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* Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, St. Bartholomew’s and Royal London School of Medicine, London, United Kingdom;
Dipartimento di Terapia Medica, Cattedra di Reumatologia, Università di Roma ‘La Sapienza’, Roma, Italy;
Maxillofacial Surgery, King’s College London, Guy’s Hospital, London, United Kingdom;
Department of Oral Pathology and Oral Medicine, King’s College London, Guy’s Hospital, London, United Kingdom;
¶ Clinica di Reumatologia, Dipartimento di Patologia e Medicina Sperimentale e Clinica, Università di Udine, Azienda Ospedaliero-Universitaria, DPMSC, Piazzale Santa Maria della Misericordia 1, Udine, Italy; and
|| Department of Immunobiology, Division of Infection, Immunity and Inflammatory Diseases, King’s College London, Guy’s Hospital, London, United Kingdom
Demonstration of ectopic germinal center-like structures (GC-LSs) in chronically inflamed tissues in patients with autoimmune disorders is a relatively common finding. However, to what extent ectopic lymphoid structures behave as true GC and are able to support class switch recombination (CSR) and somatic hypermutation (SHM) of the Ig genes is still debated. In addition, no information is available on whether CSR and SHM can take place in the absence of GCs at extrafollicular sites in an ectopic lymphoid tissue. In this study, we show that in salivary glands (SGs) of Sjögren’s syndrome (SS) activation-induced cytidine deaminase (AID), the enzyme responsible for CSR and SHM is invariably expressed within follicular dendritic cell (FDC) networks but is not detectable in SGs in the absence of ectopic GC-LSs, suggesting that FDC networks play an essential role in sustaining the Ag-driven B cell proliferation within SS-SGs. We also show that the recently described population of interfollicular large B cells selectively expresses AID outside ectopic GC in the T cell-rich areas of periductal aggregates. Finally, we report that AID retains its exclusive association with numerous, residual GCs in parotid SS-MALT lymphomas, whereas neoplastic marginal zone-like B cells are consistently AID negative. These results strongly support the notion that ectopic lymphoid structures in SS-SGs express the molecular machinery to support local autoantibody production and B cell expansion and may play a crucial role toward lymphomagenesis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 M.B. is a recipient of a Clinical Research Fellowship from the Arthritis Research Campaign (grant reference 17132). F.H. is a recipient of a Fellowship from the Guy’s and St. Thomas Charity (R050702). S.K. is recipient of a Clinical Research Fellowship from the Arthritis Research Campaign (grant reference 17571). This work was in part funded by a research grant from the British Sjogren’s Syndrome Association.
2 M.B. and F.B. contributed equally to this study.
3 Address correspondence and reprint requests to Professor C. Pitzalis, Centre for Experimental Medicine and Rheumatology, 2nd Floor, John Vane Science Centre, William Harvey Research Institute, St. Bartholomew’s and Royal London School of Medicine, Charterhouse Square, London, United Kingdom. E-mail address: c.pitzalis{at}qmul.ac.uk
4 Abbreviations used in this paper: SS, Sjögren’s syndrome; SG, salivary gland; GC-LS, germinal center-like structures; CSR, class switch recombination; SHM, somatic hypermutation; mSG, minor (labial) salivary glands; FDC, follicular dendritic cells; RF, rheumatoid factor; IF, interfollicular; MZB, marginal zone; FoB, follicular B cells; NSCS, nonspecific chronic sialoadenitis; LESA, lympho-epithelial sialoadenitis; IHC, immunohistochemistry; AID, activation-induced cytidine deaminase; LN, lymph node.
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