Antibodies from Donor B Cells Are Not Required for Initiating but Required for Persisting Scleroderma in Chronic Gvhd

We recently reported that in a chronic graft versus host disease (GVHD) model of DBA/2 donor to MHC-matched BALB/c recipient, donor CD4⁺ T and B cell interaction resulted in not only hyperglobulinemia and glomerulonephritis but also scleroderma (J. Immunol. 2012). It is well known that glomerulonephritis is caused by immune complex deposition. However, the role of antibodies from donor B cells in the pathogenesis of scleroderma remains unclear. To address this question, we generated DBA/2 mice whose B cells have APC function but cannot secrete antibodies by backcrossing IgH^µg1 mice from Dr. Rajewsky’s lab (JEM 2007). We observed that, while transplanting T-cell-depleted bone marrow (TCD-BM) and spleen cells from littermate control mice induced proteinuria and scleroderma, transplanting BM and spleen cells from IgH^µg1 DBA/2 mice induced no proteinuria, but the recipients developed scleroderma ~35 days after HCT. Interestingly, the scleroderma gradually recovered ~55 days after HCT. 40 days after HCT, scleroderma recipients transplanted with WT spleen cells (Rec-WT) or recipients transplanted with IgH^µg1 spleen cells (Rec-IgH^µg1) both had high percentage (~12%) of IFN-g⁺ or IL-17⁺ CD4⁺ T cells in the peripheral lymph node (PLN) and skin tissues, as compared to that (~3%) of GVHD-free recipients given TCD-BM alone (Rec-TCD). While Rec-WT had severe reduction of CD4⁺CD8⁺ thymocytes, the Rec-IgH^µg1 had no reduction of the thymocytes, as compared to that of Rec-TCD. By day 60 after HCT, the Rec-WT with ongoing scleroderma still had ~10% IFN-g⁺ or IL-17⁺ CD4⁺ T cells in the PLN and skin tissues; in contrast, although the Rec-IgH^µg1 with reversal of scleroderma still had >10% IFN-g⁺or IL-17⁺ CD4⁺ T cells in the PLN, those cells in the skin had reduced to <2%. This reduction was associated with DC upregulation of B7H1 and T cell upregulation of PD-1. These results suggest that antibodies from B cells are required for maintaining inflammatory status of tissue DCs and persistence of scleroderma in chronic GVHD. (This work was supported by NIH R01 AI066008).