Extranodal lymphoid microstructures in inflamed muscle and disease severity of new‐onset juvenile dermatomyositis

Abstract

Objective. Juvenile dermatomyositis (DM) is an autoimmune disease of childhood characterized by lesions in skin and muscle that are populated by plasmacytoid dendritic cells (PDCs) and lymphocyte infiltrates. We undertook this study to examine the cellular composition, organization, and molecular milieu of the cellular infiltrates in muscle in juvenile DM and to correlate the infiltrates with clinical disease manifestations.Methods. Since PDCs and lymphocyte foci express CCL19 and CCL21, we investigated for in situ formation of lymphoid microstructures that could be sites of extranodal immune activation.Results. Analyses of muscle biopsy samples from children with new-onset juvenile DM showed 3 categories of lesions: diffuse infiltrates, lymphocytic aggregates lacking follicle-like organization, and follicle-like structures. The last of these exhibited elements of classic lymphoid follicles, including networks of follicular dendritic cells and high endothelial venules. They also expressed high levels of CXCL13 and lymphotoxins known to support lymphoid organogenesis. There were also resident naive CD45RA؉ T cells and maternally derived B cells and PDCs. Patients with diffuse infiltrates or lymphocytic aggregates were responsive to standard therapy with steroids and methotrexate, but those with follicle-like structures tended to have severe disease that required additional agents such as intravenous Ig or rituximab.Conclusion. These data suggest that lymphoneogenesis is a component of the early disease process in juvenile DM. Ectopic lymphoid structures could indicate a severe course of disease; their early detection could be a tool for disease management.

The inflammatory milieu in idiopathic inflammatory myositis

“…Mature pDCs in JDM muscle are associated with clusters of T and B cells adjacent to blood vessels, with the suggestion of transmigration of DCs through endothelium [10•]. Local expression of chemokines and their receptors are also suggestive of lymphocyte maturation and ectopic lymphoid aggregation in IIM muscle tissue [7]. Nongranulomatous, nodular accumulations of infl ammatory cells have been previously reported with B cell-rich centers surrounded by a T cell-rich peripheral zone, resembling lymph nodes [9].…”

Role of cytokines and chemokines in idiopathic inflammatory myopathies

“…CXCL13 protein localizes to lymphoid follicle-like structures composed of T-cells, B-cells and plasmacytoid dendritic cells. Control muscle does not contain CXCL13-positive structures [18 ].…”

“…In juvenile dermatomyositis, higher levels of lymphotoxin-a (x2.6) and lymphotoxin-b (x3.5) messenger RNAs are found in patients compared with normal muscle preparations. Lymphotoxin-b messenger RNA is localized to intramuscular follicle-like structures that contain large numbers of T-cells, B-cells and plasmacytoid dendritic cells [18 ].…”

Permissive environment for B‐cell maturation in myositis muscle in the absence of B‐cell follicles

“…Histological features typical of germinal centers, specifically areas of B-cell maturation within lymphoid tissue, have been demonstrated in synovium in rheumatoid arthritis (RA), 2 meninges in multiple sclerosis, 3 thyroid tissue in autoimmune thyroid disease, 4 salivary gland in Sjogren's syndrome, 5,6 and muscle in juvenile dermatomyositis. 7 The appearance of these lesions suggests that B-cell maturation may occur locally within diseased tissue sites, but confirmation that such maturation does occur requires analysis of immunoglobulin sequences in these regions. Immunoglobulin sequences characteristic of B-cell affinity maturation have been demonstrated directly within such ectopic germinal centers in RA.…”