Protective Autoimmunity - Mechanism of Action

Mechanism of Action

An immune response that takes place following CNS injury elicits a cascade of molecular and cellular events that can eventually affect the organism’s functional recovery. Immediately after an injury to the CNS, there is a local innate immune response. This response is mediated primarily by microglia cells, a population of CNS-resident immune cells, which can act as phagocytes, and antigen-presenting cells. CD4+ T helper cells that were specifically activated by antigens associated with the lesion, arrive at the site of injury and locally interact with microglia and other blood-derived antigen presenting cells (e.g. dendritic cells). Local properties of antigen presenting cells (i.e. the levels of MHC-II-self antigen complexes and the type of co-stimulatory molecules) dictate the profile of the subsequent T cell response. The interaction between the T cells and the microglia/dendritic cells results in the production of a set of inflammatory cytokines (such as interferon gamma) and chemokines (chemoatractant proteins) that, in turn, orchestrate the ensuing repair process in which many cell types participate. Microglia and myeloid cells recruited from the circulating blood restrict the spread of damage by buffering excessive levels of toxic self-compounds (such as the neurotransmitter glutamate), and by producing growth factors (such as insulin-like growth factor-1) that prevent neuronal death and induce axonal re-growth. In addition, the chemokines produced at the site of injury attract endogenous stem or progenitor cells that can further contribute to repair by providing a source for new neurons and glial cells, and by restricting the local immune response.

The mechanism by which protective autoimmunity maintains the brain’s functional integrity under non-injurious conditions is still not known. One model suggests that CNS-specific autoimmune T cells which constantly circulate through the cerebrospinal fluid (CSF) interact with perivascular dendritic cells that reside at the choroid plexus and meninges. Cytokines and growth factors secreted into the CSF by the T cells and dendritic cells then diffuse into the neural parenchyma were they locally affect neurons, glial cells and stem cells. This model infers that the level of antigen presentation (i.e. the amount of MHC-II-self antigen complexes) serves as an indicator of the level of immune activity required for maintenance of the uninjured brain.