immune system of MRL/l mice by depression of antigen-specific and mitogen-induced T cell responses as well as enhancement of polyclonal B cell activation and autoantibody formation. In addition, even short-term administration of oestrogen in the preclinical phase of the disease resulted in long-lasting effects as evaluated by reduced longevity and aggravation of renal disease.     

Histocompatibility Complex Gene Products and Exposure to Oestrogen: Two Independent Disease Accelerating Factors in Murine Lupus

A number of studies have demonstrated that oestrogen exerts a significant impact on the course of experimental autoimmune diseases. Exposure to oestrogen aggravates SLE glomerulonephritis whereas the opposite outcome has been demonstrated in experimental arthritis, vasculitis, thyroiditis, and sialadenitis. In this report we have analysed the respective impact of H-2^z linked gene products and long-term treatment with physiological doses of oestradiol on clinical and immunological variables in castrated backcrosses of lupus prone NZB/W and NZB mice. Our results demonstrate that H-2^z linked gene products accelerate B-cell activation and stimulate autoantibody production resulting in aggravation of glomerulonephritis and precocious death in renal failure. These H-2^z linked gene products do not influence T-cell mediated sialadenitis. Irrespectively of the H-2 haplotype of the mice, administration of oestrogen resulted in intense polyclonal B cell activation and aggravation of glomerulonephritis. However, exposure to oestrogen resulted in amelioration of sialadenitis. Notably, our result indicates that B-cell activation achieved by oestrogen and H-2^z gene linked products, respectively is mediated by independent mechanisms. In addition, we have developed a predictive in vivo test that permits forecasts regarding efficiency of oestrogen treatment for suppression of T-cell mediated lesions. Using this test procedure in young, clinically healthy SLE mice we have been able to prove that animals displaying suppressed delayed type hypersensitivity (DTH) after short-term oestrogen exposure showed significantly lower long-term morbidity regarding development of sialadenitis upon continuous treatment with physiological doses of oestradiol.     

CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE

CR1 and CR2 expression is decreased by approximately 50% on B cells of patients with systemic lupus erythematosus (SLE). Expression is also decreased in the MRL/lpr murine model of SLE prior to the development of clinical disease, suggesting that this alteration may play a role in pathogenesis. To determine whether the decrease in receptor levels affects the development of SLE, we analyzed MRL/lpr mice in which CR1/CR2 expression was altered by gene targeting. Mice from each cohort (Cr2+/+, Cr2+/-, and Cr2-/-) were analyzed biweekly for the development of proteinuria and autoantibodies. Kidneys were examined at 12 and 16 weeks for evidence of immune complex deposition and renal disease. Deficiency of CR1/CR2 did not affect survival or development of renal disease as measured by proteinuria. Mice deficient in CR1/CR2 had significantly lower levels of IgG3 rheumatoid factor (RF) and total serum IgG3, suggesting a specific defect in production of IgG3 in response to endogenous autoantigens. Since IgG3 RF has been associated with the development of vasculitis in this model, we examined the mice for alterations in development of this clinical manifestation. Although there was no difference in the development of ear necrosis among the three groups, renal arteritis was not identified in any of the Cr2+/- mice, whereas it was present in 20% of the Cr2+/- and 40% of the Cr2+/+ mice. Finally, significantly higher levels of IgA were seen in the glomeruli of Cr2+/- mice compared to Cr2+/- or Cr2+/+ mice, suggesting that CR1/CR2 are involved in either the regulation of IgA production or the clearance of IgA immune complexes. Together these data support the concept that alterations in CR1/CR2 expression or function affect the regulation of autoantibody production and/or clearance and may have clinical consequences.     

Loss of LFA-1, but not Mac-1, protects MRL/MpJ-Fas(lpr) mice from autoimmune disease

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex-mediated tissue injury. Many different adhesion molecules are thought to participate in the development of SLE; however, few studies have directly examined the contributions of these proteins. Here we demonstrate that LFA-1 plays an essential role in the development of lupus in MRL/MpJ-Fas(lpr) mice. Mice deficient in LFA-1, but not Mac-1, showed significantly increased survival, decreased anti-DNA autoantibody formation, and reduced glomerulonephritis. The phenotype of the LFA-1-deficient mice was similar to that observed in beta(2) integrin-deficient (CD18-null) MRL/MpJ-Fas(lpr) mice, suggesting a lack of redundancy among the beta(2) integrin family members and other adhesion molecules. These studies identify LFA-1 as a key contributor in the pathogenesis of autoimmune disease in this model, and further suggest that therapeutic strategies targeting this adhesion molecule may be beneficial for the treatment of SLE.     

Studies on age-related functional changes in regulatory T cells and B cells involved in the autoantibody production of MRL/MpJ- +/+ mice

Age-related changes in anti-DNA autoantibody production of MRL/MpJ- +/+ mice were investigated. In lipopolysaccharide (LPS)-stimulated cultures, spleen cells of the mice showed an age-related, marked increase in the ability to produce IgG class of the autoantibody after the age of 12 months, while they showed a tendency to decrease with age in the production of IgM class of the autoantibody. Serum levels of anti-DNA autoantibodies rose markedly in the IgG autoantibody but not in the IgM autoantibody after 12 months of age, which is well consistent with the observation in the LPS-stimulated cultures. T cell-depleted spleen cells, however, showed only a small increase with age in the IgG autoantibody productive ability. These results suggest that the age-associated increase in the IgG autoantibody production in the mice is under T-cell control. Age-associated changes in suppressor capacity in spleen cells of the mice were also investigated. Suppressive activity of the cells stimulated by 2-day incubation with concanavalin A (Con A) showed a clear increase as the donor age advanced, when assayed on the LPS-stimulated anti-DNA autoantibody production in vitro. The results indicate that, in MRL/MpJ-+/+ mice, suppressor capacity does not decline with age and is not related as a cause to the autoantibody production.     

Bone marrow cell transfer of autoimmune diseases in a MRL strain of mice with a deficit in functional Fas ligand: dissociation of arteritis from glomerulonephritis

MRL/MpTn-gld/gld (MRL/gld) mice, which are deficient in a functional Fas ligand (FasL), spontaneously develop autoimmune diseases involving both lethal glomerulonephritis and systemic arteritis, while MRL/Mp-+/+ (MRL/+) and C3H/HeJ-gld/gld (C3H/gld) do not. To determine the cells responsible for the development of glomerulonephritis and arteritis, we transferred bone marrow cells from MRL/gld mice to undiseased MHC-compatible gld/gld or +/+ mice. In bone marrow irradiation chimeras, MRL/gld bone marrow cells were transferred to lethally irradiated MRL/+ or C3H/HeJ-+/+ (C3H/+) mice, and both recipients developed glomerulonephritis associated with hypergammaglobulinemia without causing graft-versus-host (GVH)-like diseases. However, a striking difference between them was that MRL/+ recipients developed arteritis, but C3H/+ recipients did not. In bone marrow mixed chimeras formed by transferring MRL/gld bone marrow cells to unirradiated mice, the MRL/gld bone marrow cells induced glomerulonephritis in C3H/gld mice, but not in C3H/+ and MRL/+ mice. These results indicate that bone marrow cells from MRL/gld mice can cause glomerulonephritis in mice, even in those with a C3H background, possibly if they survive longer by escaping from Fas-mediated apoptosis, while the development of arteritis requires the MRL genetic background in the recipients. This is the first report of the transfer of arteritis in lupus mice to undiseased recipients.     

Role of inducible costimulator in the development of lupus in MRL/lpr mice

Inducible costimulator (ICOS) is a costimulatory molecule expressed in activated T cells and plays an important role in T-cell-dependent immune responses. We investigated the role of ICOS in the development of autoimmune diseases in MRL/Mpj-lpr/lpr (MRL/lpr) mice. ICOS was expressed on CD4(+) T cells from adult MRL/lpr mice. ICOS-deficient MRL/lpr mice showed mild lymphoadenopathy and a decreased memory type CD4(+) T cells in the spleen. The anti-dsDNA antibody levels were decreased. CD4(+) T cells from ICOS-deficient MRL/lpr mice showed less of a bias to Th1 and an enhanced production of IL-4 in response to anti-CD3 antibody in comparison to those from wild-type MRL/lpr mice. Although ICOS-deficiency abrogated renal vasculitis completely, the severity of glomerulonephritis was not altered. ICOS is considered to play a role in CD4(+) T cell activation, autoantibody production, and renal vasculitis. However, it is not essentially required in the development of glomerulonephritis.     

Expression of Heterozygous lpr Gene in MRL Mice

The presence of the homozygous lpr gene (lpr/lpr) in MRL mice has been regarded as mandatory for the development of the early onset of lupus disease, T-cell dysfunction, and polyclonal B-cell activation. Congeneic MRL mice lacking the lpr gene (MRL +/+) display neither the lupus disease nor the immunological abnormalities within the first year of life. In this study we examined the cellular functions of MRL mice heterozygous at the lpr locus. The results indicate that MRL mice heterozygous at the lpr locus display intermediate delayed-type hypersensitivity compared with homozygous lpr/lpr mice on the one hand and congeneic +/+ mice on the other. Furthermore, proliferative responses to concanavalin A, measured by uptake of [3H]thymidine, were significantly lower in MRL mice heterozygous at the lpr locus than in +/+ mice, but significantly higher than in homozygous MRL lpr/lpr mice. Polyclonal B-cell activation, assessed by measurement of frequencies of IgG-secreting spleen cells, a prominent feature in MRL lpr/lpr mice, was significantly lower in lpr/+ mice and totally absent in +/+ mice. Furthermore, spleen cells spontaneously secreting auto-antibodies were found in large numbers in MRL lpr/lpr mice and in considerably lower but still significant numbers in heterozygous MRL +/lpr mice. In contrast, spleen cells from matched MRL +/+ mice did not display any spontaneous autoantibody production. Taken together, these data provide evidence for immunomodulatory properties of the heterozygous lpr gene.     

Quantitation and IgG subclass distribution of antichromatin autoantibodies in SLE mice

Antibodies to a native chromatin preparation were found in most mice suffering from spontaneous SLE. All MRL/Mp-lpr/lpr (MRL/lpr) sera tested (more than 500) contained antibodies to chromatin and antichromatin levels increased with age. Approximately 50% of the IgG antichromatin antibody in the MRL/lpr sera was of the IgG2a subclass, 30% IgG2b, 10% IgG1, and 10% IgG3. Interestingly, the relative restriction of antichromatin autoantibodies to the IgG2a subclass was apparent in MRL/lpr mice as young as 1 month, well before the onset of lymphadenopathy. Antichromatin autoantibodies were also detectable in sera from MRL/Mp- +/+ (MRL/+), NZB, (NZB x NZW)F1 (B x W), and BXSB mice, but were not found in sera from normal mice. A similar subclass distribution skewed toward IgG2a was seen for MRL/+, B x W, and NZB mice. These results indicate that the spontaneous autoantibody directed against chromatin is a good marker for murine SLE, and is predominantly of the IgG2a subclass.     

Beneficial effects of non-depleting anti-CD4 in MRL/Mp-lpr/lpr mice with active systemic lupus erythematosus and microscopic angiitis.

MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop lymphoproliferation and systemic autoimmune disease. The majority of mice in any cohort develop systemic lupus erythematosus (SLE) and up to a quarter of them develop a syndrome that resembles microscopic angiitis (MPA). Both conditions are characterized by vasculitis, glomerulonephritis and autoantibody formation. Depleting anti-CD4 monoclonal antibody (mAb) treatment is ineffective in MRL/lpr mice after disease onset. The present study investigates the effects of a non-depleting anti-CD4 mAb in MRL/lpr mice with active SLE or MPA. This antibody increased survival compared to control Ig but did not prolong survival compared to non-treated mice. However, anti-CD4 significantly reduced lymphoproliferation in the mice and furthermore reduced the vasculitis component of the autoimmune disease following several weeks of treatment.     

Activation of the lectin pathway in murine lupus nephritis

In systemic lupus erythematosus (SLE), hypocomplementaemia and complement deposition have been described both in man and in experimental models. A major involvement of the classical pathway of complement activation has been demonstrated in this disease, however relatively little is known about the involvement of the lectin pathway. Therefore in the present study we have analyzed the activity of all three pathways of complement activation in murine models of SLE. In the mouse, MBL is expressed in two forms, namely MBL-A and MBL-C. In the present study young and old MRL-lpr and control MRL+/+ mice were compared for the levels of complement activity with specific attention for the lectin pathway. It was found that upon aging of both MRL-lpr and MRL+/+ mice, a marked decrease in the activity of the classical pathway (CP) occurs. Levels of alternative pathway (AP) and lectin pathway (LP) activity remain unchanged. Key-molecules of these pathways, C1q, C3, MBL-A and MBL-C were analyzed and were all found to be decreased in aged mice of both strains. The levels of MBL-A and MBL-C showed a high degree of correlation and decreased equally. In aged MRL-lpr mice in which autoimmunity is most pronounced, we observed high autoantibody titers and strong deposition of glomerular immune complexes in association with deposition of C1q, C3, MBL-A and MBL-C. In conclusion, these data suggest that in addition to the classical pathway and the alternative pathway also the lectin pathway of complement activation is involved in murine lupus nephritis.     

FcgammaRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease

MRL.Fas(lpr/lpr) mice, a model for systemic lupus erythematosus (SLE) and arthritis in humans, have a Fas mutation that results in spontaneous development of systemic autoimmune diseases and a short life span. Half of them die by 5-6 months of age due to massive progression of systemic autoimmune diseases, such as lupus nephritis. However, C57BL/6 (B6).Fas(lpr/lpr) strain does not develop such disorders within the normal life span, indicating that suppressor gene(s) in B6 mice may control the onset and exacerbation of disease. Here, we show that the gene for a unique inhibitory Fc receptor for IgG (Fc gamma RIIB) is a critical SLE suppressor. Fc gamma RIIB-deficient B6.Fas(lpr/lpr) (B6.IIB(-/-)Fas(lpr/lpr)) mice developed systemic autoimmune diseases, including anti-DNA and anti-type II collagen autoantibodies and cryoglobulin production, immune complex glomerulonephritis and arthritis. They were short-lived, due to enhanced autoantibody production by B cells culminating in fatal lupus nephritis. Thus, Fc gamma RIIB deletion with Fas mutation is sufficient for the development of systemic autoimmunity in B6 mice. The inhibitory signaling cascade via Fc gamma RIIB may be critical for suppressing SLE in humans.     

Expression of Heterozygous lpr Gene in MRL Mice

Recently we showed that not only homozygous MRL lpr/lpr mice but also heterozygous MRL +/lpr mice display defective antigen- and mitogen-driven T-cell responses as well as polyclonal B-cell activation compared with congeneic MRL +/+ mice. In this study we examined the impact of the heterozygous lpr gene on organ pathology in kidneys, joints, and salivary glands, as well as serum levels of immunoglobulins and autoantibodies in young and old MRL mice. Only 1 out of 17 heterozygous lpr-bearing MRL mice developed clinically overt renal disease with significant proteinuria and haematuria during the first year of life. However, examination of Ig and C3 deposits in glomeruli of kidneys from these mice revealed that the expression of the heterozygous lpr gene in MRL mice accelerates glomerulonephritis. In addition, histological examination of the submandibular salivary glands showed an increased focus score in heterozygous MRL mice at 4-5 months of age compared with that of matched congeneic +/+ mice. In contrast, no signs of arthropathy were registered in the heterozygous lpr-bearing MRL mice. Heterozygous MRL mice displayed an expanding lymphoid system as evaluated by significantly increased spleen and lymph node weights compared with those of matched MRL +/+ mice. Further evidence for immunomodulatory properties of the heterozygous lpr gene was obtained when analysing serum levels of IgG, IgM, and autoantibodies. Thus, heterozygous MRL +/lpr mice produced significantly higher levels of both Ig and autoantibodies than matched MRL +/+ mice. We conclude that the expression of the heterozygous lpr gene in MRL mice results in acceleration of the autoimmune process, giving rise to precocious clinical disease.     

Induction of microthrombotic thrombocytopenia in normal mice by transferring a platelet-reactive, monoclonal anti-gp70 autoantibody established from MRL/lpr mice: an autoimmune model of thrombotic thrombocytopenic purpura

MRL/MpJ-lpr/lpr (MRL/lpr) mice spontaneously develop immune complex-mediated glomerulonephritis and thrombocytopenia. Although the presence of cross-reactive anti-phospholipid antibodies in sera of MRL/lpr mice has been demonstrated, possible relationships between detected autoantibodies and the development of thrombocytopenia have not been elucidated. Recent genetic analyses in a few different strains of lupus-prone mice have pointed out a close correlation between autoantibodies reactive with endogenous retroviral env gene product, gp70, and the development and severity of glomerulonephritis. In the process of establishing possibly nephritogenic anti-gp70 autoantibody-producing hybridoma cells from MRL/lpr mice, we identified an IgG2a-producing anti-gp70 hybridoma clone that induced microvascular intraluminal platelet aggregation, thrombocytopenia, and amenia upon transplantation into syngeneic non-autoimmune mice. This and two other anti-gp70 antibodies bound onto the surface of mouse platelets, and purified IgG2a of the anti-gp70 autoantibody induced glomerular lesions with characteristics of thrombotic thrombocytopenic purpura when injected into non-autoimmune mice. The pathogenic anti-gp70 autoantibody specifically precipitated a platelet protein with an approximate relative molecular mass of 40 000.     

Pathogenesis of autoimmunity in αβ T cell-deficient lupus-prone mice

Murine lupus in MRL mice has been strongly attributed to αβ T cell-dependent mechanisms. Non-αβ T cell-dependent mechanisms, such as γδ T cells, have been shown to drive antibody and autoantibody production, but they have not been considered capable of inducing end-organ disease. Here, we have expanded upon the findings of such previous work by examining the mechanism and extent of end-organ disease attainable via γδ T cells and/or non-αβ T cell-dependent mechanisms, assessing two prototypical lupus lesions, renal and skin disease, in TCR α?/? MRL mice that possessed either functional or defective Fas antigen (Fas + or lpr). Observed to 1 year of age, TCR α?/? MRL mice developed disease characterized by increased mortality, overt renal disease and skin lesions. While delayed in onset and/or reduced in severity compared with TCR α+/+ MRL/lpr animals, renal and skin lesions in αβ T cell-deficient animals were clearly increased in severity compared with age-matched control non-autoimmune mice. In contrast to TCR α+/+ MRL mice, whose disease reflected pan-isotype immune complex deposition with significant complement fixation, renal disease in TCR α?/? MRL animals reflected predominantly IgG1 immune complex deposition, with poor complement fixation. Thus, this study demonstrates conclusively that non-αβ T cell-dependent mechanisms can induce renal and skin injury in murine lupus, but at least in the kidney, only via humoral autoimmunity of a relatively non-pathological isotype which results in the delayed onset of end-organ damage.     

Use of genetic knockouts to modulate disease expression in a murine model of lupus,MRL/Ipr mice

MRL-MPJ Fas^1pr (MRL/lpr) mice are a prototypic murine model for lupus characterized by an accelerated autoimmune syndrome. Disease begins as early as 8-wk-of-age in these animals with polyclonal B cell activation and elevated levels of serum IgM. By 12 to 16-wk-or-age MRL/lpr mice begin to produce a variety of autoantibodies including anti-dsDNA and anti-ss-DNA antibodies. From 16 to 24 wk, MRL/lpr mice develop proliferative immune complex mediated glomerulonephritis, vasculitis, arthritis, and massive lymphadenopathy that results in ren al failure and death in 50% of the mice by 24-wk-of-age. This review will discuss several different genetic knockout experimental approaches used to study disease expression in MRL/lpr mice including various approaches in our laboratory aimed at autoantibody (Ab) production and inflammatory mediators.     

Immunoregulation of SLE-like disease by the IL-1 receptor: Disease modifying activity on BDF1 hybrid mice and MRL autoimmune mice

Due to the immunopharmacological profile of the recombinant IL-1 receptor (IL-1-R) and its potential to modulate biological activity in various inflammatory autoimmune disease models, we further elucidated its disease modifying activity on the development of a systemic lupus erythematosus (SLE)-like disease in BDF1 hybrid mice and in MRL/lpr autoimmune mice. Treatment of BDF1 mice with the IL-1-R during the induction phase resulted in a strong inhibition of the development of a glomerulonephritis, prolonged the survival time and improved the survival rate. Even a therapeutic effect was demonstrated when this receptor was given after the appearance of clinical symptoms. Treating MRL/lpr mice, which develop spontaneously a SLE-like disease, with the IL-1-R resulted in an inhibition of the developing glomerulonephritis and splenomegaly, in a reduction of swollen lymph nodes and in a decrease of autoantibody formation. Even in the established autoimmune disease of MRL/1pr mice the IL-1-R reduced proteinuria, the levels of autoantibodies and also improved the survival rate.     

The NOD mouse as a model of SLE.

In addition to developing a high incidence of type 1 diabetes caused by a specific autoimmune response against pancreatic beta cells in the islets of Langerhans, NOD mice also demonstrate spontaneous autoimmunity to other targets including the thymus, adrenal gland, salivary glands, thyroid, testis, nuclear components and red blood cells. Moreover, treatment of pre-diabetic NOD mice with an intravenous dose of heat killed Mycobacterium bovis (M. bovis; bacillus Calmette-Guèrin (BCG)) protects them from developing type 1 diabetes, but instead precipitates an autoimmune rheumatic disease similar to systemic lupus erythematosus (SLE), characterised by accelerated and increased incidence of haemolytic anaemia (HA), anti-nuclear autoantibody (ANA) production, exacerbation of sialadenitis, and the appearance of immune complex-mediated glomerulonephritis (GN). The reciprocal switching between the two phenotypes by a single environmental trigger (mycobacterial exposure) raised the possibility that genetic susceptibility for type 1 diabetes and SLE may be conferred by a single collection of genes in the NOD mouse. This review will focus on the genetic components predisposing NOD mice to SLE induced by BCG treatment and compare them to previously determined diabetes susceptibility genes in this strain and SLE susceptibility genes in the BXSB, MRL and the New Zealand mouse strains.     

Successful treatment of autoimmune manifestations in MRL/l and MRL/n mice using total lymphoid irradiation (TLI)

The autoimmune manifestations of MRL-+/+ (MRL/n) and MRL/Mp-lpr/lpr (MRL/l) murine models of systemic lupus erythematosus (SLE) were successfully reversed following total lymphoid irradiation (TLI) therapy consisting of 8-12 daily fractions of 200 rad. Following radiotherapy the characteristic lymphadenopathy of MRL/l disappeared, proteinuria was 334 mg% compared to a peak of 2272 mg% in untreated controls, and the median survival time was prolonged to 423 days compared to 214 days in untreated mice. The albuminuria of TLI-treated MRL/n mice was 194 mg% compared to 1180 mg% in untreated controls. The survival of treated MRL/n mice was prolonged to a median of 389 as compared to 190 days in untreated controls. The effect of TLI on antiDNA antibodies in both MRL/l and MRL/n was less remarkable. However, the antiDNA activity reached normal levels in most long-living mice. The most impressive finding was complete reversal and/or prevention of the SLE-like glomerulonephritis in MRL/l mice as documented by light and electron microscopy. Immunomanipulation with TLI should be further evaluated as a possible treatment modality in intractable human autoimmune disorders.     

The NOD Mouse as a Model of SLE

In addition to developing a high incidence of type 1 diabetes caused by a specific autoimmune response against pancreatic β cells in the islets of Langerhans, NOD mice also demonstrate spontaneous autoimmunity to other targets including the thymus, adrenal gland, salivary glands, thyroid, testis, nuclear components and red blood cells. Moreover, treatment of pre-diabetic NOD mice with an intravenous dose of heat killed Mycobacterium bovis (M. bovis; bacillus Calmette-Guerin (BCG)) protects them from developing type 1 diabetes, but instead precipitates an autoimmune rheumatic disease similar to systemic lupus erythematosus (SLE), characterised by accelerated and increased incidence of haemolytic anaemia (HA), anti-nuclear autoantibody (ANA) production, exacerbation of sialadenitis, and the appearance of immune complex-mediated glomerulonephritis (GN). The reciprocal switching between the two phenotypes by a single environmental trigger (mycobacterial exposure) raised the possibility that genetic susceptibility for type 1 diabetes and SLE may be conferred by a single collection of genes in the NOD mouse. This review will focus on the genetic components predisposing NOD mice to SLE induced by BCG treatment and compare them to previously determined diabetes susceptibility genes in this strain and SLE susceptibility genes in the BXSB, MRL and the New Zealand mouse strains