Abstract
Abstract In the spleen, membrane expressed Lymphotoxin (LT) on B cells maintains the integrity of marginal zone macrophages (MZM) which acts as the final barrier to prevent follicular entry of autoantigens derived from apoptotic debris. In this study, we found that there was an age-dependent decrease in the number of MZMs and clearance of apoptotic debris in the spleens of autoimmune BXD2 mice. Selective depletion of MZMs by repeated injection of recombinant LTR fusion protein to BXD2 mice accelerated autoimmune phenotypes. Interestingly, in BXD2 spleen, the major LT producing MZ and MZ precursor B cells are primarily localized in the follicles due to type I IFN-induced upregulation of CD69. Adoptive transfer of B cells from BXD2-Ifnar-/- but not BXD2 to BXD2-Rag2-/- mice resulted in retention of B cells in the MZ, leading to repopulation of MZMs. Consistent with this, there was no age-related loss of MZMs in the spleens of BXD2-Ifnar-/- mice. Reconstitution of BXD2-Rag2-/- with a mixed bone marrow of BXD2-GFP+Ifnar+ and BXD2-GFP-Ifnar- (1:1) resulted in a 50:50 repopulation of donor MZMs in recipient mice, thereby excluding the direct effect of type I IFNs on MZM maintenance. Our present study suggests that one novel mechanism associated with type I IFN-induced autoimmunity is related to the effects on promoting follicular migration of LT expressing B cells. The dissociation of LT+ B cells and MZMs disrupts MZ barrier and enables follicular entry of apoptotic antigens.
Published Version
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