Characterization of inflammatory cell infiltrate of scleroderma skin: B cells and skin score progression

Abstract

BackgroundThe purpose of this study was to investigate the frequency and the distribution of inflammatory cell infiltrate in two sets of cutaneous biopsies derived from clinically affected and unaffected skin in patients with systemic sclerosis (SSc) and to test correlation between the cell infiltrate and the progression of skin involvement.MethodsSkin was immunohistochemically assessed to identify CD68, CD3, CD20 and CD138-positive (+) cells in clinically affected and unaffected skin in 28 patients with SSc. Patients were followed for 6 months and the characteristics of the infiltrate were analyzed according to disease duration, clinical features and skin involvement progression.ResultsIn all SSc cutaneous specimens, cellular infiltrates were found in a perivascular location predominantly in the mid and deeper portions of the dermis. All the analyzed biopsies showed a CD3+ and CD68+ cell infiltrate and the mean number of CD3+ and of CD68+ cells was higher in clinically involved skin (CD3+, 71.7 ± 34.6 and CD68+, 26.3 ± 8.4, respectively) than in clinically uninvolved skin (CD3+, 45.7 ± 36.0 and CD68+, 13.6 ± 6.1, respectively) (p < 0.001 for both comparisons). CD20+ cells were found in 17 (60.7%) patients and in these patients the mean number of CD20+ cells was higher in clinically involved (4.7 ± 5.9) than in uninvolved skin (1.9 ± 2.9), (p = 0.04). There was a greater number of CD20+ cells in patients with early SSc compared with patients with long-standing disease. CD138+ cells were found in 100% of biopsies of clinically involved skin and in 89.3% of biopsies of uninvolved skin. The mean number of CD138+ cells was higher in clinically involved skin (3.6 ± 2.3) than in clinically uninvolved skin (1.9 ± 1.7), (p < 0.001). Seven patients experienced more than 20% worsening in the skin score after 6 months of follow up; all of them had a CD20+ skin infiltrate on biopsy of clinically involved skin.ConclusionsOur results confirm that mononuclear cells are present in the skin of all patients with SSc, underlining the role of inflammatory cell infiltrates in skin involvement in SSc. B cells in the skin seem to characterize patients with early diffuse skin disease and to correlate with skin progression.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1569-0) contains supplementary material, which is available to authorized users.

Skin-Associated B Cells in Health and Inflammation

“…Although an increase in skininfiltrating B cells already suggested a role for B cells in cutaneous inflammation, the therapeutic success of systemic B cell depletion with rituximab confirmed a pathogenic role for B cells in a number of these diseases (54)(55)(56). In pemphigus, atopic dermatitis, and scleroderma, disease severity and progression are positively correlated with the number of skin-infiltrating B cells (18,48,52). Specifically, in scleroderma, a chronic connective tissue disorder that often progresses to extensive cutaneous and vascular fibrosis, only those patients with skin-infiltrating B cells advanced in disease severity over a period of 12 mo (48).…”

“…Recently, B cells are increasingly recognized as an important part of the infiltrating immune compartment in autoimmune and inflammatory skin diseases. B cell numbers are elevated in lesional skin relative to control skin specimens in a number of inflammatory diseases, including, but not limited to, psoriasis (47), pemphigus (18), lupus profundus (19,20), systemic sclerosis (scleroderma) (48), discoid lupus erythematosus (49,50), Sjögren's syndrome (51), IgG4related skin diseases (33,34), atopic dermatitis (52), and allergic contact dermatitis (53). Although an increase in skininfiltrating B cells already suggested a role for B cells in cutaneous inflammation, the therapeutic success of systemic B cell depletion with rituximab confirmed a pathogenic role for B cells in a number of these diseases (54)(55)(56).…”

“…In pemphigus, atopic dermatitis, and scleroderma, disease severity and progression are positively correlated with the number of skin-infiltrating B cells (18,48,52). Specifically, in scleroderma, a chronic connective tissue disorder that often progresses to extensive cutaneous and vascular fibrosis, only those patients with skin-infiltrating B cells advanced in disease severity over a period of 12 mo (48). Furthermore, a pathogenic role for B cells in the initiation phase of skin fibrosis was confirmed using B cell depletion therapy in scleroderma patients and mouse models of the disease (57)(58)(59).…”

“…In support of this notion, Yuan et al (18) recently showed that autoreactive Dsg1-and Dsg3-specific Ab-secreting cells and B cells localize to lesional skin relative to healthy skin, suggesting a pathogenic role in situ by these autoreactive cells. Akin to pemphigus, the majority of scleroderma patients present with both systemic and local autoantibodies as well as skin lesion-infiltrating B cells and plasma cells (48). Finally, IgG4-related skin diseases, which are fibroinflammatory disorders affecting multiple organs, are induced by accumulation of terminally differentiated IgG4 + plasma cells and Ab deposition in affected skin (33,34).…”

A Niche for Plasma Cells: The Skin

“…Skin-reactive IgG, IgA, and IgE can disrupt adhesions, interfere with signaling, fix complement, and trigger inflammatory cascades causing devastating autoimmunity. Classic examples are immunobullous disorders, and recent data suggest that systemic sclerosis may be similar (Bosello et al, 2018). It has been presumed that pathogenic autoantibodies are generated by ASC in the bone marrow, spleen, and lymph node and are subsequently transported to the skin via blood.…”