Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity.

In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45 int /CD11b + /CD11c ؊ microglia at days 6 -7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of " circulating " (Gr1 ؊ (Ly6C lo )CX3CR1 + ) and " infl ammatory " (Gr1 hi /Ly6C hi /CCR2 + ) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS -enhanced green fl uorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP + ) microglia expressing GR1 + (Ly6C + ) at day 7 p.i., suggesting that the infl ammatory monocyte is a microglial precursor. This was confi rmed by adoptive transfer of labeled BM (Ly6C hi /CD115 + ) or circulating infl ammatory monocytes that traffi cked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in infl ammatory monocyte traffi cking. Neutralization of CCL2 not only reduced the number of GFP + microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent infl ammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.

Several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and multiple sclerosis, are genetically linked to distinct human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins as well as geographical distribution of disease risk point towards environmental factors in the genesis of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. In this review, we outline mechanisms by which pathogens can trigger autoimmune disease, and also pathways by which infection and immune control of infectious disease might be dysregulated during autoimmunity.

Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3–mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate–induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.

Antigen-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide antigens linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-SP) has been demonstrated to be a highly efficient method for inducing peripheral, antigen-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. Here, we show that apoptotic Ag-SP accumulate in the splenic marginal zone where their uptake by F4/80+ macrophages induces production of IL-10 which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 which is essential for Ag-SP tolerance induction. Ag-SP infusion also induces Tregs which are dispensable for tolerance induction, but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. We show for the first time that tolerance results from the synergistic effects of two distinct mechanisms – PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of Tregs. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting MS.