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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2011

Open Access 01-02-2011 | Research article

Salivary glands of primary Sjögren's syndrome patients express factors vital for plasma cell survival

Authors: Ewa A Szyszko, Karl A Brokstad, Gunnvor Øijordsbakken, Malin V Jonsson, Roland Jonsson, Kathrine Skarstein

Published in: Arthritis Research & Therapy | Issue 1/2011

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Abstract

Introduction

The presence of circulating Ro/SSA and La/SSB autoantibodies has become an important marker in the classification criteria for primary Sjögren's syndrome (pSS). Plasma cells producing these autoantibodies are mainly high affinity plasma cells originating from germinal centre reactions. When exposed to the right microenvironment these autoimmune plasma cells become long-lived and resistant to immunosuppressive treatment. Since autoimmune plasma cells have been detected in the salivary glands of SS patients, we wanted to investigate if the glandular microenvironment is suitable for plasma cell survival and if glandular residing plasma cells are the long-lived plasma cell subset.

Methods

Single, double and triple immunohistochemistry as well as immunofluorescence staining was performed on minor salivary gland tissue retrieved from pSS, chronically inflamed and normal subjects.

Results

We detected significant numbers of CD138+, non-proliferating, Bcl-2 expressing plasma cells in the salivary glands of pSS patients with high focus score (FS). Furthermore, we demonstrated that CXCL12 and interleukin (IL)-6 survival factors were highly expressed in pSS salivary gland epithelium and by focal mononuclear infiltrating cells. Notably, adipocytes when present in the salivary gland tissue were an important source of CXCL12. We clearly demonstrate that plasma cells are localised in close proximity to CXCL12 and IL-6 expressing cells and thus that the environment of salivary glands with high FS provide factors vital for plasma cell survival.

Conclusions

Plasma cells residing in the salivary glands of pSS patients with high FS showed phenotypic characteristics of the long-lived plasma cell subtype. Furthermore, the pSS salivary gland microenvironment provided niches rich in factors vital for plasma cell survival.
Appendix
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Literature
1.
Shlomchik M, Mascelli M, Shan H, Radic MZ, Pisetsky D, Marshak-Rothstein A, Weigert M: Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med. 1990, 171: 265-292. 10.1084/jem.171.1.265.CrossRefPubMed
2.
Tengner P, Halse AK, Haga HJ, Jonsson R, Wahren-Herlenius M: Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjogren's syndrome. Arthritis Rheum. 1998, 41: 2238-2248. 10.1002/1529-0131(199812)41:12<2238::AID-ART20>3.0.CO;2-V.CrossRefPubMed
3.
Halse A, Harley JB, Kroneld U, Jonsson R: Ro/SS-A-reactive B lymphocytes in salivary glands and peripheral blood of patients with Sjogren's syndrome. Clin Exp Immunol. 1999, 115: 203-207. 10.1046/j.1365-2249.1999.00778.x.PubMedCentralCrossRefPubMed
4.
Pourmand N, Wahren-Herlenius M, Gunnarsson I, Svenungsson E, Lofstrom B, Ioannou Y, Isenberg DA, Magnusson CG: Ro/SSA and La/SSB specific IgA autoantibodies in serum of patients with Sjogren's syndrome and systemic lupus erythematosus. Ann Rheum Dis. 1999, 58: 623-629. 10.1136/ard.58.10.623.PubMedCentralCrossRefPubMed
5.
Halse AK, Marthinussen MC, Wahren-Herlenius M, Jonsson R: Isotype distribution of anti-Ro/SS-A and anti-La/SS-B antibodies in plasma and saliva of patients with Sjogren's syndrome. Scand J Rheumatol. 2000, 29: 13-19.CrossRefPubMed
6.
Iwasaki K, Okawa-Takatsuji M, Aotsuka S, Ono T: Detection of anti-SS-A/Ro and anti-SS-B/La antibodies of IgA and IgG isotypes in saliva and sera of patients with Sjogren's syndrome. Nihon Rinsho Meneki Gakkai Kaishi. 2003, 26: 346-354.CrossRefPubMed
7.
Jonsson R, Kroneld U, Backman K, Magnusson B, Tarkowski A: Progression of sialadenitis in Sjogren's syndrome. Br J Rheumatol. 1993, 32: 578-581. 10.1093/rheumatology/32.7.578.CrossRefPubMed
8.
Jonsson R, Nginamau E, Szyszko E, Brokstad KA: Role of B cells in Sjogren's syndrome-from benign lymphoproliferation to overt malignancy. Front Biosci. 2007, 12: 2159-2170. 10.2741/2219.CrossRefPubMed
9.
Jonsson MV, Skarstein K: Follicular dendritic cells confirm lymphoid organization in the minor salivary glands of primary Sjogren's syndrome. J Oral Pathol Med. 2008, 37: 515-521. 10.1111/j.1600-0714.2008.00674.x.CrossRefPubMed
10.
Vogelsang P, Brun JG, Oijordsbakken G, Skarstein K, Jonsson R, Appel S: Levels of plasmacytoid dendritic cells and type-2 myeloid dendritic cells are reduced in peripheral blood of patients with primary Sjogren's syndrome. Ann Rheum Dis. 2010, 69: 1235-1238. 10.1136/ard.2009.118158.CrossRefPubMed
11.
Barone F, Bombardieri M, Manzo A, Blades MC, Morgan PR, Challacombe SJ, Valesini G, Pitzalis C: Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren's syndrome. Arthritis Rheum. 2005, 52: 1773-1784. 10.1002/art.21062.CrossRefPubMed
12.
Amft N, Curnow SJ, Scheel-Toellner D, Devadas A, Oates J, Crocker J, Hamburger J, Ainsworth J, Mathews J, Salmon M, Bowman SJ, Buckley CD: Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjogren's syndrome. Arthritis Rheum. 2001, 44: 2633-2641. 10.1002/1529-0131(200111)44:11<2633::AID-ART443>3.0.CO;2-9.CrossRefPubMed
13.
Salomonsson S, Larsson P, Tengner P, Mellquist E, Hjelmstrom P, Wahren-Herlenius M: Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sjogren's syndrome. Scand J Immunol. 2002, 55: 336-342. 10.1046/j.1365-3083.2002.01058.x.CrossRefPubMed
14.
Jonsson MV, Szodoray P, Jellestad S, Jonsson R, Skarstein K: Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjogren's syndrome. J Clin Immunol. 2005, 25: 189-201. 10.1007/s10875-005-4091-5.CrossRefPubMed
15.
Jonsson MV, Skarstein K, Jonsson R, Brun JG: Serological implications of germinal center-like structures in primary Sjogren's syndrome. J Rheumatol. 2007, 34: 2044-2049.PubMed
16.
Barcellos KS, Nonogaki S, Enokihara MM, Teixeira MS, Andrade LE: Differential expression of Ro/SSA 60 kDa and La/SSB, but not Ro/SSA 52 kDa, mRNA and protein in minor salivary glands from patients with primary Sjogren's syndrome. J Rheumatol. 2007, 34: 1283-1292.PubMed
17.
Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren-Herlenius M, Jonsson R: Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren's syndrome. Arthritis Rheum. 2003, 48: 3187-3201. 10.1002/art.11311.CrossRefPubMed
18.
McMillan R, Longmire RL, Yelenosky R, Lang JE, Heath V, Craddock CG: Immunoglobulin synthesis by human lymphoid tissues: normal bone marrow as a major site of IgG production. J Immunol. 1972, 109: 1386-1394.PubMed
19.
Slifka MK, Ahmed R: Long-lived plasma cells: a mechanism for maintaining persistent antibody production. Curr Opin Immunol. 1998, 10: 252-258. 10.1016/S0952-7915(98)80162-3.CrossRefPubMed
20.
Slifka MK, Antia R, Whitmire JK, Ahmed R: Humoral immunity due to long-lived plasma cells. Immunity. 1998, 8: 363-372. 10.1016/S1074-7613(00)80541-5.CrossRefPubMed
21.
Manz RA, Thiel A, Radbruch A: Lifetime of plasma cells in the bone marrow. Nature. 1997, 388: 133-134. 10.1038/40540.CrossRefPubMed
22.
Minges Wols HA, Underhill GH, Kansas GS, Witte PL: The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J Immunol. 2002, 169: 4213-4221.CrossRefPubMed
23.
Cassese G, Arce S, Hauser AE, Lehnert K, Moewes B, Mostarac M, Muehlinghaus G, Szyska M, Radbruch A, Manz RA: Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J Immunol. 2003, 171: 1684-1690.CrossRefPubMed
24.
Manz RA, Radbruch A: Plasma cells for a lifetime?. Eur J Immunol. 2002, 32: 923-927. 10.1002/1521-4141(200204)32:4<923::AID-IMMU923>3.0.CO;2-1.CrossRefPubMed
25.
Cambridge G, Leandro MJ, Teodorescu M, Manson J, Rahman A, Isenberg DA, Edwards JC: B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum. 2006, 54: 3612-3622. 10.1002/art.22211.CrossRefPubMed
26.
Vallerskog T, Gunnarsson I, Widhe M, Risselada A, Klareskog L, van Vollenhoven R, Malmstrom V, Trollmo C: Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE. Clin Immunol. 2007, 122: 62-74. 10.1016/j.clim.2006.08.016.CrossRefPubMed
27.
Schaumann DH, Tuischer J, Ebell W, Manz RA, Lauster R: VCAM-1-positive stromal cells from human bone marrow producing cytokines for B lineage progenitors and for plasma cells: SDF-1, flt3L, and BAFF. Mol Immunol. 2007, 44: 1606-1612. 10.1016/j.molimm.2006.08.021.CrossRefPubMed
28.
Odendahl M, Mei H, Hoyer BF, Jacobi AM, Hansen A, Muehlinghaus G, Berek C, Hiepe F, Manz R, Radbruch A, Dörner T: Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood. 2005, 105: 1614-1621. 10.1182/blood-2004-07-2507.CrossRefPubMed
29.
Hauser AE, Debes GF, Arce S, Cassese G, Hamann A, Radbruch A, Manz RA: Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J Immunol. 2002, 169: 1277-1282.CrossRefPubMed
30.
Kunkel EJ, Butcher EC: Chemokines and the tissue-specific migration of lymphocytes. Immunity. 2002, 16: 1-4. 10.1016/S1074-7613(01)00261-8.CrossRefPubMed
31.
Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, European Study Group on Classification Criteria for Sjögren's Syndrome: Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002, 61: 554-558. 10.1136/ard.61.6.554.PubMedCentralCrossRefPubMed
32.
Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, Radbruch A, Hiepe F, Manz RA: Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med. 2004, 199: 1577-1584. 10.1084/jem.20040168.PubMedCentralCrossRefPubMed
33.
Merville P, Dechanet J, Desmouliere A, Durand I, de Bouteiller O, Garrone P, Banchereau J, Liu YJ: Bcl-2+ tonsillar plasma cells are rescued from apoptosis by bone marrow fibroblasts. J Exp Med. 1996, 183: 227-236. 10.1084/jem.183.1.227.CrossRefPubMed
34.
Medina F, Segundo C, Campos-Caro A, Gonzalez-Garcia I, Brieva JA: The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. Blood. 2002, 99: 2154-2161. 10.1182/blood.V99.6.2154.CrossRefPubMed
35.
Manzo A, Paoletti S, Carulli M, Blades MC, Barone F, Yanni G, Fitzgerald O, Bresnihan B, Caporali R, Montecucco C, Uguccioni M, Pitzalis C: Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur J Immunol. 2005, 35: 1347-1359. 10.1002/eji.200425830.CrossRefPubMed
36.
Weninger W, Carlsen HS, Goodarzi M, Moazed F, Crowley MA, Baekkevold ES, Cavanagh LL, von Andrian UH: Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis. J Immunol. 2003, 170: 4638-4648.CrossRefPubMed
37.
Manzo A, Bugatti S, Caporali R, Prevo R, Jackson DG, Uguccioni M, Buckley CD, Montecucco C, Pitzalis C: CCL21 expression pattern of human secondary lymphoid organ stroma is conserved in inflammatory lesions with lymphoid neogenesis. Am J Pathol. 2007, 171: 1549-1562. 10.2353/ajpath.2007.061275.PubMedCentralCrossRefPubMed
38.
Bombardieri M, Barone F, Humby F, Kelly S, McGurk M, Morgan P, Challacombe S, De Vita S, Valesini G, Spencer J, Pitzalis C: Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjogren's syndrome. J Immunol. 2007, 179: 4929-4938.CrossRefPubMed
39.
Stott DI, Hiepe F, Hummel M, Steinhauser G, Berek C: Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjogren's syndrome. J Clin Invest. 1998, 102: 938-946. 10.1172/JCI3234.PubMedCentralCrossRefPubMed
40.
William J, Euler C, Christensen S, Shlomchik MJ: Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science. 2002, 297: 2066-2070. 10.1126/science.1073924.CrossRefPubMed
41.
Salomonsson S, Rozell BL, Heimburger M, Wahren-Herlenius M: Minor salivary gland immunohistology in the diagnosis of primary Sjogren's syndrome. J Oral Pathol Med. 2009, 38: 282-288. 10.1111/j.1600-0714.2008.00697.x.CrossRefPubMed
42.
Halse A, Wahren-Herlenius M, Jonsson R: Ro/SS-A- and La/SS-B-reactive B lymphocytes in peripheral blood of patients with Sjogren's syndrome. Clin Exp Immunol. 1999, 115: 208-213. 10.1046/j.1365-2249.1999.00779.x.PubMedCentralCrossRefPubMed
43.
Tarte K, Jourdan M, Veyrune JL, Berberich I, Fiol G, Redal N, Shaughnessy J, Klein B: The Bcl-2 family member Bfl-1/A1 is strongly repressed in normal and malignant plasma cells but is a potent anti-apoptotic factor for myeloma cells. Br J Haematol. 2004, 125: 373-382. 10.1111/j.1365-2141.2004.04908.x.PubMedCentralCrossRefPubMed
44.
Spets H, Stromberg T, Georgii-Hemming P, Siljason J, Nilsson K, Jernberg-Wiklund H: Expression of the bcl-2 family of pro- and anti-apoptotic genes in multiple myeloma and normal plasma cells: regulation during interleukin-6(IL-6)-induced growth and survival. Eur J Haematol. 2002, 69: 76-89. 10.1034/j.1600-0609.2002.01549.x.CrossRefPubMed
45.
Jourdan M, De Vos J, Mechti N, Klein B: Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. Cell Death Differ. 2000, 7: 1244-1252. 10.1038/sj.cdd.4400758.PubMedCentralCrossRefPubMed
46.
Rahman Z, Yoshikawa H, Nakajima Y, Tasaka K: Down-regulation of Pim-1 and Bcl-2 is accompanied with apoptosis of interleukin-6-depleted mouse B-cell hybridoma 7TD1 cells. Immunol Lett. 2001, 75: 199-208. 10.1016/S0165-2478(00)00322-9.CrossRefPubMed
47.
Barone F, Bombardieri M, Rosado MM, Morgan PR, Challacombe SJ, De Vita S, Carsetti R, Spencer J, Valesini G, Pitzalis C: CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjogren's syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization. J Immunol. 2008, 180: 5130-5140.CrossRefPubMed
48.
Hargreaves DC, Hyman PL, Lu TT, Ngo VN, Bidgol A, Suzuki G, Zou YR, Littman DR, Cyster JG: A coordinated change in chemokine responsiveness guides plasma cell movements. J Exp Med. 2001, 194: 45-56. 10.1084/jem.194.1.45.PubMedCentralCrossRefPubMed
49.
Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T: Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity. 2004, 20: 707-718. 10.1016/j.immuni.2004.05.001.CrossRefPubMed
50.
Manz RA, Arce S, Cassese G, Hauser AE, Hiepe F, Radbruch A: Humoral immunity and long-lived plasma cells. Curr Opin Immunol. 2002, 14: 517-521. 10.1016/S0952-7915(02)00356-4.CrossRefPubMed
51.
Katsiougiannis S, Kapsogeorgou EK, Manoussakis MN, Skopouli FN: Salivary gland epithelial cells: a new source of the immunoregulatory hormone adiponectin. Arthritis Rheum. 2006, 54: 2295-2299. 10.1002/art.21944.CrossRefPubMed
52.
Katsiougiannis S, Tenta R, Skopouli FN: Activation of AMP-activated protein kinase by adiponectin rescues salivary gland epithelial cells from spontaneous and interferon-gamma-induced apoptosis. Arthritis Rheum. 62: 414-419.
53.
Alexaki VI, Notas G, Pelekanou V, Kampa M, Valkanou M, Theodoropoulos P, Stathopoulos EN, Tsapis A, Castanas E: Adipocytes as immune cells: differential expression of TWEAK, BAFF, and APRIL and their receptors (Fn14, BAFF-R, TACI, and BCMA) at different stages of normal and pathological adipose tissue development. J Immunol. 2009, 183: 5948-5956. 10.4049/jimmunol.0901186.CrossRefPubMed
54.
Miyasaka M, Tanaka T: Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol. 2004, 4: 360-370. 10.1038/nri1354.CrossRefPubMed
55.
Yang BG, Tanaka T, Jang MH, Bai Z, Hayasaka H, Miyasaka M: Binding of lymphoid chemokines to collagen IV that accumulates in the basal lamina of high endothelial venules: its implications in lymphocyte trafficking. J Immunol. 2007, 179: 4376-4382.CrossRefPubMed
Metadata
Title
Salivary glands of primary Sjögren's syndrome patients express factors vital for plasma cell survival
Authors
Ewa A Szyszko
Karl A Brokstad
Gunnvor Øijordsbakken
Malin V Jonsson
Roland Jonsson
Kathrine Skarstein
Publication date
01-02-2011
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2011
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3220

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