Session Title: B cells in Human and Animal Arthritis
Session Type: Abstract Submissions (ACR)
Signaling through the tyrosine kinase receptor Flt3 plays an important role in early B-cell development. Mice lacking either Flt3 or its ligand (Flt3L) have reduced numbers of pre-B-cells in the bone marrow (BM) but normal numbers of mature B-cells in the periphery and normal serum levels of Igs. Flt3L is included in a predictive model for the development of rheumatoid arthritis (RA). We have previously shown that Flt3L is increased in RA patients and that interfering with Flt3 signaling during experimental arthritis reduces antibody production. In the present study we investigate how Flt3 signaling on activated B-cell affects terminal differentiation and antibody production during experimental arthritis.
C57/Bl6 mice deficient for Flt3L (FLKO) and their wild type (WT) counterparts were immunized with mBSA on day 0 and day 7. On day 21, arthritis was induced by an intraarticular injection of mBSA. Mice were sacrificed on day 14 or day 28 and splenocytes and bone marrow cells were isolated. B-cell populations were analyzed using flow cytometry and B-cell associated transcription factors by qPCR. Also, isolated splenocytes stimulated with either LPS or LPS+IL-4, were cultured for antibody and germ-line transcript measurements.
mBSA immunization and LPS activation in vitro induced Flt3 expression on splenic B-cells. Flt3 expressing B-cells represented an activated population recognize by higher expression of MHCII, CD80, CD86 and CD40 when compared to B-cells not expressing the receptor. Lack of Flt3 signaling was associated with enlarged plasma cell population in spleen (P=0.0014) and bone marrow (P = 0.016), supported by high gene expression of transcription factors IRF4, Blimp1 and XBP1 essential for plasma cell maturation. FLKO mice had increased serum levels of IgM and impaired affinity maturation of mBSA specific IgG1 antibodies. The low IgG1 production by FLKO mice was supported by low formation of germ-line transcripts for IgG1. Stat6 activation (pStat6) controlling IgG1 switch was low FLKO mice compared to WT.
We show that antigen stimulation induces expression of Flt3 on mature B-cells during arthritis. Flt3 signaling is essential for differentiation of antigen specific plasma cells during experimental arthritis. Functional Flt3/Stat6 pathway regulates class switch recombination of IgG1.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fms-like-tyrosine-kinase-3-signaling-is-essential-for-differentiation-of-antigen-specific-plasma-cells-during-experimental-arthritis/