The role of IL-10 and TGF-beta1 secretion by B lymphocytes in lupus prone mice
Zusammenfassung der Projektergebnisse
The cellular mechanisms that promote and regulate autoimmune disease have been the subject of intense interest and study. B cell targeted therapies ameliorate disease severity in murine and several human autoimmune disorders, and this has focused attention on B cells. In addition to classical antibody-mediated mechanisms of pathogenesis, antibody-independent roles of B cells have been increasingly recognized, both from genetic studies as well as from the disconnect between clinical responses and the fall in autoantibody titers often seen in patients. As a result, antigen presentation by B cells and direct T cell-mediated tissue damage have come to the forefront of disease pathogenesis concepts. However, recent studies suggested that native B cells might also suppress disease in mouse models of systemic lupus erythematosus by secreting the anti-inflammatory cytokine IL-10. Hence, non-specific B cell directed therapies might be a double-edged sword. The role of cell type widely considered to be most important for initiating T cell responses in infections, dendritic cells (DCs), has not been evaluated in spontaneous, systemic autoimmunity. It could be assumed that they are the primary antigen presenting cell to induce T cell autoimmunity. However, depending on their activation state DCs might also support peripheral T cell self-tolerance. By specifically inactivating the gene encoding for IL-10 in B cells in lupus-prone mice we demonstrate that IL-10 release by endogenous, unmanipulated B cells does not restrain disease. Further, putative regulatory B cell subsets such as CD1dhiCD5+ and CD21hiCD23hi B cells were not enriched in Il10 transcription. Thus, the pathogenic effects of B cells were not detectably counterbalanced by their IL-10 dependent regulatory functions. In lupus-prone mice genetically rendered deficient for DCs disease was greatly ameliorated, in particular organ inflammation. DCs were crucial for the expansion and differentiation of T cells but, surprisingly, not required for their initial activation. Correspondingly, kidney interstitial infiltrates developed in the absence of DCs, but failed to progress. These findings reveal that DCs operate in unanticipated ways in murine lupus. Taken together, we show that the importance of regulatory B cell functions might have been overestimated in lupus and validate DCs as a potential therapeutic target.
Projektbezogene Publikationen (Auswahl)
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(2010). Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33, 967-978
Teichmann, L.L., Ols, M.L., Kashgarian, M., Reizis, B., Kaplan, D.H., and Shlomchik, M.J.
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(2011). An acquired defect in IgG-dependent phagocytosis explains the impairment in antibody- mediated cellular depletion in Lupus. J Immunol 187, 3888-3894
Ahuja, A., Teichmann, L.L., Wang, H., Dunn, R., Kehry, M.R., and Shlomchik, M.J.
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(2011). B Cell-Derived IL-10 Does Not Regulate Spontaneous Systemic Autoimmunity in MRL.Faslpr Mice. J Immunol 188, 678-685
Teichmann, L.L., Kashgarian, M., Weaver, C.T., Roers, A., Müller, W., and Shlomchik, M.J.
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(2013). Signals via the Adaptor MyD88 in B Cells and DCs Make Distinct and Synergistic Contributions to Immune Activation and Tissue Damage in Lupus. Immunity 38, 528-540
Teichmann, L.L., Schenten, D., Medzhitov, R., Kashgarian, M., and Shlomchik, M.J.
