Inclusion body myositis pathogenesis: Steady progress.

Inclusion body myositis (IBM) is a slowly progressive skeletal muscle disease for which no effective pharmacological therapy is available. Since its initial pathological description 50 years ago, substantial progress has been made in our clinical understanding of IBM. We now have extensive understanding of its demographics, pattern of muscle involvement, and diagnostic criteria, and large amounts of cross-sectional, and more limited longitudinal, data regarding disease duration and clinical severity. Progress in understanding the pathogenesis of IBM, crucial to identifying rational therapeutic strategies, has come more gradually. A series of pivotal publications from 1984–1988 reported the use of a novel technology, monoclonal antibodies (invented in 1975) as histochemical reagents, to study the types of immune cells present in IBM and other disease muscle. These studies identified cytotoxic T-cell injury to IBM myofibers and launched a highly productive line of still-continuing investigation of the properties of these T cells. These studies have suggested that in IBM muscle there are specific molecules against which the adaptive immune system has concentrated its attack (an IBM autoantigen). Unfortunately, largely for technical reasons, studies of these T cells have failed to identify any of these molecules. In contrast, these pivotal studies found little involvement in IBM of B cells, another key arm of the adaptive immune system. No studies of IBM pertaining to B cells, the plasma cells they differentiate into, or the antibodies they produce were published for at least 15 years. The use of another novel technology in 2002 (gene expression profiling by microarrays, a technique developed in the early 1990s), however, identified robust B-cell and plasma cell activation in IBM muscle. This new method launched a series of studies that led in 2011 to the identification in approximately 50% of IBM patients of a serum autoantibody present against an incompletely characterized muscle protein. This protein was identified in 2013 as cytoplasmic 50 nucleotidase (NT5C1A; cN1A). AnticN1A antibody detection is now used as a diagnostic test with approximate sensitivity of 35% and specificity of 95%. In parallel to these observations pertaining to autoimmunity, various muscle pathological abnormalities have been observed and collectively called “degeneration.” The recognition of myonuclear degeneration, mitochondrial pathology, and abnormal protein aggregation were important steps forward for IBM research. Advances in understanding muscle protein processing machinery (the immunoproteasome), endoplasmic reticulum (ER) stress, and altered autophagy (with impaired p62 binding to LC3) in IBM have led to diagnostic muscle biomarkers such as p62, TDP-43, and LC3 aggregates. The relationship between autoimmunity and degeneration in IBM has been a source of speculation and debate. Notable in this regard is IBM’s striking autoimmune genetic background (the only robust association of genetic variation in IBM lies within the major histocompatibility gene [MHC] loci). In addition, there is diffuse upregulation of MHC-1, antigen-directed (T cells and plasma cells) and innate (myeloid dendritic cells and macrophages) immune cells, and their secreted products. Functionally, there is evidence that such an environment can result in degenerative changes: (1) upregulation of the immunoproteasome (present in IBM muscle) causes abnormal protein processing; (2) inflammation is highly correlated with mitochondrial pathology; (3) cytokines (interleukin 1b and interferongamma together) can produce abnormal protein aggregates in cultured myofibers; and (4) MHC-1 expression is sufficient in a murine model to result in ER stress and a severe myopathy with rimmed vacuoles. These observations, however, are indirect. In the current issue of the Annals of Neurology, Tawara et al provide more direct evidence addressing this debate. The passive transfer of patient sera to in vitro or in vivo models has been a productive investigational method for the study of certain human diseases, for example myasthenia gravis >40 years ago. Tawara et al now report for the first time the use of this functional approach for IBM. Specifically, the authors exposed a cell culture model (in vitro) to and injected into mice (in vivo) purified blood immunoglobulin G (IgG) fractions from 3 anti-cN1A– positive IBM patients and 3 anti-cN1A–negative IBM patients. The sera IgG from the anti-cN1A–positive IBM patients, but not the anti-cN1A–negative patients, resulted in a muscle “degenerative” histological change (p62 protein aggregation) similar to that present in IBM muscle. Muscle from these mice additionally showed atrophic fibers and macrophage infiltration. Thus, although caution