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It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)-mediated arthritis depend on Fcgamma receptor type III (FcgammaRIII). Local adenoviral overexpression of interferon-gamma (IFNgamma) in the knee joint prior to onset of IC-mediated arthritis aggravated severe cartilage destruction. In FcgammaRI(-/-) mice, however, chondrocyte death was not enhanced by IFNgamma, whereas matrix metalloproteinase (MMP)-mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating FcgammaRIII in the latter process. We undertook this study to determine the role of FcgammaRIII in joint inflammation and severe cartilage destruction in IFNgamma-stimulated IC-mediated arthritis, using FcgammaRIII(-/-) mice.FcgammaRIII(-/-) and wild-type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFNgamma (AdIFNgamma) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC-mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMP-mediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and FcgammaR expression levels were determined in synovial washouts and synovium, respectively.Injection of AdIFNgamma in naive knee joints markedly increased levels of messenger RNA for FcgammaRI, FcgammaRII, and FcgammaRIII. Upon IFNgamma overexpression prior to induction of IC-mediated arthritis, joint inflammation was similar in FcgammaRIII(-/-) and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1alpha. Furthermore, IFNgamma induced 2-fold and 3-fold increases in chondrocyte death in WT controls and FcgammaRIII(-/-) mice, respectively. Notably, VDIPEN expression also remained high in FcgammaRIII(-/-) mice.IFNgamma bypasses the dependence on FcgammaRIII in the development of IC-mediated arthritis. Furthermore, both FcgammaRI and FcgammaRIII can mediate MMP-dependent cartilage matrix destruction.

The F1 hybrid of New Zealand black and New Zealand white mice--the NZB/NZW mouse--spontaneously develops a disease similar to human systemic lupus erythematous, characterized by impaired cell-mediated and enhanced humoral immune responses, development of antibodies to nuclear antigens, and immune complex glomerulonephritis. Because there is experimental evidence that prostaglandin E1 (PGE1) can enhance T-cell function and cell-mediated responses and suppress B-cell activity, NZB/NZW mice were treated with 200 microgram PGE1 subcutaneously once or twice daily from 6 weeks of age. PGE1 treatment of female and male mice prevents giomerular deposition of immunoglobulins and complement (monitored by immunofluorescence), and development of the proliferative glomerulonephritis (determined by light and electron microscopy) characteristic of untreated NZB/NZW mice. After 1 year of treatment, 18 of 19 female mice survived, whereas only 2 of 19 untreated control mice were alive. Male mice treated with 200 microgram PGE1 daily were also protected: 9 of 11 versus 2 of 9 untreated mice were alive at 65 weeks. PGE1 treatment did not prevent development of antibodies to nuclear material in any of the treated groups.

Young, syngeneic thymocytes and spleen cells were administered to F1 hybrids of New Zealand Black by New Zealand White (NZB/W) mice beginning at 3 weeks of age and were continuted at 2-week intervals for 8 to 9 months. The development of autoimmunity as assessed by measuring the incidence and level of anti-DNA antibody, the degree of renal involvement, and the survival of recipient mice was evaluated and compared to a control group of animals. No significant differences were noted in these parameters in mice receiving cell transfers as compared to the control group. Therefore, in contrast to other reports, these results suggest that the transfer of young thymus or spleen cells into aging NZB/W mice fails to influence immunoregulation and the subsequent development of autoimmunity.

The avidity of antibodies to DNA in the sera of 8 patients with SLE was determined by saturation analysis and Scatchard plots. Five of the patients had severe lupus nephritis; the other 3 had relatively mild or no kidney disease. The Scatchard plots revealed components with high relative avidity in the patients with severe nephritis (K values 4.4-10.4 X 10(5) M-1 for nDNA), compared with the patients who had mild or no kidney disease (K values 0.3-1.8 X 10(5) M-1 for nDNA). Avidity measurements may be helpful in the evaluation and treatment of patients with SLE.

Urticaria, angioedema, and arthritis are cardinal features of hypocomplementemic urticarial vasculitis syndrome (HUVS). Considered to be an immune complex-mediated disorder, HUVS has been differentiated from systemic lupus erythematosus (SLE), based on its clinical manifestations and the C1q precipitin (C1q-p) reaction, which is manifested as gel precipitation of C1q by a small percentage of HUVS IgG molecules. This phenomenon has been attributed to an Fc region abnormality, and the responsible IgG molecules are said to possess C1q-p activity. We purified IgG from 4 HUVS patients and confirmed that HUVS IgG contains C1q binding activity. F(ab')2 fragments from these patients also bound to C1q, as measured by 2 different C1q binding methods at physiologic ionic strength; HUVS IgG Fc fragments did not bind to C1q. Preincubation of HUVS F(ab')2 fragments with antibody to human F(ab')2 prevented subsequent binding to C1q. We conclude that IgG antibodies to C1q are present in HUVS serum, and it is likely that these antibodies are C1q-p. Because the clinical manifestations of HUVS and the presence of anti-C1q antibodies have been described in patients with SLE, our findings support the concept that HUVS is an autoimmune syndrome related to SLE.

NZB/W F1 female mice were treated from 20 weeks of age with ribavirin (a broad spectrum antiviral drug), cyclophosphamide, or saline. Treatment with ribavirin (250 mg/kg twice weekly) prolonged survival from 9.8 to 18.5 months, reduced anti-DNA antibodies, and prevented proteinuria. Ability of ribavirin to prolong survival was dose related when given on a twice weekly schedule. However, daily ribavirin (25 mg/kg/day) was as effective as higher intermittent doses. Optimal ribavirin therapy was equal to cyclophosphamide treatment with regard to prolongation of survival. Ribavirin treatment did not significantly alter the body weight, hematocrit, WBC count, serum immunoglobulins, or Coombs reactivity. No alterations in either cellular or humoral immune responses were noted in NZB/W F1 or BALB/c mice treated for prolonged periods with ribavirin. The impressive therapeutic response to a broad spectrum antiviral agent seen in mice already manifesting immune complex nephritis provides a new therapeutic approach to the treatment of autoimmunity.

Seventeen patients with characteristic disseminated gonococcal arthritis-dermatitis syndrome were studied for the presence of immune complexes, and circulating gonococcal antigen and antibody. The two immune complex techniques, monoclonal rheumatoid factor assay and cryoglobulin survey, did not reveal any consistent abnormalities. Complement levels (CH50, C″3, C″4) were not consistent with peripheral consumption except in 2 patients with coinciding systemic lupus erythematosus. Gonococcal antibody was detected in 47% of patients when they presented with the syndrome. However, gonococcal antigen was not found in either serum or synovial fluid. These results do not support the hypothesis that circulating immune complexes are involved in the pathogenesis of disseminated gonococcal arthritis-dermatitis syndrome.

NZB/NZW F1 female mice received levamisole in an attempt to increase suppressor T cell function. Responses varied with dosage of drug and age of mice. When treatment with 25 microgram/gm doses (intermittent or daily) was begun at 12 weeks of age, nephritis was accelerated in spite of transient reduction of anti-DNA antibodies. When treatment was begun at 4 weeks, or when doses of 250 microgram/gm were given, no clinical effects were observed. In the mice with accelerated disease, delayed hypersensitivity and antibody responses to sheep erythrocytes increased; antibody responses to pneumococcal polysaccharide were unaffected. It is possible that some increased immune responses associated with levamisole are undesirable in murine lupus.

Regular administration of cyclophosphamide to NZB/NZW female mice effectively protects against the nephritis that is thought to be a model for human SLE nephritis. Reductions in serologic, histologic, and immunofluorescent parameters of the disease are correlated. Intermittent as well as continuous administration of the drug is effective without the development of leukopenia. Possible mechanisms of drug action and a modified approach to therapy of immune complex disease are discussed.

Azathioprine, cyclophosphamide, and methylprednisolone given individually to NZB/NZW mice retard the development of autoimmune nephritis and prolong survival in these mice. Administration of the combination of all three drugs is superior to one or two drug regimens. In the present study the kidneys of mice treated with all single, double, and triple drug regimens were compared for the degree of deposition of immunoglobulin and complement. The triple drug regimen significantly reduced overall deposition of immunoglobulin and complement compared with any other regimen. Complement and gamma2 were significantly reduced by triple drug therapy compared with any other regimen. The triple drug regimen reduced gamma1 compared with untreated and double drug treated mice. The single, double, and triple drug regimens significantly reduced gammaM deposition to about the same degree. Deposition of gammaA was not significantly reduced by any regimen. Circulating levels of these immunoglobulin classes were not reduced, a fact suggesting that the reduction in autoimmune nephritis resulting from triple drug therapy is associated with superior reduction in immune complex deposition rather than with generalized, non-specific immunodepression.

An experimental model in mice was investigated to test the hypothesis that the immunohistochemical findings in skin lesions of human systemic lupus erythematosus (SLE) might be due to circulating antibody reacting with nuclear antigens. Mice were immunized with ultraviolet (UV)-irradiated DNA to produce high titers of circulating antibody to a DNA photoproduct, thymine dimer. These immunized mice were then whole-body irradiated with UV, a procedure which caused thymine dimer formation in DNA of skin cells and subsequent release of thymine dimers extracellularly during spontaneous repair of the photochemically damaged DNA. In immunized irradiated mice, immunofluorescent studies showed fixation of mouse Ig and complement in the form of finely stippled and large lumpy deposits in the dermal—epidermal areas and in nuclei of epidermal cells. These findings were morphologically quite similar to those seen in human SLE skin lesions. These immunohistochemical lesions in mice were not observed in mice receiving only immunization or only irradiation. These and other data lend support to the immune complex theory of pathogenesis of SLE skin lesions.

Large antigen-antibody complexes that are selectively removed from circulation were not selectively removed when injected into the knees of a normal rabbit. The subsequent selective removal of the complexes depended on the influx of neutrophils. Nevertheless, macrophages of the normal synovial lining were able to phagocytize some immune complexes. When antigen and antibodies were administered separately by intravenous or intraarticular routes, little or no soluble complexes were found in synovial fluid, and most of the antigen-antibody union was thought to occur in the synovial tissue.