The ubiquitin proteasome system (UPS) has been the subject of intensive research over the past 20 years to define its role in normal physiology and in pathophysiology. Many of these studies have ...focused in on the cardiovascular system and have determined that the UPS becomes dysfunctional in several pathologies such as familial and idiopathic cardiomyopathies, atherosclerosis, and myocardial ischemia. This review presents a synopsis of the literature as it relates to the role of the UPS in myocardial ischemia. Studies have shown that the UPS is dysfunctional during myocardial ischemia, and recent studies have shed some light on possible mechanisms. Other studies have defined a role for the UPS in ischemic preconditioning which is best associated with myocardial ischemia and is thus presented here. Very recent studies have started to define roles for specific proteasome subunits and components of the ubiquitination machinery in various aspects of myocardial ischemia. Lastly, despite the evidence linking myocardial ischemia and proteasome dysfunction, there are continuing suggestions that proteasome inhibitors may be useful to mitigate ischemic injury. This review presents the rationale behind this and discusses both supportive and nonsupportive studies and presents possible future directions that may help in clarifying this controversy.
IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity ST2) is a differentially expressed gene in pathogenic TH2 cells, but its role in ...T-cell effector function has not been elucidated.
We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses. We hypothesized that selective ST2 expression on allergen-specific CD4+ T cells would confer susceptibility to the effects of IL-33.
PBMCs from subjects with food allergy, inhalant allergy, and no allergy were obtained on the basis of clinical history and serum IgE level. A T-cell receptor–dependent CD154 upregulation assay and direct peptide major histocompatibility complex class II tetramer staining were used to profile allergen-specific CD4+ T cells by flow cytometry. Allergen-specific CD4+ T cell cytokine production was evaluated during IL-33 exposure. ST2 expression was also tracked by using a 2-color flow-based assay.
ST2 expression on peripheral allergen-specific CD4+ T cells was confined to subjects with allergy and restricted to TH2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of TH2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive TH2A cells. Allergen-induced ST2 expression on peripheral CD4+ T cells can be used to track allergen-reactive TH2A cells from donors with allergy.
ST2 expression on circulating CD4+ T cells represents a transient phenotype associated with TH2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic TH2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.
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Interferon regulatory factor 5 (IRF5) is widely recognized as a risk locus for systemic lupus erythematosus (SLE). Risk gene and IRF5 activation is triggered through toll-like receptor signaling. In ...myeloid cells, this leads to production of type I interferon and inflammatory cytokines, with enhanced production in cells of individuals harboring IRF5 risk alleles. Mouse models have also demonstrated the importance of IRF5 in B cell function, particularly plasma cell differentiation and isotype switching. Here, we evaluated the major SLE risk haplotype of IRF5 on the functional attributes of freshly isolated B cells from human subjects who do not have evidence of SLE or other forms of autoimmunity. We took this approach to avoid the complications of studying genotype-phenotype relationships in B cells that have been chronically exposed to an inflammatory disease environment before isolation. We focused on B cell endophenotypes that included gene expression, antibody secretion, class switching, and apoptotic susceptibility. We performed IRF5 overexpression studies, genetic reporter assays and electro-mobility shift assays on B and myeloid cell lines. Somewhat surprisingly, the results of our analyses indicate that IRF5 risk genotypes do not have a B cell intrinsic effect on these B cell functions. By contrast, we confirmed that the IRF5 risk and non-risk haplotypes exert differential effects in myeloid cells, including an increased susceptibility to apoptosis conferred by the risk haplotype. We also demonstrated an increased binding of the transcription factor specificity protein 1 to an insertion/deletion present in the risk haplotype. Our findings raise the specter that genetic risk alleles can have complex and unexpected lineage-specific effects, and these must be carefully considered when guiding or developing therapies based on understanding disease risk haplotypes.
DNA-reactive B cells in lupus Suurmond, Jolien; Calise, Justine; Malkiel, Susan ...
Current opinion in immunology,
12/2016, Letnik:
43
Journal Article
Recenzirano
Odprti dostop
Highlights • Diverse tolerance checkpoints prevent production of IgG anti-DNA antibodies. • Genetic factors contribute to failed tolerance in SLE and may explain patient heterogeneity. • ...Understanding of the function of risk alleles may advance personalized medicine.
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Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions.
This study aimed to determine whether inherent ...qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT).
We first performed ex vivo T-cell profiling on peanut-reactive CD154+CD137+ T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4+ T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT.
Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6−CRTH2+ and CCR6+CRTH2−). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of TH2A pTeff cells. PnOIT induced elimination of TH2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of TH2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation.
Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and increased expression of interferon inducible genes. Interferon regulatory factor 5 (IRF5) is ...an SLE risk gene with several associated polymorphisms. IRF5 activation is induced by toll-like receptor (TLR) activation. In myeloid cells, this leads to production of type I interferon (IFN) and inflammatory cytokines, with enhanced production in cells of individuals harboring risk alleles. Mouse models have demonstrated the importance of IRF5 in B cell function. Mouse models have also suggested regulation occurring between IRF5 and the Fc receptor IIb for immunoglobulin gamma (FcγRIIb), and synergy occurring involving IRF5, estrogen, and IFN. Here, we defined an IRF5 SLE risk haplotype and examined the effects of estrogen and IFN on IRF5 in human B cells and monocytes. we also investigate the possibility of a relationship between IRF5 and FcγRIIb. We found that IRF5 expression is not altered by estrogen in B cells or monocytes, and IRF5 does not regulate FcγRIIb expression as previously reported in mice. We confirm the IRF5 risk haplotype exerts differential effects in myeloid cells, conferring increased susceptibility to apoptosis and increased binding of the transcription factor specificity protein 1 (SP1) to an indel in the risk haplotype. While we also confirm that IRF5 is functional in human B cells, the risk haplotype does not affect gene expression or B cell function. Our findings demonstrate that genetic risk alleles exert lineage-specific effects and have implications for development of novel risk haplotype-based therapies.
IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity ST2) is a differentially expressed gene in pathogenic T
2 cells, but its role in ...T-cell effector function has not been elucidated.
We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses. We hypothesized that selective ST2 expression on allergen-specific CD4
T cells would confer susceptibility to the effects of IL-33.
PBMCs from subjects with food allergy, inhalant allergy, and no allergy were obtained on the basis of clinical history and serum IgE level. A T-cell receptor-dependent CD154 upregulation assay and direct peptide major histocompatibility complex class II tetramer staining were used to profile allergen-specific CD4
T cells by flow cytometry. Allergen-specific CD4
T cell cytokine production was evaluated during IL-33 exposure. ST2 expression was also tracked by using a 2-color flow-based assay.
ST2 expression on peripheral allergen-specific CD4
T cells was confined to subjects with allergy and restricted to T
2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of T
2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive T
2A cells. Allergen-induced ST2 expression on peripheral CD4
T cells can be used to track allergen-reactive T
2A cells from donors with allergy.
ST2 expression on circulating CD4
T cells represents a transient phenotype associated with T
2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic T
2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.
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