At least 20 insulin-dependent diabetes (Idd) loci modify the progression of autoimmune diabetes in the NOD mouse, an animal model of human type 1 diabetes. The NOD.c3c4 congenic mouse, which has multiple B6- and B10-derived Idd-resistant alleles on chromosomes 3 and 4, respectively, is completely protected from autoimmune diabetes. We demonstrate in this study, however, that NOD.c3c4 mice develop a novel spontaneous and fatal autoimmune polycystic biliary tract disease, with lymphocytic peribiliary infiltrates and autoantibodies. Strains having a subset of the Idd-resistant alleles present in the NOD.c3c4 strain show component phenotypes of the liver disease: NOD mice with B6 resistance alleles only on chromosome 3 have lymphocytic liver infiltration without autoantibody formation, while NOD mice with B10 resistance alleles only on chromosome 4 show autoantibody formation without liver infiltration. The liver disease is transferable to naive NOD.c3c4 recipients using splenocytes from affected NOD.c3c4 mice, demonstrating an autoimmune etiology. Thus, substitution of non-NOD genetic intervals into the NOD strain can prevent diabetes, but in turn cause an entirely different autoimmune syndrome, a finding consistent with a generalized failure of self-tolerance in the NOD genetic background. The complex clinical phenotypes in human autoimmune conditions may be similarly resolved into largely overlapping biochemical pathways that are then modified, potentially by alleles at a few key chromosomal regions, to produce specific autoimmune syndromes.

Objective-To investigate the incidence of retinopathy in systemic lupus erythematosus (SLE) and to clarify its significance in relation to other clinical manifestations. Methods-A cross sectional study on lupus retinopathy was made in 69 patients with SLE. One expert ophthalmologist examined the ocular fundi of the lupus patients without any information of their disease state. Clinical and laboratory findings in the patients with retinopathy and those without were compared. Results-Retinopathy was found in 7/69 (10%) patients. The findings included haemorrhages, vasculitis, cotton wool spots, and hard exudates, all of which were considered to reflect vascular damage. Retinopathy was found to be associated with the presence of anticardiolipin antibody (p<0.05) and with central nervous system lupus (p<0.01). The patients with retinopathy had higher levels of serum creatinine than the patients without retinopathy (p<0.01). The disease activity of lupus, as assessed by the maximum SLE disease activity index (SLEDAI) score of the patients, was also significantly higher in the patients with retinopathy (p<0.03). Conclusion-Incidence of retinopathy in SLE was similar to that in previous reports and it may reflect tissue microangiopathy, particularly associated with vasculitis or anticardiolipin antibodies, or both.

The objective of this study was to define prospectively the early development of corticosteroid-induced osteonecrosis of femoral head (ONF) in patients with systemic lupus erythematosus (SLE) and to identify the association of initial steroid treatment with the development of early (silent) ONE Forty-five patients who were newly diagnosed as having SLE and required 40 mg/day or more prednisolone were enrolled. To detect silent ONF, examinations using magnetic resonance imaging (MRI) were done three months after starting steroid therapy, followed by every year's MRI and plain radiography for over five years. Clinical and laboratory data were compared between silent ONF and non-ONF groups. Of 45 patients, 15 (33%) developed silent ONF and five (11%) symptomatic ONE It was of interest that MRI detected silent ONF very early (by three months) in 14 patients (93%). It should be noted that pulse therapy with 1000 mg/day methylprednisolone was found to be done very frequently (13 of 15, 87%) in the silent ONF group compared to non-ONF group (11 of 30, 37%) (P < 0.01) although other clinical features were not significantly different between both groups. High dose corticosteroids caused elevation of serum levels of total cholesterol, albumin, and leukocyte count in most of patients. The degree of elevation of those parameters at one or three months was more prominent in the silent ONF group. In particular, the change ratio of total cholesterol at one month was outstanding in the silent ONF group compared to non-ONF group (0.551 versus 0.374, P < 0.05). In conclusion, pathological ONF develops very early in one-third of SLE patients who received high dose corticosteroids and steroid pulse therapy could be a significant risk factor. An abrupt elevation of serum total cholesterol and/or sensitivity to steroids seem to be associated with the pathogenesis of ONF.

Objective. Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus.Methods. We crossed gene-targeted IRF5-deficient (IRF5 ؊/؊ ) mice with MRL/MpJ-lpr/lpr (MRL/ lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function.Results. IRF5 ؊/؊ MRL/lpr mice survived longer than control IRF5 ؉/؉ MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLErelated nuclear antigens were lower in IRF5 ؊/؊ MRL/lpr mouse serum, and numbers of activated CD4؉ T cells were reduced in the spleen. Splenic DCs from IRF5 ؊/؊ MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-␣ production in response to CpG was also decreased. Conclusion.Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients.

Objective. Platelet endothelial cell adhesion molecule 1 (PECAM-1; CD31) is a member of the immunoglobulin superfamily that is expressed in platelets, leukocytes, and endothelial cells. PECAM-1 has been shown to play a role in transendothelial migration of leukocytes and contains immunoreceptor tyrosinebased inhibitory motifs in its cytoplasmic tail and inhibits cellular responses. We examined the role of PECAM-1 in the development of collagen-induced arthritis (CIA).Methods. CIA was induced in PECAM-1-deficient DBA/1 mice. The incidence of arthritis and the arthritis index were examined. Anti-type II collagen (anti-CII) antibody levels and interferon-␥ (IFN␥) production by lymph node cells and spleen cells were determined. Lymphocytes from arthritic PECAM-1-deficient and wild-type mice were labeled with dye, transferred to arthritic PECAM-1 ؉/؊ mice, and cell migration to inflamed joints was examined.Results. PECAM-1-deficient mice showed accelerated onset of arthritis and increased severity only during the early phase. Anti-CII antibody levels were also increased during the early phase. IFN␥ production by lymph node cells and spleen cells from PECAM-1-deficient mice in response to CII was higher than that in wild-type mice. Lymphocytes from arthritic PECAM-1-deficient mice showed accelerated migration to inflamed joints, but not lymph nodes or spleen. The development of anti-CII antibody-induced arthritis was similar in PECAM-1-deficient and wild-type mice.Conclusion. These results indicate that PECAM-1 negatively regulates humoral and cell-mediated immune responses and lymphocyte migration into joints and, consequently, the development of CIA. In addition, the role of PECAM-1 in the transendothelial migration of leukocytes appears to be redundant in this model.

Although osteonecrosis of femoral head (ONF) is one of the serious complications in systemic lupus erythematosus (SLE) associated with corticosteroid therapy, there has been few trials of prevention of ONF described. We aimed to prevent ONF in steroid-treated SLE patients using anticoagulant, warfarin, conducting a multicenter prospective study. Sixty newly diagnosed SLE patients requiring 40 mg/day or more prednisolone were alternately assigned to either of two groups; a warfarin group and a control one. Warfarin (1 to approximately 5 mg/day) was started together with the beginning of steroid therapy and continued at least for three months. Patients were observed for the development of silent ONF by magnetic resonance imaging (MRI) and symptomatic ONF by plain radiography for over five years. The warfarin group consisted of 31 patients (62 hips) and the control one 29 patients (58 hips). Silent ONF developed in 13 hips (21%) and 19 hips (33%) in the warfarin group and the control group, respectively (P = 0.13). On the other hand, warfarin tended to prevent symptomatic ONF; only three hips of 62 (4.8 %) in the warfarin group and eight hips of 58 (14%) in the control group (P = 0.08) developed silent ONF. It was also found that silent ONF developed, if it did, very early; within three months in 16 of 18 patients (89%). Among risk factors for silent ONF, steroid pulse therapy was most outstanding and it seemed to overcome the effect of warfarin. Taken together, for the time being, anti-coagulant therapy, if not significantly sufficient, may be of use for the prevention of steroid-induced ONF in SLE. We consider that this study added to important evidence for the pathogenesis and prevention of ONF.

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