Complement-independent pathogenic influences of anti-HMGCR + and anti-SRP + immune-mediated necrotizing myopathy autoantibodies on engineered muscle function.

backgroundImmune-mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies. The direct pathogenic effects of IMNM patient autoantibodies on skeletal muscle contractile force, independent of the downstream activation of the complement pathway, remain understudied.

methodsThis study leverages a custom 3-D human skeletal muscle microtissue (hMMT) culture platform that encourages muscle cell contractile apparatus maturation and enables analysis of contractile function. Force generation competent hMMTs were treated with total immunoglobulins (IgGs) isolated from the plasma of IMNM patients with amplification of anti-SRP

resultsExposure to total IgGs isolated from a subset of IMNM patients induced a decline in hMMT twitch and tetanus contractile force and were associated with sarcomere fragility and slowed muscle cell contraction and relaxation rates. Pathogenic influences on hMMT force generation were observed at a greater frequency in response to total IgGs isolated from IMNM patients with anti-HMGCR + autoantibodies. Substantial intracellular human IgG staining was observed in conditions where myotubes were treated with total IgGs from IMNM patients.

conclusionsThis study demonstrates that total IgGs isolated from IMNM patients have the aberrant capacity to enter muscle cells in the absence of complement. Further, a subset of patient IgGs exert direct pathogenic influences on engineered muscle contractile function that are independent of the complement system. Together, these findings have important implications for the advancement of IMNM precision medicine therapies.