{Reference Type}: Journal Article
{Title}: Autoantibodies against the melanoma differentiation-associated protein 5 in patients with dermatomyositis target the helicase domains.
{Author}: Van Gompel E;Demirdal D;Fernandes-Cerqueira C;Horuluoglu B;Galindo-Feria A;Wigren E;Gräslund S;De Langhe E;Benveniste O;Notarnicola A;Chemin K;Lundberg IE;
{Journal}: Rheumatology (Oxford)
{Volume}: 63
{Issue}: 5
{Year}: 2024 May 2
{Factor}: 7.046
{DOI}: 10.1093/rheumatology/kead400
{Abstract}: <B>OBJECTIVE: </B>Clinical observations in patients with dermatomyositis (DM) and autoantibodies against the melanoma differentiation-associated protein 5 (MDA5) suggest that the autoantibodies contribute to the pathogenesis of MDA5(+) DM. To gain insight into the role of the anti-MDA5 autoantibodies, we aimed to identify their binding sites on the different domains of the MDA5 protein.<BR><B>METHODS: </B>We developed an in-house ELISA to assess the reactivity against the MDA5 domains (conformational epitopes) in plasma (n = 8) and serum (n = 24) samples from MDA5(+) patients with varying clinical manifestations and disease outcomes. The reactivities were also assessed using western blot (linearized epitopes). An ELISA-based depletion assay was developed to assess cross-reactivity among the different MDA5 domains.<BR><B>RESULTS: </B>All eight plasma samples consistently showed reactivity towards conformational and linearized epitopes on the helicase domains of the MDA5 protein. The ELISA-based depletion assay suggests that anti-MDA5 autoantibodies specifically target each of the three helicase domains. Twenty-two of the 24 serum samples showed reactivity in the in-house ELISA and all 22 displayed reactivity towards the helicase domains of the MDA5 protein.<BR><B>CONCLUSIONS: </B>Our data revealed that the main immunogenic targets of anti-MDA5 autoantibodies from MDA5(+) patients are the helicase domains. Considering that the helicase domains are responsible for the enzymatic activity and subsequent triggering of an inflammatory response, our findings suggest that binding of anti-MDA5 autoantibodies could alter the canonical activity of the MDA5 protein and potentially affect the downstream induction of a pro-inflammatory cascade.