The role of the gut microbiota in the pathogenesis of antiphospholipid syndrome

Abstract

Infectious triggers are associated with the induction of transient antiphospholipid antibodies. One therefore wonders if microbes that permanently colonize us play a role in the pathogenesis of antiphospholipid syndrome (APS). The microbiota represents the collection of all microorganisms colonizing humans and is necessary for normal host physiology. The microbiota, however, is a constant stress on the immune system, which is tasked with recognizing and eliminating pathogenic microbes while tolerating commensal populations. A growing body of literature supports a critical role for the commensal-immune axis in the development of autoimmunity against colonized barriers (e.g., gut or skin) and sterile organs (e.g., pancreas or joints). Whether these interactions affect the development and sustainment of autoreactive CD4(+) T cells and pathogenic autoantibodies in APS is unknown. This review provides an overview of the current understanding of the commensal-immune axis in autoimmunity with a focus on the potential relevance to APS. Additionally, we discuss emerging findings supporting the involvement of the gut microbiota in a spontaneous model of APS, the (NZW × BXSB)F1 hybrid, and formalize hypotheses to explain how interactions between the immune system and the microbiota may influence human APS etiopathogenesis.

Fig. 1

Proposed influence of the gut microbiota on induction and maintenance of anti-β₂-glycoprotein I antibodies (anti-β₂GPIs). In genetically predisposed individuals, the gut microbiota may drive the induction of anti-β₂GPI antibodies by several mechanisms that can occur separately or in combination. 1 Cross-reactive gut commensal antigens are recognized by mucosal dendritic cells (DCs) sampling the intestinal lumen or by phagocytosis after barrier disruption or apoptosis of intestinal epithelial cells (not shown). 2 Commensal-derived LPS, phospholipids, and oxidative stress lead to a conformational change of β₂GPI that exposes cryptic epitopes in domains I and V of β₂GPI. DCs and other antigen-presenting cells take up unfolded β₂GPI bound to LPS or phospholipids via receptors that bind these complexes, e.g., Toll-like receptors. 3 DCs present cross-reactive commensal antigens, cryptic β₂GPI antigens, or both in an HLA class II-restricted manner to cognate CD4⁺ helper T cells in secondary lymphoid organs. CD4⁺ helper Tcell subsets assist antigen-specific B cells via CD40 ligand and other co-stimulatory receptors (not shown). These B cells then secrete IgA/IgG in the mucosal lumen and in the systemic circulation, respectively. The helper T cells leading to IgA/IgG production are follicular helper Tcells (Tfh) or, as shown in the gut, also ex-Th17 cells that convert to Tfh-like cells [•]. A “second hit” in the vasculature then leads to thrombotic events as detailed in the main text [41].