Extranodal Lymphoid Microstructures in Inflamed Muscle and Disease Severity of New-Onset Juvenile Dermatomyositis

Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Arthritis & Rheumatology (Impact Factor: 7.76). 04/2009; 60(4):1160-72. DOI: 10.1002/art.24411
Source: PubMed


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.
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.
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.
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.

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Available from: Consuelo Lopez De Padilla, Jul 16, 2014
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    • "In a major knowledge gap, the contribution of TLT to pathology is defined predominately by correlation and association. The presence of TLT in man is associated with more severe disease, e.g., in juvenile dermatomyositis, Sjogren’s syndrome, and multiple sclerosis (163–165). In rodents, TLT can enhance viral defense in lung infections, naïve T cell recruitment, and epitope spreading in diabetes and exacerbate heart allograft rejection (152, 166–168). "
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    ABSTRACT: Lymphoid organs are meeting zones where lymphocytes come together and encounter antigens present in the blood and lymph or as delivered by cells migrating from the draining tissue bed. The exquisite efficiency of this process relies heavily on highly specialized anatomy to direct and position the various players. Gated entry and exit control access to these theaters and reticular networks and associated chemokines guide cells into the proper sections. Lymphoid tissues are remarkably plastic, being able to expand dramatically and then involute upon resolution of the danger. All of the reticular scaffolds and vascular and lymphatic components adapt accordingly. As such, the lymph node (LN) is a wonderful example of a physiologic remodeling process and is potentially a guide to study such elements in pathological settings such as fibrosis, chronic infection, and tumor metastasis. The lymphotoxin/LIGHT axis delivers critical differentiation signals that direct and hone differentiation of both reticular networks and the vasculature. Considerable progress has been made recently in understanding the mesenchymal differentiation pathways leading to these specialized networks and in the remodeling that occurs in reactive LNs. In this article, we will review some new advances in the area in terms of developmental, differentiation, and maintenance events mediated by this axis.
    Frontiers in Immunology 02/2014; 5:47. DOI:10.3389/fimmu.2014.00047
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    • "While classical SLO are encapsulated structures that develop in predictable locations as a consequence of normal immune system development, under pathologic conditions, ectopic lymphoid tissues (aka TLO) may develop in peripheral tissue sites of chronic inflammation (13, 26). TLO formation has been reported within inflamed organs of patients with rheumatoid arthritis (27–29), psoriatic arthritis (30), diabetes mellitus (31–33), autoimmune gastritis [AIG; Ref. (32)], juvenile dermatomyositis (34), and Sjögren’s syndrome (35), among others. TLO formation has also been identified in the lungs of influenza virus-infected mice (36), the livers of hepatitis C virus (HCV)-infected patients (37) and in the stomachs of patients infected with Helicobacter pylori (38). "
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    ABSTRACT: Ectopic lymphoid tissue, also known as tertiary lymphoid organs (TLO) develop adaptively within sites of chronic tissue inflammation, thereby allowing the host to efficiently crossprime specific immune effector cells within sites of disease. Recent evidence suggests that the presence of TLO in the tumor microenvironment (TME) predicts better overall survival. We will discuss the relevance of extranodal T cell priming within the TME as a means to effectively promote anti-tumor immunity and the strategic use of dendritic cell (DC)-based therapies to reinforce this clinically preferred process in the cancer-bearing host.
    Frontiers in Immunology 11/2013; 4:388. DOI:10.3389/fimmu.2013.00388
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    • "Also, muscle fibers positive for this chemokine and infiltrating lymphocytes positive for the receptor have been demonstrated [17]. Further dissection for extranodal lymphoid microstructures has been performed, and indeed such structures can be found [18]. The existence of such lymph node structures indicates that lymphocyte activation and differentiation could take place within the muscle, and there is support from studies of B cells, plasma cells, and immunoglobulin sequences that plasma cell differentiation can take place in this location [19]. "
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    ABSTRACT: T cells of both the CD4 and CD8 lineage are commonly found in affected tissues of patients with idiopathic inflammatory myopathies, but understanding the contribution of these cells to immunopathogenesis remains challenging. Given recent advances in identifying more myositis-associated autoantibodies and their putative targets, we suggest that studies on autoreactive T cells targeting those autoantigens are one way forward. Another (so far, more frequently used) approach comes from studies on effector T cells in the context of myositis. This review summarizes recent advances and current hypotheses in both of these contexts.
    Arthritis research & therapy 12/2012; 14(6):230. DOI:10.1186/ar4116 · 3.75 Impact Factor
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