Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome

• Published in: Arthritis and rheumatism Vol. 48; no. 11; pp. 3187 - 3201
• Main Authors: Salomonsson, Stina, Jonsson, Malin V., Skarstein, Kathrine, Brokstad, Karl A., Hjelmström, Peter, Wahren‐Herlenius, Marie, Jonsson, Roland
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2003; Wiley
• Subjects: Apoptosis; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biological and medical sciences; Biomarkers; Cell Count; Choristoma; Dendritic Cells, Follicular - metabolism; Dendritic Cells, Follicular - pathology; Diseases of the osteoarticular system; Endothelium, Lymphatic - metabolism; Endothelium, Lymphatic - pathology; Germinal Center - metabolism; Germinal Center - pathology; Humans; Immunoenzyme Techniques; In Situ Nick-End Labeling; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Salivary Gland Diseases - metabolism; Salivary Gland Diseases - pathology; Salivary Glands, Minor - metabolism; Salivary Glands, Minor - pathology; Sjogren's Syndrome - metabolism; Sjogren's Syndrome - pathology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Human; Immunopathology; Center; Stomatology; Rheumatology; Autoantibody; Autoimmune disease; Sjögren syndrome; Eye disease; Target; Systemic disease; Production; Ectopia; Cell; Formation; Organ
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.11311

Objective To investigate functional properties of the germinal center (GC)–like structures observed in salivary glands of patients with Sjögren's syndrome (SS) and to determine the frequency with which such structures develop. Methods Hematoxylin and eosin–stained sections from 165 minor salivary gland biopsy samples were screened for GC‐like structures. Expression of markers for GCs (CD3, CD20, Ki‐67, CD35, CD31), adhesion molecules (intercellular adhesion molecule 1, lymphocyte function–associated antigen 1, vascular cell adhesion molecule 1, very late activation antigen 4), chemokines (CXCL13, CCL21, CXCL12), and production of autoantibodies (anti‐Ro/SSA and anti‐La/SSB) was investigated by immunohistochemistry. Apoptosis was investigated by TUNEL staining. Results GC‐like structures were observed in 28 of 165 patients (17%). When GCs were defined as T and B cell aggregates with proliferating cells with a network of follicular dendritic cells and activated endothelial cells, such microenvironments were found in all patients in whom structures with GC‐like morphology were observed. The defined microenvironments were not found in patients without apparent GC‐like structures. The GCs formed within the target tissue showed functional features with production of autoantibodies (anti‐Ro/SSA and anti‐La/SSB) and apoptotic events (by TUNEL staining), and the local production of anti‐Ro/SSA and anti‐La/SSB autoantibodies was significantly increased (P = 0.04) in patients with GC development. Conclusion Lymphoid neogenesis and functional ectopic GC formation take place in salivary glands of a subset of patients with SS. Our data suggest that the ectopic secondary lymphoid follicles contain all elements needed for driving the autoimmune response. Our findings underscore a key role for the target organ in recruitment of inflammatory cells and propagation of the disease process.