In vivopathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy

Abstract

ObjectivesIn autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) aAb has been individualised and is referred to as immune-mediated necrotising myopathy (IMNM). The level of aAb correlates with IMNM activity and disease may respond to immunosuppression, suggesting that they are pathogenic. We aimed to evaluate the pathogenicity of IgG from patients with anti-SRP or anti-HMGCR aAb in vivo by developing the first mouse model of IMNM.MethodsIgG from patients suffering from anti-SRP or anti-HMGCR associated IMNM were passively transferred to wild-type, Rag2-/- or complement C3-/- mice. Muscle deficiency was evaluated by muscle strength on electrostimulation and grip test. Histological analyses were performed after haematoxylin/eosin staining or by immunofluorescence or immunohistochemistry analysis. Antibody levels were quantified by addressable laser bead assay (ALBIA).ResultsPassive transfer of IgG from patients suffering from IMNM to C57BL/6 or Rag2-/- mice provoked muscle deficiency. Pathogenicity of aAb was reduced in C3-/- mice while increased by supplementation with human complement. Breakage of tolerance by active immunisation with SRP or HMGCR provoked disease.ConclusionThis study demonstrates that patient-derived anti-SRP+ and anti-HMGCR+ IgG are pathogenic towards muscle in vivo through a complement-mediated mechanism, definitively establishing the autoimmune character of IMNM. These data support the use of plasma exchanges and argue for evaluating complement-targeting therapies in IMNM.

Autoantibody Biomarkers in Rheumatic Diseases

“…In either anti-SRP or anti-HMGCR-positive muscle sections, greater sarcolemmal MAC deposits were observed in lesional areas than in anti-Jo-1-positive muscle tissues, correlating with the degree of muscle necrosis [50]. The pathogenic role of anti-SRP and anti-HMGCR IgG was directly shown in an in vivo study where passive transfer of anti-SRP or anti-HMGCR IgG led to significant muscle weakness, histologic deposits of MAC, and necrotic muscle fibers [51].…”

“…The latter antibody was particularly positive among IMNM patients with previous statin exposure [48]. While the roles of many other MSAs remain largely unclear, the pathogenic roles of these two antibodies have been better understood by animal models, as well as in vitro studies [49][50][51].…”

Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients

“…It was later found that autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) define that myopathy [2][3][4], that very high serum levels of creatine kinase (CK) and widespread damage on magnetic resonance imaging (MRI) are common [5], that sarcolemmal and capillary membrane attack complex (MAC) deposition are present on muscle biopsy [2,[6][7][8], and that intense immunosuppressive treatment is often needed [2,[7][8][9][10][11][12]. Recently, the pathogenicity of anti-HMGCR was demonstrated [13][14][15], and during the 224th European Neuromuscular Centre (ENMC) International Workshop [16], in the presence of proximal weakness and elevated CK levels, anti-HMGCR myopathy was defined. Compellingly, limb-girdle muscular dystrophy presentation [17] and isolated hyperCKemia [8] were reported as part of the spectrum of anti-HMGCR myopathy.…”

Autophagy markers LC3 and p62 accumulate in immune‐mediated necrotizing myopathy

“…The association with anti–signal recognition particle (anti‐SRP) and anti–3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (anti‐HMGCR) autoantibodies is frequent, but some IMNM are not associated with these specific autoantibodies and may be paraneoplastic . The pathogenic role of anti‐SRP has been observed in vitro and in vivo , and anti‐HMGCR autoantibody levels are correlated with CK levels and inversely correlated with muscle strength in IMNM …”