Overview - B7 in Inflammatory Myopathies

Recent studies have continued to clarify the pathogenic mechanisms responsible for muscle damage and weakness in inflammatory myopathies. Traditionally, adaptive immune mechanisms such as cell mediated (cytotoxic) and humoral (autoantibodies and complement) components have been implicated in the pathogenesis of polymyositis/inclusion body myositis and dermatomyositis, respectively.(1) B7-H3 is a cell surface molecule in the immunoglobulin superfamily that is frequently upregulated in response to autoantigens and pathogens during host T cell immune responses. However, B7-H3's role in the differential regulation of T cell subsets remains largely unknown. (2)

Evidence
Results from several studies suggest B7-H3 has a costimulatory function on Th1/Th17 but a coinhibitory function on Th2 responses. Other studies reveal that B7-H3 could affect different T cell subsets which have important implications for regulating pathogenesis and disease progression in human autoimmune disease.(3)

In 2001, one laboratory initially identified B7-H3 (CD276) as a costimulatory molecule that promotes an in vitro T cell response. B7-H3 mRNA has been found in human liver, lung, bladder, testis, prostate, breast, and placenta, suggesting that B7-H3 may participate in organ-specific inflammation and autoimmune diseases. (3)

Structure
Similar to other B7 family homologues, B7-H3 has a single IgV- and IgC-like domain (2Ig form) with a transmembrane and intracellular tail in humans, mice, and other species. In humans, a duplicate of the classic B7-H3 (4Ig form) was also identified, but the physiological differences between the 2Ig and 4Ig form have yet to be elucidated. The role of endogenous B7-H3 in the pathogenesis and progression of autoimmune disease has been evaluated by various laboratories using both monoclonal antibodies (mAb) and B7-H3 deficient mice (KO), but the results are somewhat contradictory with both costimulatory and coinhibitory effects being described in various model systems (4)

Role
B7-H3 plays a differential role in the regulation of distinct T cell subsets. Therefore, the effect of B7-H3 would be determined by the dominance or bias of T cell subsets in each system or disease status. It is well known that CD4+ T cells consist of multiple functional subsets upon encountering antigens and these subsets regulate T cell responses against different antigens in different and complex environments. Th1 cells, for example, secrete IFN-γ, IL-2, and GM-CSF; they actively regulate T cell proliferation, functional maturation of CD8+ T cells, and activation of several innate immune cell components, including myeloid dendritic cells, macrophages, and granulocytes.In vitro studies using human recombinant B7-H3 showed enhanced T cell growth in the presence of TCR engagement, which led to the hypothesis that B7-H3 is a costimulatory molecule for T cell growth (4)(2)

Relevance
B7-H3 differentially regulates T cell subsets by costimulating Th1 and Th17 while suppressing Th2 responses.(1) This finding may explain, at least in part, the previously contradictory findings in various model systems. The molecular basis for this differential effect, however, has yet to be characterized. This will largely rely on the discovery of the B7-H3 counter-receptor and, in this regard, a different counter-receptor on these T cell subsets may cause the observed effects. Finally, these findings have important implications for the manipulation of B7-H3 in clinical applications to treat human autoimmune diseases like PM and DM or to develop new markers for treatment follow. (5)

The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in  autoimmune disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. (5)

we propose the existence of a novel B7-H1–mediated immune-regulatory pathway in T cells, which selectively limits murine and human T_H17 cell responses and might be therapeutically exploited to control T_H17-mediated autoimmunity.

Footnotes:
Travis B. K.Pathogenesis of myositis: Lessons learned from animal studies.Indian Journal of Rheumatology.Volume 8, Issue 4, December 2013, Pages 170–178. http://www.sciencedirect.com/science/article/pii/S0973369813001210

1. Liqun L  .B7-H3 Promotes Pathogenesis of Autoimmune Disease and Inflammation by Regulating the Activity of Different T Cell Subsets.Published: June 11, 2015.DOI: 10.1371/journal.pone.0130126 . http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130126
    
2. Zhu Y. Cell surface signaling molecules in the control of immune responses: a tide model. Immunity. 2011 Apr 22;34(4):466–478. doi: 10.1016/j.immuni.2011.04.008. pmid:21511182 .View Article 
    
3. Chen L DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013 Apr;13(4):227–242. doi: 10.1038/nri3405. pmid:23470321 View Article.
    
4. Sabrina C.B7 family checkpoint regulators in immune regulation and disease.. doi:10.1016/j.it.2013.07.003. Trends in immunology. Volume 34, Issue 11, November 2013, Pages 556–563. http://www.sciencedirect.com/science/article/pii/S1471490613001105