Although overall mortality was higher in cART-treated HIV-infected adults, a subgroup with especially good prognosis can be identified, and these characteristics should be targeted for long-term treatment.

Objective. Cytotoxic T lymphocyte-mediated killing using granzyme B has recently been proposed to be a preferential and selective source of autoantigens in systemic autoimmune diseases, including systemic lupus erythematosus (SLE), while other reports have indicated that cytolytic activity in SLE patients was decreased. The aim of this study was to examine the phenotypic and functional status of the CD8؉ T cells in SLE patients.Methods. Phenotype analysis of CD8؉ T cells was carried out using flow cytometry. The cytotoxic potential of CD8؉ T cells and its consequences were examined in redirected-killing experiments. SLE patients with quiescent disease (n ‫؍‬ 41) were compared with SLE patients with active disease (n ‫؍‬ 20), normal individuals (n ‫؍‬ 36), and control patients with vasculitis (n ‫؍‬ 14). Cytotoxic CD8؉ T cell differentiation was examined by coculture with differentiated dendritic cells (DCs) in the presence of SLE patient sera.Results. Patients with disease flares were characterized by higher proportions of perforin-and/or granzyme B-positive lymphocytes with a differentiated effector phenotype (CCR7؊ and CD45RA؉). The frequency of these cells in peripheral blood correlated with clinical disease activity as assessed by the SLE Disease Activity Index. These cells generated high amounts of soluble nucleosomes as well as granzyme B-dependent unique autoantigen fragments. Finally, the activation of DCs with serum from a patient with active lupus induced granzyme B expression in CD8؉ T lymphocytes.Conclusion. DCs generated in the presence of sera from SLE patients with active disease could promote the differentiation of CD8؉ effector T lymphocytes that are fully functional and able to generate SLE autoantigens. Our data disclose a new and pivotal role of activated CD8؉ T lymphocytes in SLE pathogenesis.

Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by the involvement of multiple organs and an immune response against nuclear components. Although its pathogenesis remains poorly understood, type I interferon (IFN) and CD40 ligand (CD154) are known to contribute. Because platelets are involved in inflammatory processes and represent a major reservoir of CD154, we hypothesized that they participate in SLE pathogenesis. Here, we have shown that in SLE patients, platelets were activated by circulating immune complexes composed of autoantibodies bound to self-antigens through an Fc-gamma receptor IIa (CD32)-dependent mechanism. Further, platelet activation correlated with severity of the disease and activated platelets formed aggregates with antigen-presenting cells, including monocytes and plasmacytoid dendritic cells. In vitro, activated platelets enhanced IFN-alpha secretion by immune complex-stimulated plasmacytoid dendritic cells through a CD154-CD40 interaction. Finally, in lupus-prone mice, depletion of platelets or administration of the P2Y(12) receptor antagonist (clopidogrel) improved all measures of disease and overall survival; transfusion of activated platelets worsened the disease course. Together, these data identify platelet activation as an important contributor to SLE pathogenesis and suggest that this process and its sequelae may provide a new therapeutic target.

Summary Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS+ blood Tfh cells in SLE. OX40 signals promoted naïve and memory CD4+ T cells to express multiple Tfh cell molecules, and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.