Background. SLE is characterized by plasmacytosis-mediated hypergammaglobulinemia and autoantibody production, which lead to glomerulonephritis. In SLE patients and mouse models, autoantibodies are present long before clinical manifestations. Moreover, our data indicate that progression from autoimmunity to disease is accompanied by translocation of autoantibody-producing plasma cells (PCs) from the spleen to the bone marrow and eventually into inflamed kidneys. PC populations include long-lived PCs, which are relatively resistant to immunosuppression (Nat Med. 14:748). We found that during aging and plasmacytosis, PCs are an important source of IL-10, which has immunosuppressive effects, including neutrophil inhibition and promotion of Treg activity (JACI 137:1487; Front Immunol. 10:1183, Fig. A2-1).

Objectives. (i) Provide a comprehensive picture of changes of autoreactive B cell/PC populations during disease progression in murine SLE. (ii) Explore the role of B lineage-derived IL-10 during different stages of SLE development.

Work program. Track the progression and tissue localization of (autoreactive) B cell/PC populations and changes in their antibody isotypes in lupus-prone mice; evaluate the correlations with neutrophil and Treg activity and pathogenesis. For this purpose, IL-10+ cells will be identified by use of IL-10-reporter mice. In the functional studies, IL-10 will be blocked using antibodies at various time points, and its consequences on Treg and neutrophil functions and disease will be investigated. Because disease develops in ageing in lupus-prone mice, adoptive cell transfer from old/diseased to young/healthy lupus-prone mice will be employed to study the impact of B cell populations on disease progression together with A3.