Autoimmunity against melanoma differentiation-associated gene 5 induces interstitial lung disease mimicking dermatomyositis in mice

Anti- melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated ILD frequently develop rapidly progression and present high mortality rate in the acute phase. Here, we established a murine model of ILD mediated by autoimmunity against MDA5. Mice immunized with recombinant murine MDA5 whole protein, accompanied with complete Freund's adjuvant once a week for four times, developed MDA5- reactive T cells and anti-MDA5 antibodies. After acute lung injury induced by intranasal administration of polyinosinic- polycytidylic acid [poly (I:C)] mimicking viral infection, the MDA5- immunized mice developed fibrotic ILD representing prolonged respiratory inflammation accompanied by fibrotic changes 2 wk after poly (I:C)- administration, while the control mice had quickly and completely recovered from the respiratory inflammation. Treatment with anti-CD4 depleting antibody, but not anti-CD8 depleting antibody, suppressed the severity of MDA5- induced fibrotic ILD. Upregulation of interleukin (IL) - 6 mRNA, which was temporarily observed in poly (I:C)- treated mice, was prolonged in MDA5- immunized mice. Treatment with antiIL - 6 receptor antibody ameliorated the MDA5- induced fibrotic ILD. These results suggested that autoimmunity against MDA5 exacerbates toll - like receptor 3- mediated acute lung injury, and prolongs inflammation resulting in the development of fibrotic ILD. IL - 6 may play a key role initiating ILD in this model.