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The prevalence of scleroderma-type capillary abnormalities, as observed by in vivo microscopy, was determined in 173 patients from three rheumatic disease centers. The patients had a variety of connective tissue diseases: scleroderma (systemic sclerosis) 50; systemic lupus erythematosus 60, mixed connective tissue disease 26; Raynaud's disease 11; other rheumatic disorders 26. Enlarged and deformed capillary loops surrounded by relatively avascular areas, most prominently in the nailfolds, were found in 82% of patients with scleroderma and in 54% with mixed connective tissue disease. The rarity of these abnormalities in systemic lupus erythematosus (2%) despite the presence of Raynaud's phenomenon suggests that they are not an expression of the Raynaud's phenomenon frequently associated with scleroderma and mixed connective tissue disease. The single patient with Raynaud's disease and sclerodermatype capillary changes subsequently developed scleroderma.

Objective. To determine the long-term clinical and immunologic outcomes in a well-characterized cohort of 47 patients with mixed connective tissue disease (MCTD), including reactivity with U small nuclear RNP (snRNP) polypeptides.Methods. Patients were followed up over a period of 3-29 years with immunogenetic and systematic clinical and serologic analysis. Sera were analyzed for reactivity with snRNP polypeptides U1-70 kd, A, C, B/B , and D, for anti-U1 RNA, and for anticardiolipin antibodies (aCL).Results. The typical core clinical features of MCTD tended to develop over time; features of inflammation as well as Raynaud's phenomenon and esophageal hypomotility diminished, while pulmonary hypertension, pulmonary dysfunction, and central nervous system disease persisted, following treatment. A favorable outcome was observed in 62% of patients; 38% had continued active disease or had died, with death associated with pulmonary hypertension and aCL. All patients had autoantibodies to the U1-70 kd polypeptide of snRNP, and most were positive for anti-U1 RNA. An orderly progression of intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, as was the novel finding of "epitope contraction" followed by disappearance of anti-snRNP autoantibodies during prolonged remission.Conclusion. These patients demonstrated the typical immunogenetic, clinical, and serologic findings of MCTD, and the condition rarely evolved into systemic lupus erythematosus or systemic sclerosis. The majority of patients had favorable outcomes, with pulmonary hypertension being the most frequent disease-associated cause of death. Intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, followed by "epitope contraction" and ultimate disappearance of anti-snRNP autoantibodies during prolonged disease remission.

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Extractable nuclear antigen contains ribo-nuclease-sensitive (ribonucleoprotein) and ribonuclease-resistant (Sm) components. To determine the diagnostic usefulness of antibodies to these antigens, a multicenter study was undertaken in which serums were analyzed for these antibodies and the findings compared with clinical and other laboratory characteristics of the patients. Of 100 patients with hemagglutinating antibodies to ribonuclease-sensitive extractable nuclear antigen, and only the same antibodies by immunodiffusion, 74 per cent had typical features of mixed connective-tissue disease; 12 features of systemic lupus erythematosus, eight those of scleroderma and six an undifferentiated mild connective-tissue disease. Of 27 patients with hemagglutinating antibodies to ribonuclease-resistant extractable nuclear antigen (and Sm antibodies by immunodiffusion), 85 per cent had typical systemic lupus. Thus, antibodies to nuclear ribonucleoprotein and Sm are of diagnostic use; if the serum contains only ribonucleoprotein antibody in high titer, it is likely that the patient has mixed connective-tissue disease.

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Spontaneous autoimmune thyroiditis (SAT) is an organ-specific autoimmune disease characterized by chronic inflammation of the thyroid by T and B lymphocytes. To investigate the roles of Th1 and Th2 cytokines in the pathogenesis of SAT, IFN-γ−/− and IL-4−/− NOD.H-2h4 mice were generated. IL-4−/− mice developed lymphocytic SAT (L-SAT) comparable to that of wild-type (WT) mice. They produced little anti-mouse thyroglobulin (MTg) IgG1, but had levels of anti-MTg IgG2b comparable to WT mice. Compared with WT mice, IFN-γ−/− mice produced significantly less anti-MTg IgG1 and IgG2b. Absence of IFN-γ resulted in abnormal proliferation of thyroid epithelial cells with minimal lymphocyte infiltration. Thyroids of IFN-γ−/− mice had markedly reduced B lymphocyte chemoattractant expression, B cell and plasma cell infiltration, and decreased MHC class II expression on thyrocytes compared with WT mice. Adoptive transfer of WT splenocytes to IFN-γ−/− mice restored the capacity to develop typical L-SAT, enhanced anti-MTg IgG1 and IgG2b production, up-regulated MHC class II expression on thyrocytes and decreased thyrocyte proliferation. These results suggest that IFN-γ plays a dual role in the development of SAT. IFN-γ is required for development of L-SAT, and it also functions to inhibit thyroid epithelial cell proliferation.