Ectopic Germinal Centers Are Rare in Sjögren’s Syndrome Salivary Glands and Do Not Exclude Autoreactive B Cells

Abstract

This study reports on the characterization of B cells of germinal center (GC)-like structures infiltrating the salivary glands (SGs) of patients with Sjögren’s syndrome. Eight two-color combinations were devised to characterize the phenotype of these B cells in 11 SG specimens selected from biopsies obtained from 40 Sjögren’s syndrome patients and three normal tonsils. The 9G4 mAb, which recognizes V4.34-encoded autoAbs, enabled us to identify autoreactive B cells. Quantitative RT-PCR was used to determine the level of mRNAs for activation-induced cytidine deaminase (AICDA), repressors and transcription factors. CD20+IgD−CD38+CD21+CD24− B cells, similar to those identified in tonsil GCs, were seen in the SGs of four patients and, and since they expressed AICDA, they were termed “real GCs”. CD20+IgD+CD38−CD21+CD24+ B cells, seen in aggregates from the remaining seven samples, were characteristically type 2 transitional B cells and marginal zone-type B cells. They lacked AICDA mRNAs and were termed “aggregates”. Real GCs from SGs contained mRNAs for Pax-5 and Bcl-6, like tonsil GC cells, whereas aggregates contained mRNAs for Notch-2, Blimp-1, IRF-4, and BR3, similar to marginal zone B cells. Further experimental data in support of this dichotomy included the restriction of CXCR5 expression to real GC cells, while sphingosine 1-phosphate receptor 1 was expressed only in aggregates. In contrast, both types of B cell clusters expressed the idiotype recognized by the 9G4 mAb. Our data indicate that, in SGs, a minority of B cell clusters represent genuine GC cells, while the majority manifest features of being type 2 transitional B cells and marginal zone cells. Interestingly, both types of B cell aggregates include autoreactive B cells.

Is minor salivary gland biopsy more than a diagnostic tool in primary Sjo¨gren׳s syndrome? Association between clinical, histopathological, and molecular features: A retrospective study

“…Therefore, in patients developing GC-like infiltrates, a different genetic, serological, and glandular cytokine profile is detectable compared to those without GC structures or healthy controls [24][25][26][27].…”

“…Furthermore, it has been suggested that GC-like structures may correlate with later lymphoma development [21][22][23]. Moreover, patients developing GC-like infiltrates display a different genetic, serological, and glandular cytokine profile when compared to those without GCs [24][25][26][27].…”

Identification of New Pathogenic Players in Lupus: Autoantibody-Secreting Cells Are Present in Nephritic Kidneys of (NZBxNZW)F1 Mice

“…Rather than the result of migratory processes, ASCs could also be generated locally in inflamed kidneys, within structures resembling secondary lymphoid tissues. Lymphoid neogenesis is indeed strongly associated with autoimmunity (43), and has been described in several autoimmune disorders among which Sjögren's syndrome (in salivary glands), rheumatoid arthritis (in the synovium), and in the lipogranulomas developing in the tetramethylpentadecane-induced lupus mouse model (44)(45)(46). However, it is still a matter of debate whether these ectopic lymphoid structures merely correspond to a site of immune cells accumulation or a real lymphoid tissue where autoimmune responses develop.…”

“…lupus (A, B). Centered on nucleosome immunity, these mechanisms involve either direct binding of nucleosome/dsDNA autoantibodies to inherent glomerular constituents, such as membrane structures or a-actinin or nucleosome-mediated binding of nucleosome/dsDNA autoantibodies to heparan sulfate, collagen IV, laminin, or other constituents of the GBM (10,14,16,(43)(44)(45)(46)(47)(48). Based on the present findings in NZB/W mice, an additional player has to be included in this scheme (C).…”

Intrahepatic B‐cell follicles of chronically hepatitis C virus‐infected individuals lack signs of an ectopic germinal center reaction

“…Interestingly, B-cell follicles are regularly seen in the liver of chronic HCV carriers, and a fraction of these structures have characteristics of GCs, such as expression of BCL6, the master transcription factor for GC B cells [20]. For autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and Sjögren´s syndrome, it has been shown that B-cell proliferation and somatic hypermutation can occur in ectopic GC-like structures outside secondary lymphoid organs [21][22][23], and these have been associated with the production of autoantibodies [23,24]. Thus, it is an intriguing possibility that the B-cell follicles in the liver of HCV-infected patients are the histological structures where HCV-specific or autoreactive B cells undergo clonal expansion and affinity maturation linked with active somatic hypermutation.…”