Controlling autoimmunity in sporadic inclusion-body myositis

Sporadic inclusion-body myositis (s-IBM) spans two areas of interest in my research lab, the role of protein aggregation in neurodegenerative disease^1–4 and the role of secondary autoimmunity in degenerative conditions in the nervous system^5–10 and in muscle.^11,12 After some comments on the potential pathologic role of inclusion bodies themselves, I shall focus attention on two approaches to controlling the autoimmune response in muscle tissue: inhibition of lymphocyte homing with antibodies to alpha 4 beta 1 integrin,^13–15 and nonspecific downregulation of autoimmunity with statins.^14–16

Aggregations in neurodegenerative disease.

We have studied the role of transglutaminase in the crosslinking of huntingtin aggregates in Huntington disease (HD).^1–4 The aggregates in HD have characteristics of covalently linked protein multimers, with occasional ordered areas of amyloid with its accompanying birefrigent optical properties when stained with Congo red. In HD we can ameliorate the disease modestly by inhibiting the enzyme transglutaminase, TGase. TGase catalyzes the formation of glutaminyl-lysyl linkages. Inhibtion of TGase in vivo prolonged lifespan, and diminished tremor and weight loss in a transgenic animal model of HD. Despite the fact that TGase is part of the aggregate in HD, and that TGase inhibition ameliorates disease in the transgenic animal model of HD, treatment with cystamine does not appreciably reverse gross aggregates, unless instituted at a very early stage of disease. Increasing evidence suggests that whereas early microaggregates may have pathologic properties, gross aggregates may not be pathogenic per se, and might even have protective characteristics.^1–4 Strategies aimed at blocking aggregates could certainly be given together with treatments that block the accumulation of inflammatory cells in muscle.

Treating the inflammatory/autoimmune features of s-IBM.

The inflammatory response in muscle in s-IBM has …