Background/Purpose: Type 2 innate lymphoid cells (ILC2s), are recently identified as population of cells with lymphoid morphology lacking re-arranged antigen-specific receptors. Although findings in animal models of fibrotic diseases demonstrate increased numbers of ILC2s in fibrotic lesions, data on ILC2s in humans are mainly limited to allergic diseases. We aimed to evaluate the contributive role of ILC2s in the pathogenesis of systemic sclerosis (SSc), their levels and correlations with fibrotic manifestations in SSc.

Methods: Sixty-nine patients with SSc and 47 healthy controls were included into the study. Blood samples and skin sections were analyzed by flow cytometry and immunohistochemistry. ILC2 counts were correlated with clinical manifestations of SSc.

Results: Elevated numbers of ILC2s were detected in the skin (10-fold increase) as well as in the blood (4-fold increase) of SSc patients compared to healthy controls. As no single marker can sufficiently distinguish ILC2s from other cell population, we used two established sets of ILC2 markers to quantify ILC2 cells in the peripheral blood and the skin of SSc patients and healthy individuals, both of which yielded comparable results. Notably, activation markers are lacking on circulating ILC2s, however, after migration into the dermis ILC2s become activated as indicated by expression of IL-17RB and thymic stromal lymphopoietin protein (TSLP) receptor as well as by positive staining for the skin homing marker cutaneous lymphocyte antigen (CLA). Our data also suggest that ILC2s may be involved in the pathogenesis of fibrosis in SSc by showing multiple associations of ILC2 counts with fibrotic manifestations in SSc patients. Stratification of the SSc population in patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc) demonstrated increased levels of ILC2 in both subgroups with significantly higher frequencies in dcSSc compared to lcSSc. Moreover, dermal and circulating ILC2 counts correlated closely with the modified Rodnan skin score (mRSS). Increased ILC2 numbers were not only associated with more extensive skin fibrosis, but also with anti-topoisomerase antibodies and pulmonary fibrosis. ILC2 counts were highest in patients with extensive lung involvement assessed by CT scan. A comparison of circulating ILC2 frequencies between different cohorts of patients with rheumatoid arthritis, systemic lupus erythematosus and SSc demonstrated strong upregulation of ILC2s only in SSc patients.

Conclusion: Here, we provide first evidence for a role of ILC2s in the pathogenesis of rheumatic diseases by demonstrating increased ILC2 counts in the skin and blood of patients with SSc as compared to healthy individuals. Migration of circulating ILC2s into the skin, the activated state of dermal ILC2s and correlations of ILC2 counts with dermal and pulmonary fibrosis suggests a central role of ILC2s in the pathogenesis of fibrosis and encourage follow-up studies to further evaluate the potential of ILC2 as biomarkers in SSc patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/innate-lymphoid-cells-new-players-in-systemic-sclerosis-correlate-with-extent-of-skin-and-lung-fibrosis/