Self-tolerance in multiple sclerosis

Abstract

During the last decade, several defects in self-tolerance have been identified in multiple sclerosis. Dysfunction in central tolerance leads to the thymic output of antigen-specific T cells with T cell receptor alterations favouring autoimmune reactions. In addition, premature thymic involution results in a reduced export of naïve regulatory T cells, the fully suppressive clone. Alterations in peripheral tolerance concern costimulatory molecules as well as transcriptional and epigenetic mechanisms. Recent data underline the key role of regulatory T cells that suppress Th1 and Th17 effector cell responses and whose immunosuppressive activity is impaired in patients with multiple sclerosis. Those recent observations suggest that a defect in self-tolerance homeostasis might be the primary mover of multiple sclerosis leading to subsequent immune attacks, inflammation and neurodegeneration. The concept of multiple sclerosis as a consequence of the failure of central and peripheral tolerance mechanisms to maintain a self-tolerance state, particularly of regulatory T cells, may have therapeutic implications. Restoring normal thymic output and suppressive functions of regulatory T cells appears an appealing approach. Regulatory T cells suppress the general local immune response via bystander effects rather than through individual antigen-specific responses. Interestingly, the beneficial effects of currently approved immunomodulators (interferons β and glatiramer acetate) are associated with a restored regulatory T cell homeostasis. However, the feedback regulation between Th1 and Th17 effector cells and regulatory T cells is not so simple and tolerogenic mechanisms also involve other regulatory cells such as B cells, dendritic cells and CD56bright natural killer cells.

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

“…Autoimmune diseases, such as MS, result from the breakdown of mechanisms controlling immune tolerance and the subsequent failure of the host immune system to distinguish self from non-self antigens (8,9). In MS, autoreactive T cells are thought to escape endogenous immune tolerance mechanisms, inflicting subsequent damage to the myelin sheath and leading to neurodegeneration (1,8,10).…”

“…Classical immunology dictates that two signals are required for T cell activation by professional antigenpresenting cells (pAPCs), an antigen-specific signal (signal 1) and a "context" signal (signal 2, co-stimulatory/inhibitory) that ultimately dictates the resulting immune response (8,11,12). Co-delivery of both antigen and a co-stimulatory context signal activates an antigen-specific adaptive immune response, whereas delivery of a co-inhibitory context signal or absence of either signal can render an anergic response (i.e., no response) and is believed to be a main mechanism of peripheral immune tolerance (8,9,13). Thus, co-delivery of a synthetic co-inhibitory context signal and autoantigen may be a suitable pharmacological template to restore immune tolerance and treat various autoimmune disorders (13)(14)(15)(16).…”

“…To mount appropriate immune responses, the immune system uses several cell surface signaling proteins such as those in the B7 (CD80/CD86) pathway, CD40, PD-1 (CD279), ICOS (CD278), and others (9,11,12). The B7 signaling pathway is one of the most well-characterized co-stimulatory pathways in T cell activation (9,11,12).…”

“…The B7 signaling pathway is one of the most well-characterized co-stimulatory pathways in T cell activation (9,11,12). B7, found on pAPCs, has the ability to either activate T cells through binding with CD28 (costimulatory function) or to inhibit T cell activation and promote tolerance upon binding CTLA-4 (co-inhibitory function) (9,11,12).…”

Emerging Concepts on the Gut Microbiome and Multiple Sclerosis

“…In addition, defects in tolerance mechanisms have been identified in MS (Gonsette 2012). It is possible that the associated HLA molecules may be more apt at presenting antigen to T cells in the process of MS development, there is change in the activation threshold of certain components of the overall immune response associated with certain immune susceptibility loci, and there is an abnormal escape of self-antigen-specific T cells from the thymus in MS.…”