Pub Date : 2024-06-01Epub Date: 2024-03-05DOI: 10.1007/s00251-024-01338-8
Manisha Ghosh, Surajit Basak, Shanta Dutta
The transmembrane pattern recognition receptor, Toll-like receptor (TLR), are best known for their roles in innate immunity via recognition of pathogen and initiation of signaling response. Mammalian TLRs recognize molecular patterns associated with pathogens and initiate innate immune response. We have studied the evolutionary diversity of mammalian TLR genes for differences in immunological response. Reconstruction of ancestral sequences is a key aspect of the molecular evolution of TLR to track changes across the TLR genes. The comprehensive analysis of mammalian TLRs revealed a distinct pattern of evolution of TLR9. Various sequence-based features such as amino acid usage, hydrophobicity, GC content, and evolutionary constraints are found to influence the divergence of TLR9 from other TLRs. Ancestral sequence reconstruction analysis also revealed that the gradual evolution of TLR genes in several ancestral lineages leads to the distinct pattern of TLR9. It demonstrates evolutionary divergence with the progressive accumulation of mutations results in the distinct pattern of TLR9.
{"title":"Evolutionary divergence of TLR9 through ancestral sequence reconstruction.","authors":"Manisha Ghosh, Surajit Basak, Shanta Dutta","doi":"10.1007/s00251-024-01338-8","DOIUrl":"10.1007/s00251-024-01338-8","url":null,"abstract":"<p><p>The transmembrane pattern recognition receptor, Toll-like receptor (TLR), are best known for their roles in innate immunity via recognition of pathogen and initiation of signaling response. Mammalian TLRs recognize molecular patterns associated with pathogens and initiate innate immune response. We have studied the evolutionary diversity of mammalian TLR genes for differences in immunological response. Reconstruction of ancestral sequences is a key aspect of the molecular evolution of TLR to track changes across the TLR genes. The comprehensive analysis of mammalian TLRs revealed a distinct pattern of evolution of TLR9. Various sequence-based features such as amino acid usage, hydrophobicity, GC content, and evolutionary constraints are found to influence the divergence of TLR9 from other TLRs. Ancestral sequence reconstruction analysis also revealed that the gradual evolution of TLR genes in several ancestral lineages leads to the distinct pattern of TLR9. It demonstrates evolutionary divergence with the progressive accumulation of mutations results in the distinct pattern of TLR9.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-03-07DOI: 10.1007/s00251-024-01337-9
Rosalyn Jurjus, Laura Dosh, Rima Farhat, Tatiana Daccache, Jad El Masri, Maya Ghazi, Jihad Hawi, Angelo Leone, Abdo Jurjus
Syndecan-1 (Sdc-1), a transmembrane heparan sulfate protein, is implicated in several pathophysiological processes including rheumatoid arthritis (RA). The exact role of Syndican-1 in this autoimmune disease is still undetermined. This study explores the involvement level of Sdc-1 in the development of RA in a collagen II-induced arthritis mice model. RA was induced in two mice strains (wild-type BALB/c group and Sdc-1 knockout) by collagen II. Mice underwent regular clinical observations and scoring. After sacrifice, leg biopsies were taken from mice for histological examination, using a variety of stains. In addition, proteins were extracted, and molecular assessment of TNF-α was performed using the western blot technique. In the Sdc-1 knockout group, clinical scoring results showed a significantly more severe experimental RA; histology showed a significant increase in bone erosion, cartilage destruction, inflammation, and less granulated mast cells than the wild-type. In addition, molecular assessment of TNF-α showed more increase in expression in the Sdc-1 knockout models compared to the wild-type. Data suggest that lack of Sdc-1 enhances the inflammatory characteristics in RA. However, more molecular studies and investigations are needed to determine its exact role and possible mechanisms involved.
Syndecan-1(Sdc-1)是一种跨膜硫酸肝素蛋白,与包括类风湿性关节炎(RA)在内的多种病理生理过程有关。Syndican-1在这种自身免疫性疾病中的确切作用仍未确定。本研究在胶原蛋白 II 诱导的关节炎小鼠模型中探讨了 Sdc-1 在类风湿性关节炎发病过程中的参与水平。通过胶原蛋白 II 诱导两种小鼠品系(野生型 BALB/c 组和 Sdc-1 基因敲除组)的 RA。小鼠定期接受临床观察和评分。小鼠牺牲后,取其腿部活组织切片进行组织学检查,使用多种染色剂。此外,还提取了蛋白质,并使用 Western 印迹技术对 TNF-α 进行了分子评估。在Sdc-1基因敲除组中,临床评分结果显示实验性RA明显更严重;组织学显示骨侵蚀、软骨破坏、炎症和肉芽肥大细胞比野生型明显增加。此外,TNF-α的分子评估显示,与野生型相比,Sdc-1基因敲除模型中的TNF-α表达量增加更多。数据表明,缺乏Sdc-1会增强RA的炎症特征。然而,还需要更多的分子研究和调查来确定其确切作用和可能的机制。
{"title":"Lack of Syndecan-1 promotes the pathogenesis of experimental rheumatoid arthritis.","authors":"Rosalyn Jurjus, Laura Dosh, Rima Farhat, Tatiana Daccache, Jad El Masri, Maya Ghazi, Jihad Hawi, Angelo Leone, Abdo Jurjus","doi":"10.1007/s00251-024-01337-9","DOIUrl":"10.1007/s00251-024-01337-9","url":null,"abstract":"<p><p>Syndecan-1 (Sdc-1), a transmembrane heparan sulfate protein, is implicated in several pathophysiological processes including rheumatoid arthritis (RA). The exact role of Syndican-1 in this autoimmune disease is still undetermined. This study explores the involvement level of Sdc-1 in the development of RA in a collagen II-induced arthritis mice model. RA was induced in two mice strains (wild-type BALB/c group and Sdc-1 knockout) by collagen II. Mice underwent regular clinical observations and scoring. After sacrifice, leg biopsies were taken from mice for histological examination, using a variety of stains. In addition, proteins were extracted, and molecular assessment of TNF-α was performed using the western blot technique. In the Sdc-1 knockout group, clinical scoring results showed a significantly more severe experimental RA; histology showed a significant increase in bone erosion, cartilage destruction, inflammation, and less granulated mast cells than the wild-type. In addition, molecular assessment of TNF-α showed more increase in expression in the Sdc-1 knockout models compared to the wild-type. Data suggest that lack of Sdc-1 enhances the inflammatory characteristics in RA. However, more molecular studies and investigations are needed to determine its exact role and possible mechanisms involved.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-03-13DOI: 10.1007/s00251-024-01336-w
Nicky A Beelen, Stefan J J Molenbroeck, Lisette Groeneveld, Christien E Voorter, Gerard M J Bos, Lotte Wieten
Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of malignant plasma cells in the bone marrow. Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called "education" to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression ("Missing-self" hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1+C2+Bw4+) was not associated with MM occurrence. However, MM patients were more likely to be C1-/C2+/Bw4+ (p = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (p = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2/KIR2DL1 and Bw4/KIR3DL1 (p = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM.
多发性骨髓瘤(MM)是一种由骨髓中恶性浆细胞克隆性扩增引起的血液恶性肿瘤。骨髓瘤细胞容易被自然杀伤(NK)细胞杀死,但NK细胞无法控制疾病的进展,这表明存在免疫抑制。NK效应功能的激活阈值受KIR与自身HLA I类之间相互作用的调节,这一过程被称为 "教育",以确保自身耐受。NK 细胞可以在缺乏 HLA I 类表达的情况下对病变细胞做出反应("缺失自我 "假说)。HLA 和 KIR 基因库极其多样化;因此,本研究旨在描述 MM 患者和健康对照组之间 HLA I 类 NK 表位和 KIR 基因型组成的潜在差异。本研究分析了 172 名 MM 患者和 195 名健康对照者的 KIR 和 HLA(HLA-C 组-C1/C2 和 Bw4 标记,包括 HLA-A*23、A*24 和 A*32)基因型表达。与健康对照组相比,我们没有发现特定的 KIR 基因或基因型或 HLA NK 表位在 MM 患者中具有更高的流行率。三种 HLA NK 表位(C1+C2+Bw4+)的存在与 MM 的发生无关。然而,MM 患者更有可能是 C1-/C2+/Bw4+(p = 0.049,OR 1.996)。与此相一致的是,MM 患者中 Bw4 和 KIR3DL1 的基因共存率呈上升趋势(p = 0.05,OR 1.557)。此外,MM 患者更有可能同时遗传表达 C2/KIR2DL1 和 Bw4/KIR3DL1(p = 0.019,OR 2.453)。我们的研究结果揭示了一种与 MM 发生相关的 HLA NK 表位组合。没有特定的 KIR 基因型与 MM 相关。
{"title":"HLA class I NK-epitopes and KIR diversities in patients with multiple myeloma.","authors":"Nicky A Beelen, Stefan J J Molenbroeck, Lisette Groeneveld, Christien E Voorter, Gerard M J Bos, Lotte Wieten","doi":"10.1007/s00251-024-01336-w","DOIUrl":"10.1007/s00251-024-01336-w","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of malignant plasma cells in the bone marrow. Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called \"education\" to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression (\"Missing-self\" hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1<sup>+</sup>C2<sup>+</sup>Bw4<sup>+</sup>) was not associated with MM occurrence. However, MM patients were more likely to be C1<sup>-</sup>/C2<sup>+</sup>/Bw4<sup>+</sup> (p = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (p = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2/KIR2DL1 and Bw4/KIR3DL1 (p = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11087314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-29DOI: 10.1007/s00251-024-01342-y
Razieh Khoshnevisan, Shakiba Hassanzadeh, Christoph Klein, Meino Rohlfs, Bodo Grimbacher, Newsha Molavi, Aryana Zamanifar, Ali Khoshnevisan, Mahbube Jafari, Bahram Bagherpour, Mahdiyeh Behnam, Somayeh Najafi, Roya Sherkat
Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton’s agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5–10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in BTK. Three novel mutations in the BTK gene include c.115 T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (IGHM) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (CD79A) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (TCF3) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern, which includes a missense variant in PIK3CD, a novel missense variant in PIK3R1 and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (RASGRP1) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.
无 B 细胞的低丙种球蛋白血症是先天性免疫错误(IEI)的一个亚组,其特征是所有血清免疫球蛋白异型显著下降,同时 B 细胞明显减少或缺失。约 80% 至 90% 的患者表现出布鲁顿酪氨酸激酶(BTK)的遗传变异,而少数病例(约 5% 至 10%)为常染色体隐性遗传性丙种球蛋白血症(ARA)。只有极少数病例可分为不同的亚类。我们对来自 13 个不同家族的 27 名患有低丙种球蛋白血症且无 B 细胞的患者进行了表型和遗传评估。遗传分析是通过全外显子组和桑格测序法进行的。最常见的遗传原因是 BTK 基因突变。BTK 基因的三个新型突变包括 c.115 T > C(p.Tyr39His)、c.685-686insTTAC(p.Asn229llefs5)和 c.163delT(p.Ser55GlnfsTer2)。我们的 3 位 ARA 患者包括免疫球蛋白重常 Mu 链(IGHM)基因的新型同源终止-增益突变、B 细胞抗原受体复合物相关蛋白(CD79A)基因的新型换框突变、转录因子 3(TCF3)基因的新型双等位终止-增益突变。三位农夫球蛋白血症患者具有常染色体显性遗传模式,其中包括 PIK3CD 基因的一个错义变体、PIK3R1 基因的一个新型错义变体以及磷脂酰肌醇-3-激酶调节亚基(RASGRP1)基因的一个同源沉默突变。这项研究拓宽了无 B 细胞低丙种球蛋白血症的基因谱,并在伊朗人群体中发现了一些新型变异体,这可能对其他中东人群也有影响。值得注意的是,在有多个病例的家庭中,第二个受影响家庭成员的疾病控制情况更好。
{"title":"B-cells absence in patients diagnosed as inborn errors of immunity: a registry-based study","authors":"Razieh Khoshnevisan, Shakiba Hassanzadeh, Christoph Klein, Meino Rohlfs, Bodo Grimbacher, Newsha Molavi, Aryana Zamanifar, Ali Khoshnevisan, Mahbube Jafari, Bahram Bagherpour, Mahdiyeh Behnam, Somayeh Najafi, Roya Sherkat","doi":"10.1007/s00251-024-01342-y","DOIUrl":"https://doi.org/10.1007/s00251-024-01342-y","url":null,"abstract":"<p>Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton’s agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5–10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in <i>BTK</i>. Three novel mutations in the <i>BTK</i> gene include c.115 T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (<i>IGHM</i>) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (<i>CD79A</i>) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (<i>TCF3</i>) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern, which includes a missense variant in <i>PIK3CD</i>, a novel missense variant in <i>PIK3R1</i> and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (<i>RASGRP1</i>) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140809120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-12DOI: 10.1007/s00251-024-01339-7
Ata Shirizadeh, Shiva Borzouei, Zahra Razavi, Amir Taherkhani, Javad Faradmal, Ghasem Solgi
One of the probable hypotheses for the onset of autoimmunity is molecular mimicry. This study aimed to determine the HLA-II risk alleles for developing Hashimoto’s thyroiditis (HT) in order to analyze the molecular homology between candidate pathogen-derived epitopes and potentially self-antigens (thyroid peroxidase, TPO) based on the presence of HLA risk alleles. HLA-DRB1/-DQB1 genotyping was performed in 100 HT patients and 330 ethnically matched healthy controls to determine the predisposing/protective alleles for HT disease. Then, in silico analysis was conducted to examine the sequence homology between epitopes derived from autoantigens and four potentially relevant pathogens and their binding capacities to HLA risk alleles based on peptide docking analysis. We identified HLA-DRB1*03:01, *04:02, *04:05, and *11:04 as predisposing alleles and DRB1*13:01 as a potentially predictive allele for HT disease. Also, DRB1*11:04 ~ DQB1*03:01 (Pc = 0.002; OR, 3.97) and DRB1*03:01 ~ DQB1*02:01 (Pc = 0.004; OR, 2.24) haplotypes conferred a predisposing role for HT. Based on logistic regression analysis, carrying risk alleles increased the risk of HT development 4.5 times in our population (P = 7.09E-10). Also, ROC curve analysis revealed a high predictive power of those risk alleles for discrimination of the susceptible from healthy individuals (AUC, 0.70; P = 6.6E-10). Analysis of peptide sequence homology between epitopes of TPO and epitopes derived from four candidate microorganisms revealed a homology between envelop glycoprotein D of herpes virus and sequence 151–199 of TPO with remarkable binding capacity to HLA-DRB1*03:01 allele. Our findings indicate the increased risk of developing HT in those individuals carrying HLA risk alleles which can also be related to herpes virus infection.
{"title":"Determination of HLA class II risk alleles and prediction of self/non-self-epitopes contributing Hashimoto’s thyroiditis in a group of Iranian patients","authors":"Ata Shirizadeh, Shiva Borzouei, Zahra Razavi, Amir Taherkhani, Javad Faradmal, Ghasem Solgi","doi":"10.1007/s00251-024-01339-7","DOIUrl":"https://doi.org/10.1007/s00251-024-01339-7","url":null,"abstract":"<p>One of the probable hypotheses for the onset of autoimmunity is molecular mimicry. This study aimed to determine the <i>HLA-II</i> risk alleles for developing Hashimoto’s thyroiditis (HT) in order to analyze the molecular homology between candidate pathogen-derived epitopes and potentially self-antigens (thyroid peroxidase, TPO) based on the presence of <i>HLA</i> risk alleles. <i>HLA-DRB1/-DQB1</i> genotyping was performed in 100 HT patients and 330 ethnically matched healthy controls to determine the predisposing/protective alleles for HT disease. Then, in silico analysis was conducted to examine the sequence homology between epitopes derived from autoantigens and four potentially relevant pathogens and their binding capacities to <i>HLA</i> risk alleles based on peptide docking analysis. We identified <i>HLA-DRB1*03:01, *04:02, *04:05</i>, and *<i>11:04</i> as predisposing alleles and <i>DRB1*13:01</i> as a potentially predictive allele for HT disease. Also, <i>DRB1*11:04</i> ~ <i>DQB1*03:01</i> (Pc = 0.002; OR, 3.97) and <i>DRB1*03:01</i> ~ <i>DQB1*02:01</i> (Pc = 0.004; OR, 2.24) haplotypes conferred a predisposing role for HT. Based on logistic regression analysis, carrying risk alleles increased the risk of HT development 4.5 times in our population (P = 7.09E-10). Also, ROC curve analysis revealed a high predictive power of those risk alleles for discrimination of the susceptible from healthy individuals (AUC, 0.70; P = 6.6E-10). Analysis of peptide sequence homology between epitopes of TPO and epitopes derived from four candidate microorganisms revealed a homology between envelop glycoprotein D of herpes virus and sequence 151–199 of TPO with remarkable binding capacity to <i>HLA-DRB1*03:01</i> allele. Our findings indicate the increased risk of developing HT in those individuals carrying <i>HLA</i> risk alleles which can also be related to herpes virus infection.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140598745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-11DOI: 10.1007/s00251-024-01341-z
Daniel Vázquez-Coto, Christine Kimball, Guillermo M. Albaiceta, Laura Amado-Rodríguez, Marta García-Clemente, Juan Gómez, Eliecer Coto, Janardan P. Pandey
There is tremendous interindividual and interracial variability in the outcome of SARS-CoV-2 infection, suggesting the involvement of host genetic factors. Here, we investigated whether IgG allotypes GM (γ marker) 3 and GM 17, genetic markers of IgG1, contributed to the severity of COVID-19. IgG1 plays a pivotal role in response against SARS-CoV-2 infection. We also investigated whether these GM alleles synergistically/epistatically with IGHG3 and FCGR2A alleles—which have been previously implicated in COVID-19—modulated the extent of COVID-19 severity. The study population consisted of 316 COVID-19 patients who needed treatment in the intensive care unit of Hospital Universitario Central de Asturias. All individuals were genotyped for GM 3/17, IGHG3 hinge length, and FCGR2A rs1801274 A/G polymorphisms. Among the 316 critical patients, there were 86 deaths. The risk of death among critical patients was significantly higher in subjects with GM 17 (IgG1) and short hinge length (IgG3). GM 17-carriers were at almost three-fold higher risk of death than non-carriers (p < 0.001; OR = 2.86, CI 1.58–5.16). Subjects with short hinge length of IgG3 had a two-fold higher risk of death than those with medium hinge length (p = 0.01; OR = 2.16, CI 1.19–3.90). GM 3/3 and IGHG3 (MM) genotypes were less frequent among death vs. survivors (9% vs 36%, p < 0.001) and associated with protective effect (OR = 0.18, 95% CI = 0.08–0.39). This is the first report implicating IgG1 allotypes in COVID-19-spurred death. It needs to be replicated in an independent study population.
{"title":"Immunoglobulin genes and severity of COVID-19","authors":"Daniel Vázquez-Coto, Christine Kimball, Guillermo M. Albaiceta, Laura Amado-Rodríguez, Marta García-Clemente, Juan Gómez, Eliecer Coto, Janardan P. Pandey","doi":"10.1007/s00251-024-01341-z","DOIUrl":"https://doi.org/10.1007/s00251-024-01341-z","url":null,"abstract":"<p>There is tremendous interindividual and interracial variability in the outcome of SARS-CoV-2 infection, suggesting the involvement of host genetic factors. Here, we investigated whether IgG allotypes GM (γ marker) 3 and GM 17, genetic markers of IgG1, contributed to the severity of COVID-19. IgG1 plays a pivotal role in response against SARS-CoV-2 infection. We also investigated whether these GM alleles synergistically/epistatically with <i>IGHG3</i> and <i>FCGR2A</i> alleles—which have been previously implicated in COVID-19—modulated the extent of COVID-19 severity. The study population consisted of 316 COVID-19 patients who needed treatment in the intensive care unit of Hospital Universitario Central de Asturias. All individuals were genotyped for GM 3/17, <i>IGHG3</i> hinge length, and <i>FCGR2A</i> rs1801274 A/G polymorphisms. Among the 316 critical patients, there were 86 deaths. The risk of death among critical patients was significantly higher in subjects with GM 17 (IgG1) and short hinge length (IgG3). GM 17-carriers were at almost three-fold higher risk of death than non-carriers (<i>p</i> < 0.001; OR = 2.86, CI 1.58–5.16). Subjects with short hinge length of IgG3 had a two-fold higher risk of death than those with medium hinge length (<i>p</i> = 0.01; OR = 2.16, CI 1.19–3.90). GM 3/3 and <i>IGHG3</i> (MM) genotypes were less frequent among death vs. survivors (9% vs 36%, <i>p</i> < 0.001) and associated with protective effect (OR = 0.18, 95% CI = 0.08–0.39). This is the first report implicating IgG1 allotypes in COVID-19-spurred death. It needs to be replicated in an independent study population.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
X-linked hyper-immunoglobulin M (X-HIGM) syndrome and autosomal recessive hyper-immunoglobulin E syndrome (HIES) are rare inborn errors of immunity characterized by recurrent infections due to immune system impairment. In this study, we identified a novel hemizygous CD40 ligand (CD40L) mutation and compound heterozygous dedicator of cytokinesis-8 (DOCK8) mutations in two Han Chinese families with X-HIGM and HIES, respectively. We aimed to investigate the association between their genotypes and phenotypes. Genomic DNA was extracted from peripheral blood samples obtained from the families. Whole exome sequencing and Sanger sequencing were performed to identify and verify pathogenic variants in the two families. Clinical analyses of the probands were also performed. A novel hemizygous mutation of CD40L in exon 2 (c.257delA) was identified in the first proband, resulting in the substitution of glycine with glutamic acid at codon 86 of the protein. This leads to premature termination of translation at downstream codon 9 (p.E86Gfs*9). Sanger sequencing confirmed that the variant was inherited from the mother. The second proband carried two novel compound heterozygous mutations in DOCK8: one at exon 14 (c.1546C > G) inherited from the father, and the other at intron 41 (c.5355 + 6C > T; splicing) inherited from the mother. This study enhances our understanding of the pathogenetic mutation spectrum of CD40L and DOCK8 genes, facilitating the prenatal diagnosis of X-HIGM and HIES and enabling timely treatment of patients.
{"title":"A novel hemizygous CD40L mutation of X-linked hyper IgM syndromes and compound heterozygous DOCK8 mutations of hyper IgE syndromes in two Chinese families","authors":"Mingzhen Guo, Yuanxuan Ma, Kangxi Cai, Xiuxiang Liu, Wenmiao Liu, Fengqi Wang, Niyan Qu, Shiguo Liu","doi":"10.1007/s00251-024-01340-0","DOIUrl":"https://doi.org/10.1007/s00251-024-01340-0","url":null,"abstract":"<p>X-linked hyper-immunoglobulin M (X-HIGM) syndrome and autosomal recessive hyper-immunoglobulin E syndrome (HIES) are rare inborn errors of immunity characterized by recurrent infections due to immune system impairment. In this study, we identified a novel hemizygous CD40 ligand (<i>CD40L</i>) mutation and compound heterozygous dedicator of cytokinesis-8 (<i>DOCK8</i>) mutations in two Han Chinese families with X-HIGM and HIES, respectively. We aimed to investigate the association between their genotypes and phenotypes. Genomic DNA was extracted from peripheral blood samples obtained from the families. Whole exome sequencing and Sanger sequencing were performed to identify and verify pathogenic variants in the two families. Clinical analyses of the probands were also performed. A novel hemizygous mutation of <i>CD40L</i> in exon 2 (c.257delA) was identified in the first proband, resulting in the substitution of glycine with glutamic acid at codon 86 of the protein. This leads to premature termination of translation at downstream codon 9 (p.E86Gfs*9). Sanger sequencing confirmed that the variant was inherited from the mother. The second proband carried two novel compound heterozygous mutations in DOCK8: one at exon 14 (c.1546C > G) inherited from the father, and the other at intron 41 (c.5355 + 6C > T; splicing) inherited from the mother. This study enhances our understanding of the pathogenetic mutation spectrum of <i>CD40L</i> and <i>DOCK8</i> genes, facilitating the prenatal diagnosis of X-HIGM and HIES and enabling timely treatment of patients.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-15DOI: 10.1007/s00251-024-01335-x
Reza Dabbaghipour, Elham Ahmadi, Mona Entezam, Omid Rahbar Farzam, Sepideh Sohrabi, Sajjad Jamali, Ali Saber Sichani, Hadi Paydar, Behzad Baradaran
The transcription factor, known as basic leucine zipper ATF-like 3 (BATF3), is a crucial contributor to the development of conventional type 1 dendritic cells (cDC1), which is definitely required for priming CD8 + T cell-mediated immunity against intracellular pathogens and malignancies. In this respect, BATF3-dependent cDC1 can bring about immunological tolerance, an autoimmune response, graft immunity, and defense against infectious agents such as viruses, microbes, parasites, and fungi. Moreover, the important function of cDC1 in stimulating CD8 + T cells creates an excellent opportunity to develop a highly effective target for vaccination against intracellular pathogens and diseases. BATF3 has been clarified to control the development of CD8α+ and CD103+ DCs. The presence of BATF3-dependent cDC1 in the tumor microenvironment (TME) reinforces immunosurveillance and improves immunotherapy approaches, which can be beneficial for cancer immunotherapy. Additionally, BATF3 acts as a transcriptional inhibitor of Treg development by decreasing the expression of the transcription factor FOXP3. However, when overexpressed in CD8 + T cells, it can enhance their survival and facilitate their transition to a memory state. BATF3 induces Th9 cell differentiation by binding to the IL-9 promoter through a BATF3/IRF4 complex. One of the latest research findings is the oncogenic function of BATF3, which has been approved and illustrated in several biological processes of proliferation and invasion.
{"title":"Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells.","authors":"Reza Dabbaghipour, Elham Ahmadi, Mona Entezam, Omid Rahbar Farzam, Sepideh Sohrabi, Sajjad Jamali, Ali Saber Sichani, Hadi Paydar, Behzad Baradaran","doi":"10.1007/s00251-024-01335-x","DOIUrl":"10.1007/s00251-024-01335-x","url":null,"abstract":"<p><p>The transcription factor, known as basic leucine zipper ATF-like 3 (BATF3), is a crucial contributor to the development of conventional type 1 dendritic cells (cDC1), which is definitely required for priming CD8 + T cell-mediated immunity against intracellular pathogens and malignancies. In this respect, BATF3-dependent cDC1 can bring about immunological tolerance, an autoimmune response, graft immunity, and defense against infectious agents such as viruses, microbes, parasites, and fungi. Moreover, the important function of cDC1 in stimulating CD8 + T cells creates an excellent opportunity to develop a highly effective target for vaccination against intracellular pathogens and diseases. BATF3 has been clarified to control the development of CD8α<sup>+</sup> and CD103<sup>+</sup> DCs. The presence of BATF3-dependent cDC1 in the tumor microenvironment (TME) reinforces immunosurveillance and improves immunotherapy approaches, which can be beneficial for cancer immunotherapy. Additionally, BATF3 acts as a transcriptional inhibitor of Treg development by decreasing the expression of the transcription factor FOXP3. However, when overexpressed in CD8 + T cells, it can enhance their survival and facilitate their transition to a memory state. BATF3 induces Th9 cell differentiation by binding to the IL-9 promoter through a BATF3/IRF4 complex. One of the latest research findings is the oncogenic function of BATF3, which has been approved and illustrated in several biological processes of proliferation and invasion.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-01-11DOI: 10.1007/s00251-023-01331-7
Sudan Tao, Xuan You, Jielin Wang, Wei Zhang, Ji He, Faming Zhu
Killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) play crucial roles in regulating NK cell activity. Here, we report a real-time quantitative PCR (qPCR) to genotype all KIR genes and their copy numbers simultaneously. With 18 pairs of locus-specific primers, we identified KIR genes by Ct values and determined KIR copy number using the 2-∆Ct method. Haplotypes were assigned based on KIR gene copy numbers. The real-time qPCR results were consistent with the NGS method, except for one sample with KIR2DL5 discrepancy. qPCR is a multiplex method that can identify KIR copy number, which helps obtain a relatively accurate haplotype structure, facilitating increased KIR research in laboratories where NGS or other high-resolution methods are not available.
杀伤细胞免疫球蛋白样受体(KIR)和人类白细胞抗原(HLA)在调节 NK 细胞活性方面起着至关重要的作用。在此,我们报告了一种实时定量 PCR(qPCR)方法,可同时对所有 KIR 基因及其拷贝数进行基因分型。利用 18 对基因座特异性引物,我们通过 Ct 值确定了 KIR 基因,并用 2-∆Ct 法确定了 KIR 拷贝数。根据 KIR 基因拷贝数分配单倍型。实时 qPCR 的结果与 NGS 方法一致,只有一个样本的 KIR2DL5 存在差异。qPCR 是一种可识别 KIR 拷贝数的多重方法,有助于获得相对准确的单倍型结构,从而有助于在无法使用 NGS 或其他高分辨率方法的实验室开展更多的 KIR 研究。
{"title":"Determination for KIR genotype and allele copy number via real-time quantitative PCR method.","authors":"Sudan Tao, Xuan You, Jielin Wang, Wei Zhang, Ji He, Faming Zhu","doi":"10.1007/s00251-023-01331-7","DOIUrl":"10.1007/s00251-023-01331-7","url":null,"abstract":"<p><p>Killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) play crucial roles in regulating NK cell activity. Here, we report a real-time quantitative PCR (qPCR) to genotype all KIR genes and their copy numbers simultaneously. With 18 pairs of locus-specific primers, we identified KIR genes by Ct values and determined KIR copy number using the 2<sup>-∆Ct</sup> method. Haplotypes were assigned based on KIR gene copy numbers. The real-time qPCR results were consistent with the NGS method, except for one sample with KIR2DL5 discrepancy. qPCR is a multiplex method that can identify KIR copy number, which helps obtain a relatively accurate haplotype structure, facilitating increased KIR research in laboratories where NGS or other high-resolution methods are not available.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139416932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-03-01DOI: 10.1007/s00251-024-01332-0
Ou Wu, Ya Wu, Xingyu Zhang, Wei Liu, Hu Zhang, Saber Khederzadeh, Xi Lu, Xiao-Wei Zhu
To examine whether circulating interleukin-6 (IL-6) levels (CirIL6) have a causal effect on blood pressure using Mendelian randomization (MR) methods. We used data from genome-wide association studies (GWAS) of European ancestry to obtain genetic instruments for circulating IL-6 levels and blood pressure measurements. We applied several robust MR methods to estimate the causal effects and to test for heterogeneity and pleiotropy. We found that circulating IL-6 had a significant positive causal effect on systolic blood pressure (SBP) and pulmonary arterial hypertension (PAH), but not on diastolic blood pressure (DBP) or hypertension. We found that as CirIL6 genetically increased, SBP increased using Inverse Variance Weighted (IVW) method (for ukb-b-20175, β = 0.082 with SE = 0.032, P = 0.011; for ukb-a-360, β = 0.075 with SE = 0.031, P = 0.014) and weighted median (WM) method (for ukb-b-20175, β = 0.061 with SE = 0.022, P = 0.006; for ukb-a-360, β = 0.065 with SE = 0.027, P = 0.014). Moreover, CirIL6 may be associated with an increased risk of PAH using WM method (odds ratio (OR) = 15.503, 95% CI, 1.025-234.525, P = 0.048), but not with IVW method. Our study provides novel evidence that circulating IL-6 has a causal role in the development of SBP and PAH, but not DBP or hypertension. These findings suggest that IL-6 may be a potential therapeutic target for preventing or treating cardiovascular diseases and metabolic disorders. However, more studies are needed to confirm the causal effects of IL-6 on blood pressure and to elucidate the underlying mechanisms and pathways.
{"title":"Causal effect of interleukin (IL)-6 on blood pressure and hypertension: A mendelian randomization study.","authors":"Ou Wu, Ya Wu, Xingyu Zhang, Wei Liu, Hu Zhang, Saber Khederzadeh, Xi Lu, Xiao-Wei Zhu","doi":"10.1007/s00251-024-01332-0","DOIUrl":"10.1007/s00251-024-01332-0","url":null,"abstract":"<p><p>To examine whether circulating interleukin-6 (IL-6) levels (CirIL6) have a causal effect on blood pressure using Mendelian randomization (MR) methods. We used data from genome-wide association studies (GWAS) of European ancestry to obtain genetic instruments for circulating IL-6 levels and blood pressure measurements. We applied several robust MR methods to estimate the causal effects and to test for heterogeneity and pleiotropy. We found that circulating IL-6 had a significant positive causal effect on systolic blood pressure (SBP) and pulmonary arterial hypertension (PAH), but not on diastolic blood pressure (DBP) or hypertension. We found that as CirIL6 genetically increased, SBP increased using Inverse Variance Weighted (IVW) method (for ukb-b-20175, β = 0.082 with SE = 0.032, P = 0.011; for ukb-a-360, β = 0.075 with SE = 0.031, P = 0.014) and weighted median (WM) method (for ukb-b-20175, β = 0.061 with SE = 0.022, P = 0.006; for ukb-a-360, β = 0.065 with SE = 0.027, P = 0.014). Moreover, CirIL6 may be associated with an increased risk of PAH using WM method (odds ratio (OR) = 15.503, 95% CI, 1.025-234.525, P = 0.048), but not with IVW method. Our study provides novel evidence that circulating IL-6 has a causal role in the development of SBP and PAH, but not DBP or hypertension. These findings suggest that IL-6 may be a potential therapeutic target for preventing or treating cardiovascular diseases and metabolic disorders. However, more studies are needed to confirm the causal effects of IL-6 on blood pressure and to elucidate the underlying mechanisms and pathways.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}