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Systems biology analysis of Sjogren's syndrome and mucosa-associated lymphoid tissue lymphoma in parotid glands.

ABSTRACT: To identify key target genes and activated signaling pathways associated with the pathogenesis of Sjögren's syndrome (SS) by conducting a systems analysis of parotid glands manifesting primary SS or primary SS/mucosa-associated lymphoid tissue (MALT) lymphoma phenotypes.A systems biology approach was used to analyze parotid gland tissue samples obtained from patients with primary SS, patients with primary SS/MALT lymphoma, and subjects without primary SS (non-primary SS controls). The tissue samples were assessed concurrently by gene-expression microarray profiling and proteomics analysis, followed by weighted gene-coexpression network analysis.Gene-coexpression modules related to primary SS and primary SS/MALT lymphoma were significantly enriched with genes known to be involved in the immune/defense response, apoptosis, cell signaling, gene regulation, and oxidative stress. Detailed functional pathway analyses indicated that primary SS-associated modules were enriched with genes involved in proteasome degradation, apoptosis, signal peptides of the class I major histocompatibility complex (MHC), complement activation, cell growth and death, and integrin-mediated cell adhesion, while primary SS/MALT lymphoma-associated modules were enriched with genes involved in translation, ribosome biogenesis and assembly, proteasome degradation, class I MHC signal peptides, the G13 signaling pathway, complement activation, and integrin-mediated cell adhesion. Combined analyses of gene expression and proteomics data implicated 6 highly connected "hub" genes for distinguishing primary SS from non-primary SS, and 8 hub genes for distinguishing primary SS/MALT lymphoma from primary SS.Systems biology analyses of the parotid glands from patients with primary SS and those with primary SS/MALT lymphoma revealed pathways and molecular targets associated with disease pathogenesis. The identified gene modules/pathways provide further insights into the molecular mechanisms of primary SS and primary SS/MALT lymphoma. The identified disease-hub genes represent promising targets for therapeutic intervention, diagnosis, and prognosis.

SUBMITTER: Hu S

PROVIDER: S-EPMC2718690 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Systems biology analysis of Sjögren's syndrome and mucosa-associated lymphoid tissue lymphoma in parotid glands.

Hu Shen S Zhou Michael M Jiang Jiang J Wang Jianghua J Elashoff David D Gorr Sven S Michie Sara A SA Spijkervet Fred K L FK Bootsma Hendrika H Kallenberg Cees G M CG Vissink Arjan A Horvath Steve S Wong David T DT

Arthritis and rheumatism 20090101 1

<h4>Objective</h4>To identify key target genes and activated signaling pathways associated with the pathogenesis of Sjögren's syndrome (SS) by conducting a systems analysis of parotid glands manifesting primary SS or primary SS/mucosa-associated lymphoid tissue (MALT) lymphoma phenotypes.<h4>Methods</h4>A systems biology approach was used to analyze parotid gland tissue samples obtained from patients with primary SS, patients with primary SS/MALT lymphoma, and subjects without primary SS (non-pr ...[more]

PMID: 19116902

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Project description:ObjectivePatients 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.MethodsB 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.ResultsNine (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.ConclusionA 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.

Project description:BackgroundMucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal lymphoma with an indolent natural course. The thyroid gland is an uncommon site of involvement. We aimed to investigate serial ultrasound features and the disease progression during the clinical course of thyroid MALT lymphoma.MethodsWe searched our hospital's pathology database (5,418 patients with thyroid malignancy) between January 2000 and July 2022. The medical records and serial ultrasounds of 11 patients with 12 thyroid MALT lymphoma foci were analyzed retrospectively.ResultsAn enlarging neck mass, dyspnea, B symptoms, and neck lymphadenopathy were seen at diagnosis in 9 (9/11, 81.8%), 3 (3/11, 27.3%), 2 (2/11, 18.2%), and 9 (9/11, 81.8%) cases, respectively. Eleven cases were concomitant Hashimoto thyroiditis. Common ultrasound features included bilateral or unilateral asymmetric goiter or large, solid, and very hypoechoic nodules (11/12, 91.7%) interspersed with linear, reticular hyperechoic, and enhanced posterior echoes (11/12, 91.7%), and neck lymph node involvement (10/11, 90.9%). The Thyroid Imaging and Reporting Data System (TIRADS) categories showed higher diagnostic accuracy (11/12, 91.7%) than real-time ultrasound (2/12, 16.7%) in evaluating thyroid lesions for recommendation of fine-needle aspiration (FNA). Serial ultrasound showed self-limiting changes in three cases, relapse in three cases after subtotal thyroidectomy and chemotherapy, large cell transformation (LCT) in one case after left lobectomy, partial remission in one case, and complete remission after chemo/radiation in four cases; progression to enlarged thyroid nodules occurred in three cases without treatment, with no obvious change observed after diagnosis. Three patients died during follow-up.ConclusionOn sonograms, solid large thyroid nodules or goiter with very hypoechoic and enhanced posterior echoes in the setting of Hashimoto thyroiditis should raise suspicion for MALT lymphoma. TIRADS categories can improve the ultrasound diagnostic efficacy for malignancy. Serial ultrasound examinations demonstrated self-limiting and indolent natures of thyroid MALT lymphoma.

Dataset Information

Systems biology analysis of Sjogren's syndrome and mucosa-associated lymphoid tissue lymphoma in parotid glands.

Publications

Systems biology analysis of Sjögren's syndrome and mucosa-associated lymphoid tissue lymphoma in parotid glands.

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