Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice

Abstract

The intracellular tyrosine kinase Lyn mediates inhibitory receptor function in B cells and myeloid cells, and Lyn−/− mice spontaneously develop an autoimmune and inflammatory disease that closely resembles human systemic lupus erythematosus. TLR signaling pathways have been implicated in the production of anti-nuclear antibodies in SLE and mouse models of it. We used a conditional allele of Myd88 to determine whether the autoimmunity of Lyn−/− mice is dependent on TLR/MyD88 signaling in B cells and/or in dendritic cells (DCs). The production of IgG anti-nuclear antibodies, as well as the deposition of these antibodies in the glomeruli of the kidneys, leading to glomerulonephritis in Lyn−/− mice were completely abolished by selective deletion of Myd88 in B cells and the autoantibody production and glomerulonepritis were delayed or decreased by deletion of Myd88 in DCs. The reduced autoantibody production in mice lacking MyD88 in B cells or DCs was accompanied by a dramatic decrease of the spontaneous germinal center (GC) response, suggesting that autoantibodies in Lyn−/− mice may depend on GC responses. Consistent with this view, IgG anti-nuclear antibodies were absent if T cells were deleted (TCRβ−/− TCRδ−/− mice) or if T cells were unable to contribute to GC responses due to mutation of the adaptor molecule SAP. Thus, the autoimmunity of Lyn−/− mice was dependent on T cells and on TLR/MyD88 signaling in B cells and in DCs, supporting a model whereby DC hyperactivity combines with defects in tolerance in B cells to lead to a T cell-dependent systemic autoimmunity in Lyn−/− mice.

B Cell–Intrinsic TLR7 Signaling Is Essential for the Development of Spontaneous Germinal Centers

“…yaa , and sanroque , spontaneously develop elevated GC B cells, Tfh and high titers of serum autoAbs (22, 52, 63, 64). Recently, Hua and co-workers showed the requirement of GCs and MyD88-signaling in ANA production and nephritis in Lyn-deficient mice (33). These autoimmune mouse models highlight the significance of the follicular-GC pathway in B cell responses and autoAb production but do not delineate the contribution or requirement for TLR7 and TLR9 in Spt-GC formation.…”

“…This model allows for the extra-follicular differentiation of B cells (15, 30). Recently, using different TLR overexpression and knockout autoimmune mouse models, several groups have suggested B cell intrinsic and/or extrinsic roles of TLR-MyD88 signaling in the GC differentiation pathway of autoantibody production and autoimmune inflammatory responses (20, 31-33). However, the mechanisms and the requirement of physiological levels of individual TLRs in controlling the formation of Spt-GCs and Tfh development remain unclear.…”

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…Notably, many antigens recognized by autoantibodies are ligands for B cell TLRs (Table 1), suggesting a role for TLR recognition in the breakdown of tolerance against these antigens. Indeed, mice deficient in TLR7, TLR9, or the TLR-associated signaling adaptor MyD88 are partially protected against development of ANAs and lupus-like symptoms (57)(58)(59)(60). This protection derives from the effects that TLR ligation has on reducing B cell tolerance.…”

Toll-like receptors: potential targets for lupus treatment

“…The intracellular tyrosine kinase Lyn mediates the inhibitory receptor function in B cells and myeloid cells, and Lyn −/− mice spontaneously develop an autoimmune and inflammatory disease that closely resembles human SLE. Production of germinal center, antinuclear antibody in Lyn-deficient mice also requires MyD88 signaling in B cells and DCs [53] . Deletion of MyD88 in DCs alone completely reversed the lupus manifestation shown in Lyn-mutant mice [54] .…”