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Genetics and Asthma
Published in Jonathan A. Bernstein, Mark L. Levy, Clinical Asthma, 2014
Rebecca E. Slager, Xingnan Li, Deborah A. Meyers, Eugene R. Bleecker
Biomarkers such as serum immunoglobulin E (IgE) levels and blood or sputum eosinophil levels may be important in predicting the severity of asthma or the risk of exacerbations. Therefore, many asthma cohorts as well as large population-based studies have evaluated the genetic factors related to these biomarkers (Table 3.2). The GABRIEL cohort performed a GWAS for total serum IgE levels in 7087 subjects with asthma and 7667 controls, and identified one novel locus in the class II region of MHC, which was significant at the genome-wide level.2 This study also observed several genetic variants associated with IgE levels in the Fc fragment of IgE, high affinity I (FCER1A), IL-13, and signal transducer and activator of transcription 6 (STAT6) genes. These genes were also observed in a GWAS of IgE in the general populations.24,25 In the GABRIEL study, genes that were associated with asthma susceptibility generally did not overlap with those associated with IgE, though the authors suggest that loci strongly associated with IgE levels may contribute to the severity or progression of the disease.2 In order to identify IgE-associated genes in asthma populations, Li and colleagues tested SNPs on chromosome 11q13.5 between the open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32) genes, which had previously been identified in genetic analyses of related inflammatory conditions. Four SNPs in this region were significantly associated with total serum IgE levels after adjustment for multiple testing, signifying a common genetic regulation for IgE levels in atopic diseases.26
Immune targeting of three independent suppressive pathways (TIGIT, PD-L1, TGFβ) provides significant antitumor efficacy in immune checkpoint resistant models
Published in OncoImmunology, 2022
S. Elizabeth Franks, Kellsye P. Fabian, Ginette Santiago-Sánchez, Benjamin Wolfson, James W. Hodge
To further support our functional findings, interrogation of the TME revealed significant increases in genes responsible for immune activation of Responders in comparison to untreated controls (Apol6, CD28, FasL, Fcer1a, Icos, IL-12Rβ2, Irf4, Pdcd1, Prf1, TNFRSF4, TNFSF18) (Figure 7b-d), as well as increases in immune activation in Responders in comparison to Non-Responders (Fcer1a, IL-12Rβ2, Prf1, TNFRSF4, and TNFRSF18) (Figures 6 c and d, 7a and b). Additionally, several genes encoding coinhibitory receptors, such as B7-H4 and GITRL, are significantly downregulated in Responders in comparison to Non-Responders (Figure 8a). These data indicate that although we have a global increase of several classically defined positive and negative immune cell subsets, the TME of Responders versus Non-Responders and untreated cohorts remains immunostimulatory, with greater antigen-specificity of cytotoxic T cells (Figures 4 c-g, 5f and g, 6a-d, 7a and b).
Bifidobacterium animalis subspecies lactis modulates the local immune response and glucose uptake in the small intestine of juvenile pigs infected with the parasitic nematode Ascaris suum
Published in Gut Microbes, 2018
Gloria Solano-Aguilar, Terez Shea-Donohue, Kathleen B. Madden, Alejandro Quinoñes, Ethiopia Beshah, Sukla Lakshman, Yue Xie, Harry Dawson, Joseph F. Urban
A selected gene array was evaluated to test the hypothesis that the Bb12-modulated genes that regulate a local type-2 response and glucose absorption in the jejunum.. Forty-three genes were selected to represent categories of relevant cytokines, cytokine receptors, transcription factors, chemokines, mast cell and goblet cell markers, intestinal tight junction, and physiological markers. The jejunum of pigs treated with Bb12 showed no significant change in gene expression compared to placebo-treated pigs except for a <2-fold decrease in expression of IL4 (Figure 6). Infection with A. suum significantly increased (P<0.05) expression of the high affinity Fc receptor of IgE (FCER1A), Resistin-like molecule β (RETNLB), and increased expression of IL-9, IL-13, and mast cell tryptase (TPSAB1) (P<0.1). There was a significantly decreased expression of eosinophil chemotactic protein CCL11, and the inducible gene for cyclooxygenase-2, Cox-2 (PTGS2) (P<0.1) compared to control non-infected pigs (Figure 6). The interaction between Bb12 treatment and infection with A. suum showed a significant (P <0.05) up-regulation in RETNLB, IL-13, FCER1A, IGHE, and IL25(IL-17E).There was a significant (P<0.05) decrease in expression of the signature Th1-associated gene IFNG, as well as IL13RA1, IL10, MUC5AC, TLR9, PAR-1 and Treg-derived SOCS3 (Figure 6). Mast cell-associated markers CMA1 and IL3, and the gene for the tight junction protein, TJP1, and PTGS2, also were significantly (P<0.05) down-regulated in A. suum-infected pigs fed Bb12 (Figure 6).
A pilot study of differential gene expressions in patients with cough variant asthma and classic bronchial asthma
Published in Journal of Asthma, 2022
Guanghong Zhou, Qingcui Zeng, Wei Wei, Hong Teng, Chuntao Liu, Zhongwei Zhou, Binmiao Liang, Huaicong Long
After candidate gene screening and validation, we found that the expression of three genes, IL4, FCER1A and HDC, was upregulated in the CVA group compared with the HC and CA groups. This finding indicated that some genes, such as IL4, FCER1A and HDC, may be related to the process of transformation from CVA to asthma. These three genes were closely related to asthma. The IL4 gene is located at 5q31.1, which is in a susceptibility region for asthma. Interleukin-4, the genetic product of IL4, causes naive CD4+ T cells to highly express STAT6 and GATA3 and differentiate into Th2 cells, which play a critical role in the pathogenesis of asthma (15). FCER1A encodes the alpha subunit of IgE receptors, which also plays a central role in asthma. Candidate gene studies and GWAS showed that single nucleotide polymorphisms (SNPs) in FCER1A were major genetic determinants of IgE levels (16–19). HDC encodes l-histidine decarboxylase, which can catalyze histidine to histamine. Histamine is a major component participating in the pathophysiology of asthma. Ohtsu et al. (20) found that tissues from HDC-deficient mice lacked histamine-synthesizing activity and that the numbers of mast cells were decreased. Many researchers agree that HDC is closely related to asthma (21). To the best of our knowledge, we first found that IL4, FCER1A and HDC were highly related to CVA. However, these genes were not highly expressed in the CA group in our study, which was not consistent with previous studies. The endotypes of asthma can be divided into the ‘Th2-high’ and ‘Th2-low’ subtypes; they are relatively stable subgroups and can be defined by underlying distinct genetic or molecular characteristics (22). The Th2-high subtype occurs in many but not all patients (23).In the early stage of asthma, its gene expression may be up-regulated. Furthermore, a small sample size may result in errors. Therefore, we speculated that the differences between subtypes (CVA and CA) and the sample size could explain the results.