Background/Purpose: Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated DM sometimes develop rapidly progressive-ILD and present high mortality rate in acute phase. While it has been suspected that viral infection might trigger the development of anti-MDA5 antibody-positive DM, the pathogenesis of anti-MDA5 antibody-positive ILD remains unclear.

Methods: C57BL/6-background wild-type and µMT mice were subcutaneously injected with emulsion, including complete Freund’s adjuvant (CFA) and recombinant mouse MDA5 whole protein produced by a baculovirus-insect cell protein expression system, 4 times once a week. Some of the MDA5-immunized mice were intranasally administrated with polyinosinic-polycytidylic acid [poly (I:C)] at the same time of the last immunization. Control mice were subcutaneously injected with emulsion of CFA without proteins. The immunized mice were treated with intraperitoneal injections of anti-CD4 and anti-CD8 depleting antibodies, and anti-interleukin (IL)-6 receptor antibody (15A7). Lungs were histologically and immunohistochemically evaluated. The contents of hydroxyproline in the left lobes of the lungs were also measured.

Results: MDA5-reactive T cells and anti-MDA5 antibodies were detected from MDA5-immunized mice. Inflammatory foci with CD4⁺ T cells and CD11b⁺ macrophages blowing the pleurae were significantly more frequently detected in the lungs of MDA5-immunized mice than control mice. Moreover, MDA5-immunized mice with poly (I:C) administration showed more intense inflammation at day 22 in their lungs than control mice [lung inflammation score, median (interquartile range); 0.56 (0.54-0.60) and 0.41 (0.39-0.48), respectively; P < 0.05 by Mann-Whitney’s U test]. At day 35, 70% of MDA5-immunized mice developed inflammatory cell-rich and fibrotic lung disease, while no control mouse did (P < 0.01 by Fisher’s exact test). CD4⁺ T cell-rich peri-bronchial inflammation was also observed in 80% of MDA5-immunized mice, but not in any control mice (P < 0.01 by Fisher’s exact test). MDA5-immunized mice also showed higher mortality rate (42.3%) within 14 days after the poly (I:C) administration than control mice (7.1%, P < 0.01 by log-rank test). The contents of hydroxyproline of the lungs at day 35 in MDA5-immunized mice were also upregulated compared to those of control mice (mean ± standard error; 144.1 ± 16.1 µg and 60.6 ± 6.6 µg, respectively; P < 0.05 by Turkey’s multiple comparison test). Suppression of prolonged inflammation in lung at day 35 was observed in CD4-depleted mice, not in CD8-depleted mice and µMT mice. mRNA level of IL-6 in the lung of MDA5-immunized mice was significantly elevated at day 35 compared to those of control mice. Also, anti-IL-6 receptor antibody ameliorated the inflammation at day 35.

Conclusion: These results proved that autoimmunity against MDA5 exacerbates toll-like receptor 3-mediated acute lung injury, and prolongs the inflammation resulting in the development of fibrotic ILD. IL-6 may act as a key role for the ILD in this model.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoimmunity-against-melanoma-differentiation-associated-protein-5-advances-acute-lung-injury-to-interstitial-lung-disease-in-mice/