Dataset Information

Mucosa-associated lymphoid tissue lymphoma translocation 1 as a novel therapeutic target for rheumatoid arthritis.

ABSTRACT: Emerging evidence suggests that mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a key regulator of inflammatory diseases; however, the pathological role of MALT1 in rheumatoid arthritis (RA) is not well understood. Consequently, this protein has not been therapeutically targeted for the treatment of RA. MALT1 plays a role in the paracaspase pathway, has proteolytic activity and is involved in the regulation of inflammatory responses. In this study, we found that the MALT1-targeting inhibitory small molecule, MALT1 selective inhibitor 2-chloro-N-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1H-1,2,4-triazol-1-yl]phenylacetamide (MI-2) strongly suppresses the differentiation of monocytes into osteoclasts in the absence or presence of the inflammatory cytokine tumour necrosis factor ?. Furthermore, MI-2 ameliorates pathologic bone erosion and synovitis in an in vivo mouse model of collagen-induced arthritis. Mechanistically, MI-2 blocked expression of the master osteoclast regulator - nuclear factor of activated T cells 1 (NFATc1) - by inhibiting nuclear factor ?B (NF-?B), which is a critical regulator of NFATc1. These findings highlight the important regulatory role of MALT1 in the NF-?B-NFATc1-signalling axis during osteoclastogenesis and suggest that targeting MALT1 is a promising treatment option for rheumatoid arthritis.

SUBMITTER: Lee CH

PROVIDER: S-EPMC5605699 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mucosa-associated lymphoid tissue lymphoma translocation 1 as a novel therapeutic target for rheumatoid arthritis.

Lee Chang Hoon CH Bae Su Jeong SJ Kim Miok M

Scientific reports 20170919 1

Emerging evidence suggests that mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a key regulator of inflammatory diseases; however, the pathological role of MALT1 in rheumatoid arthritis (RA) is not well understood. Consequently, this protein has not been therapeutically targeted for the treatment of RA. MALT1 plays a role in the paracaspase pathway, has proteolytic activity and is involved in the regulation of inflammatory responses. In this study, we found that the MALT1-t ...[more]

PMID: 28928392

Similar Datasets

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.

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.

Dataset Information

Mucosa-associated lymphoid tissue lymphoma translocation 1 as a novel therapeutic target for rheumatoid arthritis.

Publications

Mucosa-associated lymphoid tissue lymphoma translocation 1 as a novel therapeutic target for rheumatoid arthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets