Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Abstract

Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4+ T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals do not succumb to autoimmune disease. There is growing evidence that while peripheral APCs stimulate immune responses against foreign Ags in the setting of tissue destruction and “danger,” they actually maintain tolerance against self Ags under steady state conditions. We hypothesized that tolerance against candidate autoantigens could be reversed by activation of APCs via CD40 or Toll-like receptor 9 signaling. Adult SJL mice injected i.p. with a peptide fragment of proteolipid protein (a candidate autoantigen in multiple sclerosis) emulsified in IFA fail to mount lymphoproliferative or cytokine responses and are protected from EAE upon subsequent challenge with the Ag combined with adjuvants. Here we report that tolerized proteolipid protein-specific lymph node cells regain the ability to divide, differentiate along a Th1 lineage, and transfer EAE when reactivated in the presence of agonistic Abs against CD40 or CpG oligonucleotides. The effects of both anti-CD40 and CpG oligonucleotides are dependent upon induction of IL-12. Our findings suggest two mechanisms to explain the well-documented association between infectious illnesses and flare-ups of multiple sclerosis. Microbial pathogens could 1) release molecules that bind Toll-like receptors, and/or 2) stimulate microbe-specific T cells to express CD40 ligand, thereby licensing APCs that bear both microbial and autoantigens to break tolerance.

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

“…Rather it appears to allow the T cells to persist in a non-tolerant/non-immune state such that they can be subsequently activated by Ag in CFA. To further highlight differences in soluble and insoluble "adjuvants", CpG oligonucleotides in an IFA depot have been shown to substitute for CFA in the induction of encephalitogenic Th1 cells [28,30]. We found that CpG had no effect on tolerance induced with soluble peptide (data not shown).…”

“…the antibody could provoke a productive immune response without subsequent immunization [8][9][10][11]. However, these previous studies have used an immunization protocol that gave a sustained Ag stimulus (peptide in IFA for example) [10,28]. Giving soluble peptide as we have here does not replicate this sustained Ag availability, the peptide being cleared from the system rapidly [29].…”

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

“…The mechanisms by which autoimmunity is triggered are not fully understood, but DCs and TLRs are likely to play a role in this process. Recently, Ichikawa and colleagues (30) and Waldner and associates (31) provided a conceptual framework demonstrating that TLRs are key molecules for the breakthrough of tolerance. Our data show that triggering different TLRs at the same time resulted in marked synergy with respect to the production of proinflammatory mediators, indicating that simultaneous stimulation of different TLR pathways facilitates an environment in which the breakthrough of tolerance is likely to occur.…”

“…Endogenous ligands are released upon normal cell turnover and stressful events and are likely to be abundant in the synovial compartment. The pivotal role of endogenous ligands was substantiated by the finding that such signals lead to primary immune responses under conditions of cell stress and precipitate autoimmunity in the presence of self antigens (28)(29)(30)(31). Therefore, endogenous ligands are considered to be natural initiators of autoimmunity.…”

Protection against Experimental Autoimmune Myocarditis Is Mediated by Interleukin-10-Producing T Cells that Are Controlled by Dendritic Cells

“…These results were consistent with previous studies that suggested that T cells induced by antigen:IFA may be in a transitional state and retain the ability to differentiate into pathogenic effectors under Th1-polarizing conditions. 56,67,68 Our data also suggested that antigen:IFA-induced tolerance to myocarditis is a dynamic process and can be broken by strong inflammatory stimuli produced by APCs. 68 -70 After expo- sure to high doses of exogenous IL-12, S2-16:IFA-induced cells produced increased IFN-␥ but not IL-10 in response to S2-16.…”