Cutting Edge: Defective Follicular Exclusion of Apoptotic Antigens Due to Marginal Zone Macrophage Defects in Autoimmune BXD2 Mice

Abstract

Marginal zone macrophages (MZMs) act as a barrier to entry of circulating apoptotic debris into the follicles of secondary lymphoid organs. In autoimmune BXD2 mice, there is a progressive reduction in the function and numbers of MZMs. Absence of MZMs results in retention of apoptotic cell debris within the MZ and increased loading of apoptotic cell antigens on MZ B cells and MZ-precursor (MZ-P) B cells. The MZ-P B cells are capable of translocating the apoptotic cell antigens to the follicular zone and stimulating T cells. Both MZMs and MZ-P B cells from BXD2 mice express low levels of tolerogenic signals and high levels of inflammatory signals. Thus, the present study suggests a multifaceted mechanism in which MZMs maintain tolerance to apoptotic autoantigens and suppress their translocation to follicles. Lack of clearance of apoptotic debris by MZMs drives follicular Ag–transportation by MZ-P B cells to stimulate an autoimmune response.

Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

“…A common feature of SLE in both human and mouse models of SLE is decreased clearance of ACs and increased production of type I IFNs by pDCs (1-3, 6, 9-11, 13, 14, 39). We and others have previously shown that physical deletion or spontaneous loss of MARCO + MZMs resulted in defective AC clearance (2, 12-15, 40, 41) and that such a defect is associated with the development of lupus in susceptible mouse models (2,42). We analyzed the distribution of MARCO + cells in the spleens of non-SLE controls (n = 6) and in the spleens pf patients with SLE (n = 5) and found a dense layer of MARCO + cells in the perifollicular regions in all non-lupus control spleens; however, this layer of MARCO + cells was significantly reduced in all SLE spleens ( Figure 1A).…”

“…Systemic lupus erythematosus (SLE) and mouse models of lupus both exhibit a central feature of increased circulating apoptotic cell autoantigens (AC-Ags) and, in most cases, elevated type I IFN signaling produced by plasmacytoid DCs (pDCs) (1)(2)(3). The most accepted model is that the presence of uncleared ACs or AC-autoantibody immune complexes with DNA-or RNA-containing immune components can signal production of type I IFNs by pDCs.…”

“…This in turn drives T cell activation and B cell maturation into autoantibody-producing B cells (4)(5)(6)(7)(8). Although it is well accepted that higher levels of circulating ACs can be due to decreased clearance of ACs in SLE and mouse models of lupus, the underlying mechanism for the clearance defect is not completely understood (2,(9)(10)(11). Marginal zone macrophages (MZMs) surrounding the splenic follicles have been reported to have the capability of both efficient clearance of ACs and induction of tolerance to AC-Ags (12)(13)(14)(15).…”

“…Marginal zone macrophages (MZMs) surrounding the splenic follicles have been reported to have the capability of both efficient clearance of ACs and induction of tolerance to AC-Ags (12)(13)(14)(15). Because of the advantageous anatomic location of MZMs, they act as the final follicular AC-Ag exclusion barrier (2). We recently showed that in the BXD2 mouse model of autoimmunity, lupus is first associated with a spontaneous decrease in the apoptotic debris clearance function and, later, with a loss in the number of MZMs surrounding the splenic follicles (2).…”

“…Because of the advantageous anatomic location of MZMs, they act as the final follicular AC-Ag exclusion barrier (2). We recently showed that in the BXD2 mouse model of autoimmunity, lupus is first associated with a spontaneous decrease in the apoptotic debris clearance function and, later, with a loss in the number of MZMs surrounding the splenic follicles (2). Such a defect is associated with follicular translocation of AC-Ags bearing B cells to induce an AC-Ag-reactive T cell response (16)(17)(18)(19)(20)(21).…”