Pathogenic antibodies are active participants in spinal cord injury

Abstract

The role of B cells and autoimmunity as contributing factors to poor neurological outcomes following spinal cord injury (SCI) is poorly understood. The study by Ankeny et al., in this issue of the JCI, identifies a new immunopathological mechanism arising after SCI in mice (see the related article beginning on page 2990). The study shows that B cells produce pathogenic antibodies that impair lesion repair, resulting in worse neurological outcome. This new understanding of SCI disease pathogenesis, if confirmed in humans, reveals potential avenues for the development of novel neuroprotective immunotherapies.

Figure 1. B cells and an autoimmune response contribute to poor neurological outcome following SCI.

After SCI, B cells, together with other leukocytes such as monocyte/macrophages (hMϕ) and T cells, infiltrate the lesion. Resident activated microglia, microglia-derived macrophages (mMϕ), and astrocytes, also surround and/or infiltrate the lesion. Infiltrating macrophages as well as proliferating astrocytes respond to the SCI by producing BAFF, lymphotoxin-β, and APRIL, which support B cell survival, proliferation, and differentiation as well as B cell follicle development. Follicle-like structures appear at the lesion area and house activated B cells and plasma cells. Additionally, the high levels of IFN-γ and TNF-α present at the SCI lesion will induce IDO expression, a key regulator of tolerance and a preventer of autoimmunity. IDO is expressed by activated microglia and infiltrating leukocytes. The toxic tryptophan metabolites generated by IDO render T cells but not B cells highly susceptible to apoptosis. This creates a cytokine environment that favors B cell autoimmunity and antibody production. Thus, within the SCI lesion, the local environment is conducive to the support of B cells and antibody production. Therapeutics such as blockers of BAFF, APRIL, or lymphotoxin-β; anti-CD20 monoclonal antibodies; and IVIG could prevent follicle-germinal center development, deplete B cells (but not plasma cells), and block the pathogenic activity of autoantibodies to neural antigens at the site of the SCI. These therapeutic agents could be used singly or in combination in order to obtain maximal benefit.