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Atherosclerosis is accelerated in people with systemic lupus erythematosus, and the presence of dysfunctional, pro-inflammatory high-density lipoproteins is a marker of increased risk. We developed a mouse model of multigenic lupus exposed to environmental factors known to accelerate atherosclerosis in humans – high-fat diet with or without injections of the adipokine leptin. BWF1 mice were the lupus-prone model; BALB/c were non-autoimmune controls. High-fat diet increased total serum cholesterol in both strains. In BALB/c mice, non-high-density lipoprotein cholesterol levels increased; they did not develop atherosclerosis. In contrast, BWF1 mice on high-fat diets developed increased quantities of high-density lipoproteins as well as elevated high-density lipoprotein scores, indicating pro-inflammatory high-density lipoproteins; they also developed atherosclerosis. In the lupus-prone strain, addition of leptin increased pro-inflammatory high-density lipoprotein scores and atherosclerosis, and accelerated proteinuria. These data suggest that environmental factors associated with obesity and metabolic syndrome can accelerate atherosclerosis and disease in a lupus-prone background.

METHODS.We hybridized 34 and 51 ICL patients' sera to a 9,000-human-proteome array and to a 128-known-autoantigen array, respectively. Using a flow-based method, we characterized the presence of anti-lymphocyte Abs in the whole cohort of 72 patients, as well as the Ab functional capability of inducing Ab-dependent cell-mediated cytotoxicity (ADCC), complement deposition, and complement-dependent cytotoxicity (CDC). We tested ex vivo the activation of the classical complement pathway on ICL CD4 + T cells. RESULTS.All ICL patients had a multitude of autoantibodies mostly directed against private (not shared) targets and unrelated quantitatively or qualitatively to the patients' autoimmune disease status. The targets included lymphocyte intracellular and membrane antigens, confirmed by the detection by flow of IgM and IgG (mostly IgG 1 and IgG 4 ) anti-CD4 + cell Abs in 50% of the patients, with half of these cases triggering lysis of CD4 + T cells. We also detected in vivo classical complement activation on CD4 + T cells in 14% of the whole cohort. CONCLUSION.Our data demonstrate that a high prevalence of autoantibodies in ICL, some of which are specific for CD4 + T cells, may contribute to pathogenesis, and may represent a potentially novel therapeutic target. TRIAL REGISTRATION. ClinicalTrials.gov NCT00867269.

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Background People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy. Severe mycobacterial-IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). Objective To evaluate the pathophysiologic similarities between mycobacterial-IRIS and HLH and identify clinical and immune predictors of mycobacterial-IRIS severity. Methods HLH-criteria were applied to a longitudinal cohort of 80-patients with HIV (CD4 < 100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH-criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (Non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell immune phenotypes were assessed at baseline and IRIS-equivalent timepoints. Results HLH-IRIS patients required corticosteroids more frequently (OR 21.5 [CI95% 5.6-114.8]) and for longer duration (21.2-weeks [CI95% 10.7-31.7]) than those not meeting HLH-criteria. Utilizing decision tree analyses, hemoglobin <9.2  g/dL was the best predictor of HLH-IRIS before antiretroviral treatment, whereas ferritin and immune markers (CXCL-9, sCD25) were most diagnostic for HLH at onset of IRIS. At the IRIS-timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T-cells along with greater production of IFNγ-IL18 axis biomarkers compared to both IRIS and Non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. Conclusion Severe mycobacterial-IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS or FIRIS). Hemoglobin, ferritin, CXCL-9, and sCD25 identify this high-risk population and may improve risk stratification and therapeutic strategies for mycobacterial-IRIS.