Expression of the Autoantigen Topoisomerase‐1 is Enriched in the Lung Tissues of Patients With Autoimmune Interstitial Lung Disease: A Case Control Study

Abstract

Background. Among the autoimmune rheumatic diseases, it is striking that autoantibodies targeting ubiquitously expressed proteins (eg, topoisomerase-1) associate with specific clinical complications (eg, interstitial lung disease [ILD]). It has been proposed that enriched antigen expression in inflamed target tissue may play a role in focusing the autoimmune response. We sought to determine whether topoisomerase-1 expression is enriched in lungs from patients with autoimmune/inflammatory diseases relative to normal lung. Methods. We used a 99-core lung tissue microarray (TMA) containing lung tissue from 40 patients with autoimmune inflammatory ILD (cases) and 46 control subjects with normal lungs. We stained the TMA with antibodies to compare topoisomerase-1 and CD8 expression between patients and control subjects and evaluated whether expression is enriched in specific cell types. Staining was analyzed, and statistical comparisons were performed. Results. Cases were more likely to have global topoisomerase-1 expression (53% vs 21%; P = 0.003), specifically in pneumocytes (47% vs 16%; P = 0.003) and stromal/immune cells (32% vs 5%; P = 0.002) compared with control subjects. CD8 cell density (223 cells/mm 2 vs 102 cells/mm 2 ; P = 0.018) was significantly higher in topoisomerase-1positive lung tissues compared with topoisomerase-1-negative lung tissues. Interestingly, topoisomerase-1 expression was significantly more common in scleroderma compared with normal lung (67% vs 21%; P = 0.036) and was present more frequently in pneumocytes in these patients (67% vs 16%; P = 0.018). Conclusions. Pulmonary expression of topoisomerase-1 is increased in the setting of autoimmune ILD relative to normal lung, specifically in pneumocytes. This may contribute to the amplification of pulmonary disease in patients with scleroderma with a loss of tolerance to topoisomerase-1.

Can Antinuclear Antibodies Have a Pathogenic Role in Systemic Sclerosis?

“…About half of AFA-positive patients are also positive to ATA. TOPO-I antigen is overexpressed in interstitial lung disease and overexpressed in FB from patients with SSc and is upregulated by TGF-β and tumor necrosis factor alpha (TNF-α) ( 140 , 141 ). Interestingly, FB from SSc patients cultured with non-cytotoxic dose of camptothecin (a TOPO-I inhibitor) showed a decreased mRNA expression of collagen and deposition of collagen compared to SSc without camptothecin treatment and heathy FB with camptothecin treatment ( 142 ).…”

Anti-topoisomerase 1 antibody level changes after B сell depletion therapy in systemic sclerosis

“…По данным экспериментальных исследований, иммунизация мышей Топо 1 индуцирует синтез анти-Топо 1 и развитие фиброза кожи и легких [13,14]. В ткани легких у пациентов с ССД отмечено увеличение экспрессии Топо 1 [15], а в крови у пациентов с ИЗЛ -числа аутореактивных CD4+ Т-клеток, специфичных в отношении Топо 1 и имеющих Th17-«провоспалительный» фенотип, обладающих «провоспалительным» фенотипом [16]. У некоторых пациентов с ССД снижение уровня анти-Топо 1 на фоне лечения ассоциируется с более «мягким» течением заболевания [17,18].…”