Salivary Gland Mucosa-Associated Lymphoid Tissue-Type Lymphoma From Sjögren's Syndrome Patients in the Majority Express Rheumatoid Factors Affinity-Selected for IgG

Overview

Journal Arthritis Rheumatol

Publisher Wiley

Specialty Rheumatology

Date 2020 Mar 18

PMID 32182401

Citations 18

Authors

Richard J Bende

Jerry Janssen

Anna Beentjes

Thera A M Wormhoudt

Koen Wagner

Erlin A Haacke

Frans G M Kroese

Jeroen E J Guikema

Carel J M van Noesel

Affiliations

Soon will be listed here.

Abstract

Objective: Patients with Sjӧgren's syndrome (SS) have an increased risk of developing malignant B cell lymphomas, particularly mucosa-associated lymphoid tissue (MALT)-type lymphomas. We have previously shown that a predominant proportion of patients with SS-associated salivary gland MALT lymphoma express somatically hypermutated IgM with strong amino acid sequence homology with stereotypic rheumatoid factors (RFs). The present study was undertaken in a larger cohort of patients with SS-associated MALT lymphoma to more firmly assess the frequency of RF reactivity and the significance of somatic IGV-region mutations for RF reactivity.

Methods: B cell antigen receptors (BCRs) of 16 patients with SS-associated salivary gland MALT lymphoma were analyzed. Soluble recombinant IgM was produced of 12 MALT lymphoma samples, including 1 MALT lymphoma sample that expressed an IgM antibody fitting in a novel IGHV3-30-encoded stereotypic IGHV subset. For 4 of the 12 IgM antibodies from MALT lymphoma samples, the somatically mutated IGHV and IGKV gene sequences were reverted to germline configurations. Their RF activity and binding affinity were determined by enzyme-linked immunosorbent assay and surface plasmon resonance, respectively.

Results: Nine (75%) of the 12 IgM antibodies identified in patients with SS-associated salivary gland MALT lymphoma displayed strong monoreactive RF activity. Reversion of the IGHV and IGKV mutations to germline configuration resulted in RF affinities for IgG that were significantly lower for 3 of the 4 somatically mutated IgM antibodies. In stereotypic IGHV3-7/IGKV3-15-encoded RFs, a recurrent replacement mutation in the IGKV3-15-third complementarity-determining region was found to play a pivotal role in the affinity for IgG-Fc.

Conclusion: A majority of patients with SS-associated salivary gland MALT lymphoma express somatically mutated BCRs that are selected for monoreactive, high-affinity binding of IgG-Fc. These data underscore the notion that soluble IgG, most likely in immune complexes in inflamed tissues, is the principal autoantigen in the pathogenesis of a variety of B cell lymphomas, particularly SS-associated MALT lymphomas.

Citing Articles

Malignant Salivary Gland Tumors in a Tertiary University Hospital in Northern Spain.

Chiesa-Estomba C, Rodriguez-Urzay A, Landa-Garmendia M, Larruscain-Sarasola E, Gonzalez-Garcia J, Sistiaga-Suarez J J Clin Med. 2025; 14(1.

PMID: 39797128 PMC: 11721706. DOI: 10.3390/jcm14010046.

Somatic mutations in autoinflammatory and autoimmune disease.

Torreggiani S, Castellan F, Aksentijevich I, Beck D Nat Rev Rheumatol. 2024; 20(11):683-698.

PMID: 39394526 DOI: 10.1038/s41584-024-01168-8.

Distinct groups of autoantigens as drivers of ocular adnexal MALT lymphoma pathogenesis.

Bende R, Donner N, Wormhoudt T, Beentjes A, Scantlebery A, Grobben M Life Sci Alliance. 2024; 7(9).

PMID: 38977312 PMC: 11231493. DOI: 10.26508/lsa.202402841.

B-Cell Receptor Repertoire: Recent Advances in Autoimmune Diseases.

Wang Q, Feng D, Jia S, Lu Q, Zhao M Clin Rev Allergy Immunol. 2024; 66(1):76-98.

PMID: 38459209 DOI: 10.1007/s12016-024-08984-6.

Clinical relevance of molecular aspects in extranodal marginal zone lymphoma: a critical appraisal.

Raderer M, Kiesewetter B, Du M Ther Adv Med Oncol. 2023; 15:17588359231183565.

PMID: 37389189 PMC: 10302523. DOI: 10.1177/17588359231183565.

References

van Maldegem F, Wormhoudt T, Mulder M, Oud M, Schilder-Tol E, Musler A . Chlamydia psittaci-negative ocular adnexal marginal zone B-cell lymphomas have biased VH4-34 immunoglobulin gene expression and proliferate in a distinct inflammatory environment. Leukemia. 2012; 26(7):1647-53. DOI: 10.1038/leu.2012.28. View

Smedby K, Vajdic C, Falster M, Engels E, Martinez-Maza O, Turner J . Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood. 2008; 111(8):4029-38. PMC: 2288717. DOI: 10.1182/blood-2007-10-119974. View

Miklos J, Swerdlow S, Bahler D . Salivary gland mucosa-associated lymphoid tissue lymphoma immunoglobulin V(H) genes show frequent use of V1-69 with distinctive CDR3 features. Blood. 2000; 95(12):3878-84. View

Bende R, Jochems G, Frame T, Klein M, van Eijk R, van Lier R . Effects of IL-4, IL-5, and IL-6 on growth and immunoglobulin production of Epstein-Barr virus-infected human B cells. Cell Immunol. 1992; 143(2):310-23. DOI: 10.1016/0008-8749(92)90028-n. View

Goules A, Tzioufas A . Lymphomagenesis in Sjögren's syndrome: Predictive biomarkers towards precision medicine. Autoimmun Rev. 2018; 18(2):137-143. DOI: 10.1016/j.autrev.2018.08.007. View

Bende R, van Maldegem F, van Noesel C . Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas. Haematologica. 2009; 94(8):1109-23. PMC: 2719034. DOI: 10.3324/haematol.2009.005983. View

Maibom-Thomsen S, Trier N, Holm B, Hansen K, Rasmussen M, Chailyan A . Immunoglobulin G structure and rheumatoid factor epitopes. PLoS One. 2019; 14(6):e0217624. PMC: 6568389. DOI: 10.1371/journal.pone.0217624. View

Bende R, Slot L, Hoogeboom R, Wormhoudt T, Adeoye A, Guikema J . Stereotypic rheumatoid factors that are frequently expressed in mucosa-associated lymphoid tissue-type lymphomas are rare in the labial salivary glands of patients with Sjögren's syndrome. Arthritis Rheumatol. 2014; 67(4):1074-83. DOI: 10.1002/art.39002. View

Mietzner B, Tsuiji M, Scheid J, Velinzon K, Tiller T, Abraham K . Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. Proc Natl Acad Sci U S A. 2008; 105(28):9727-32. PMC: 2474524. DOI: 10.1073/pnas.0803644105. View

10.

Charles E, Orloff M, Nishiuchi E, Marukian S, Rice C, Dustin L . Somatic hypermutations confer rheumatoid factor activity in hepatitis C virus-associated mixed cryoglobulinemia. Arthritis Rheum. 2013; 65(9):2430-40. PMC: 4026862. DOI: 10.1002/art.38041. View

11.

Borretzen M, Chapman C, Natvig J, Thompson K . Differences in mutational patterns between rheumatoid factors in health and disease are related to variable heavy chain family and germ-line gene usage. Eur J Immunol. 1997; 27(3):735-41. DOI: 10.1002/eji.1830270323. View

12.

Charles E, Brunetti C, Marukian S, Ritola K, Talal A, Marks K . Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset. Blood. 2011; 117(20):5425-37. PMC: 3109715. DOI: 10.1182/blood-2010-10-312942. View

13.

Nocturne G, Pontarini E, Bombardieri M, Mariette X . Lymphomas complicating primary Sjögren's syndrome: from autoimmunity to lymphoma. Rheumatology (Oxford). 2019; 60(8):3513-3521. PMC: 8328496. DOI: 10.1093/rheumatology/kez052. View

14.

De Re V, De Vita S, Marzotto A, Rupolo M, Gloghini A, Pivetta B . Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood. 2000; 96(10):3578-84. View

15.

Visser A, Doorenspleet M, de Vries N, Spijkervet F, Vissink A, Bende R . Acquisition of N-Glycosylation Sites in Immunoglobulin Heavy Chain Genes During Local Expansion in Parotid Salivary Glands of Primary Sjögren Patients. Front Immunol. 2018; 9:491. PMC: 5890187. DOI: 10.3389/fimmu.2018.00491. View

16.

Bende R, van Noesel C . Rheumatoid Factor Reactivity of Expanded CD21 B Cells in Patients With Sjögren's Syndrome: Comment on the Article by Glauzy et al. Arthritis Rheumatol. 2018; 71(1):169-170. DOI: 10.1002/art.40756. View

17.

Wang J, Reed J, Colella A, Russell A, Murray-Brown W, Chataway T . Molecular Profiling and Clonal Tracking of Secreted Rheumatoid Factors in Primary Sjögren's Syndrome. Arthritis Rheumatol. 2018; 70(10):1617-1625. DOI: 10.1002/art.40539. View

18.

Reed J, Gorny M, Li L, Cardozo T, Buyon J, Clancy R . Ro52 autoantibodies arise from self-reactive progenitors in a mother of a child with neonatal lupus. J Autoimmun. 2017; 79:99-104. PMC: 5386791. DOI: 10.1016/j.jaut.2017.01.004. View

19.

van Dongen J, Langerak A, Bruggemann M, Evans P, Hummel M, Lavender F . Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003; 17(12):2257-317. DOI: 10.1038/sj.leu.2403202. View

20.

Bende R, Janssen J, Wormhoudt T, Wagner K, Guikema J, van Noesel C . Identification of a novel stereotypic IGHV4-59/IGHJ5-encoded B-cell receptor subset expressed by various B-cell lymphomas with high affinity rheumatoid factor activity. Haematologica. 2016; 101(5):e200-3. PMC: 5004362. DOI: 10.3324/haematol.2015.139626. View