Gene Expression of Catalytic Proteasome Subunits and Resistance Toward Proteasome Inhibition of B Lymphocytes from Patients with Primary Sjögren Syndrome

Martínez-Gamboa, Lorena; Lesemann, Karsten; Kuckelkorn, Ulrike; Scheffler, Sonja; Ghannam, Khetam; Hahne, M.; Gaber-Elsner, Timo; Egerer, Karl; Naumann, Ludmila; Buttgereit, Frank; Dörner, Thomas; Kloetzel, Peter M.; Burmester, Gerd R.; Faustman, Denise L.; Feist, Eugen

doi:10.3899/jrheum.120680

Cited by 10 publications

(6 citation statements)

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“…As a result of duplication in Case4, the overexpression of TBP can occur, causing the failure of oocyte maturation. The 6q27 region also includes PSMB1 ( proteasome subunit , beta-type , 1 , MIM*602017), associated with Sjögren's syndrome ( Martinez-Gamboa et al , 2013 ), a chronic autoinflammatory disease, suggesting autoimmune reactions as the cause of this patient’s POF at the age of 24 years. SCARB1 ( scavenger receptor class b , member 1 at 12q43; MIM*601040), detected in Case 9, mediates cholesterol transfer to and from high-density lipoprotein (HDL).…”

Section: Discussionmentioning

confidence: 99%

Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

et al. 2016

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STUDY QUESTIONCan spontaneous premature ovarian failure (POF) patients derived from population-based biobanks reveal the association between copy number variations (CNVs) and POF?SUMMARY ANSWERCNVs can hamper the functional capacity of ovaries by disrupting key genes and pathways essential for proper ovarian function.WHAT IS KNOWN ALREADYPOF is defined as the cessation of ovarian function before the age of 40 years. POF is a major reason for female infertility, although its cause remains largely unknown.STUDY DESIGN, SIZE, DURATIONThe current retrospective CNV study included 301 spontaneous POF patients and 3188 control individuals registered between 2003 and 2014 at Estonian Genome Center at the University of Tartu (EGCUT) biobank.PARTICIPANTS/MATERIALS, SETTING, METHODSDNA samples from 301 spontaneous POF patients were genotyped by Illumina HumanCoreExome (258 samples) and HumanOmniExpress (43 samples) BeadChip arrays. Genotype and phenotype information was drawn from the EGCUT for the 3188 control population samples, previously genotyped with HumanCNV370 and HumanOmniExpress BeadChip arrays. All identified CNVs were subjected to functional enrichment studies for highlighting the POF pathogenesis. Real-time quantitative PCR was used to validate a subset of CNVs. Whole-exome sequencing was performed on six patients carrying hemizygous deletions that encompass genes essential for meiosis or folliculogenesis.MAIN RESULTS AND THE ROLE OF CHANCEEleven novel microdeletions and microduplications that encompass genes relevant to POF were identified. For example, FMN2 (1q43) and SGOL2 (2q33.1) are essential for meiotic progression, while TBP (6q27), SCARB1 (12q24.31), BNC1 (15q25) and ARFGAP3 (22q13.2) are involved in follicular growth and oocyte maturation. The importance of recently discovered hemizygous microdeletions of meiotic genes SYCE1 (10q26.3) and CPEB1 (15q25.2) in POF patients was also corroborated.LIMITATIONS, REASONS FOR CAUTIONThis is a descriptive analysis and no functional studies were performed. Anamnestic data obtained from population-based biobank lacked clinical, biological (hormone levels) or ultrasonographical data, and spontaneous POF was predicted retrospectively by excluding known extraovarian causes for premature menopause.WIDER IMPLICATIONS OF THE FINDINGSThe present study, with high number of spontaneous POF cases, provides novel data on associations between the genomic aberrations and premature menopause of ovarian cause and demonstrates that population-based biobanks are powerful source of biological samples and clinical data to reveal novel genetic lesions associated with human reproductive health and disease, including POF.STUDY FUNDING/COMPETING INTERESTThis study was supported by the Estonian Ministry of Education and Research (IUT20-43, IUT20-60, IUT34-16, SF0180027s10 and 9205), Enterprise Estonia (EU30020 and EU48695), Eureka's EUROSTARS programme (NOTED, EU41564), grants from European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, |EU324509) and Ho...

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Section: Discussionmentioning

confidence: 99%

Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

et al. 2016

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“…In this respect, PSMB5 (β5) subunits were often found upregulated upon BTZ exposure in BTZ-resistant cells to compensate for inhibitory effects on proteasome activity [ 51 ]. Interestingly, Martinez-Gamboa and colleagues [ 52 ] observed that intrinsic factors and aberrant proteasome activation established dysregulation of β1i proteasome subunit expression in B lymphocytes of SS patients, conferring diminished PI inhibition and resistance to apoptosis. PI exposure and resistance may also provoke alterations in the relative composition of constitutive and immunoproteasome subunits, the impact of which on immune functions is not clear [ 53 , 54 ].…”

Section: Mechanisms Of Proteasome Inhibitor Resistance and Implicatiomentioning

confidence: 99%

Proteasome inhibitors as experimental therapeutics of autoimmune diseases

Verbrugge¹,

Scheper²,

Lems³

et al. 2015

Arthritis Res Ther

108

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Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren’s syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.

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“…23 Interestingly, dysregulated expression levels of catalytic proteasome subunits have been detected in peripheral blood mononuclear cells (PBMCs) from patients with primary SS (pSS). 24 Moreover, the expression of LMP7 was significantly increased in the minor salivary glands of patients with SS. 25 Although previous studies have indicated the involvement of proteasome activation in SS development, it remains largely unknown whether inhibition of the proteasome possesses any therapeutic benefits for the treatment of SS.…”

Section: Introductionmentioning

confidence: 96%

Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome

et al. 2017

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Immunoproteasome activation in immune cells is involved in the modulation of immune responses. Increasing evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases, but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjögren's syndrome (SS). Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS (ESS) in mice. In this study, we detected high levels of low-molecular-weight protein 7 (LMP7), a key subunit of the immunoproteasome, in Th17 cells from ESS mice. Moreover, treatment with bortezomib (BTZ), a proteasome inhibitor, markedly suppressed Th17 differentiation in both murine and human naive T cells in culture. Furthermore, ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS mice. Notably, BTZ-treated ESS mice showed markedly decreased Th17 cells, germinal center B cells and plasma cells in the peripheral lymphoid organs. In addition, adoptively transferred wild type naive CD4 T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS induction. However, BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient mice. Taken together, our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response, which may contribute to the development of a novel therapeutic strategy for the treatment of SS.Cellular &Molecular Immunology advance online publication, 10 July 2017; doi:10.1038/cmi.2017.8.

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Gene Expression of Catalytic Proteasome Subunits and Resistance Toward Proteasome Inhibition of B Lymphocytes from Patients with Primary Sjögren Syndrome

Cited by 10 publications

References 69 publications

Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

Proteasome inhibitors as experimental therapeutics of autoimmune diseases

Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome

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