Chemokine receptor CCR5 in interferon-treated multiple sclerosis

OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were analyzed in 109 patients with relapsing-remitting MS treated with IFN-beta who were followed clinically for 1 year. Cellular CCR5 expression was measured by flow cytometry. RESULTS: Patients with MS had a higher percentage of CCR5-positive monocytes than healthy controls. Increased monocyte expression of CCR5 correlated weakly with an increased short-term relapse risk but there was no relationship between CCR5 Delta32 allele and CCR5 promoter polymorphism genotypes and relapse risk. CONCLUSIONS: The results do not support a major role of CCR5 in the pathogenesis of relapses in MS patients treated with IFN-beta, but it is possible that monocyte CCR5 expression may be used as a marker of disease activity.     

NGS-based typings for 7 HLA loci in two populations from Barra Mansa,RJ, Brazil

We investigated HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQB1, -DPA1, and -DPB1) alleles by NGS-based typing among 478 Brazilian individuals from two populations in the Barra Mansa city based on their self-declared skin color (Caucasian, N = 405, AFND-ID: 3729; Black, N = 73, AFND-ID: 3731) to calculate allelic and haplotypic frequencies, plus linkage disequilibrium. No locus deviated from Hardy-Weinberg equilibrium. Both populations shared the most frequent allele on HLA-A, -C, -DPA1, and -DPB1. Genotype and frequency data are available in the Allele Frequencies Net Database.     

A new marker in the HLA class I region is associated with the age at onset of IDDM

Summary The (MHC) class II association with insulin-dependent diabetes mellitus (IDDM) is well documented. However, it is likely that genes within the MHC class III and the class I region also play a role in determining susceptibility to IDDM. In this study we have used a novel molecular probe to investigate the class I P3A and P3B loci of 179 patients with IDDM and 142 normal control subjects. A highly significant increase in the frequency of the class I P3 4.0;1.5 kilobase (kb) and 4.0;1.8;1.5 kb genotypes was found in patients compared to the control subjects (x ² 46.8, 6 df, p<0.0001). The association with the P3B 1.5 kb allele was strongly associated with the age at onset of diabetes, being present in 96.2% of subjects who developed diabetes between the age of 10–20 years compared to 55.0 and 74.6% who developed diabetes before 10 years or after 20 years, respectively (x ² 31.4, p<0.0001). There was no evidence for linkage disequilibrium between the DQA1 and DQB1 loci and P3B suggesting that this is an independent association. In conclusion, these results suggest that genes in both the MHC class I and II regions confer susceptibility to IDDM and are related to the age at onset of the disease.Abbreviations kb Kilobase - SSC 0.3 mol/l sodium chloride, 0.3 mol/l sodium citrate - YAC yeast artificial chromosome - df degrees of freedom     

Association of human leucocyte antigen sharing with recurrent spontaneous abortions

An estimated 15% of clinically recognized pregnancies abort spontaneously. Recurrent spontaneous abortion (RSA) is defined as three or more consecutive miscarriages conceived with the same partner in the absence of uterine, genetic or autoimmune abnormalities. Evidence points to human leucocyte antigens (HLA) as playing a role in the successful development of the foetus. In particular, HLA compatibility is more prevalent in couples experiencing reproductive failure, especially RSA couples, compared to fertile couples. According to the immunological hypothesis, an adequate immune response is necessary for proper implantation of the embryo; conversely, a depressed response of maternal lymphocytes to the stimulation by paternal antigens because of HLA sharing can result in disorders, such as RSA. The genetic hypothesis implicates homozygosity for recessive lethal alleles in linkage disequilibrium with specific HLA haplotypes. The specificity of HLA alleles or haplotypes responsible for or linked to other RSA susceptibility genes remains unclear. In this study, we identified 40 observational studies (32 case-control, five cohort, one cross-sectional, one case series and one basic science) that examined the associations between HLA and RSA, focusing on HLA allele couple and maternal-foetal sharing, and the special role of HLA-G. We sought to identify consistent findings among studies examining similar questions. Evidence remains divided concerning the role of HLA allele couple sharing. Of major concern is the focus of many studies on couple sharing as a proxy measure of maternal-foetal sharing. Therefore, adequately powered studies are needed, which employ standard case definitions and reproducible methodologies to directly assess the role of maternal-foetal HLA sharing on the risk of RSA.     

Protein stability changes of the novel p.Arg180Cys mutant A glycosyltransferase resulted in a weak A phenotype

A novel A subgroup allele (c.538C>T p.Arg180Cys) showing weak A phenotype was found in a 30‐year‐old Korean woman with ABO discrepancy. Using 3D structural analysis, protein stability prediction and flow cytometric analysis of ABO antigen expression on HeLa cells transfected with plasmids containing the p.Arg180Cys mutant, we found that the Arg180 residue in the loop region of the A glycosyltransferases (GTA) structure plays significant role in stabilizing its closed conformation, which is required for substrate binding and catalysis study.     

Chagas disease immunogenetics: elusive markers of disease progression

Introduction: Chagas disease (CD) is caused by a parasitic infection. The disease usually occurs after decades of the primary infection and can involve the myocardium or the digestive system. Of note, around 30% of T. cruzi infected patients develop CD while the other 70% may remain asymptomatic for their entire life. CD is usually observed as familial clustered phenomena. Moreover, individuals with chronic Chagas heart disease (CCHD) usually present a strong, deregulated immune response, which strongly suggests an immunogenetic effect.

Areas covered: In this article we review and discuss the information currently available from the published scientific literature regarding the genetic variants of molecules of the immune system that contribute to the clinical presentation of the disease.

Expert commentary: Of note, the most promissory results are found on the polymorphisms of chemokine receptors, particularly CCR5 and CCR2. Additional investigations are required, particularly with a focus on the genes that regulate the immune system.     

CD4 + T CELL MATTERS IN TUMOR IMMUNITY

CD4 + T cells have been shown to be able to affect tumor growth through both direct and indirect means. In addition, a requirement has been demonstrated for CD4 + T cells in the regulation and induction of T cell memory, and CD4 + suppressor T cells have been identified, stressing a role for CD4 + T cells in the induction and maintenance of antitumor immune responses. A review of the involvement of CD4 + T cells at different stages of tumor immunity is provided, and based on these data we discuss how CD4 + T cell response induction could be incorporated into tumor immunotherapy strategies. dendritic cells suppressor T cells T cell memory CD4 + T cells tumor immunology     

中国汉族RhD阴性个体Rh盒子基因的测序及RHD基因的纯合性测定

目的分析中国汉族人RhD阴性个体Rh盒子基因的序列以阐明中国汉族人群RhD阴性表型形成的分子机理，并对Rh盒子基因的扩增产物进行分析以确定RHD基因的纯合性。方法74例RhD阴性个体的DNA样品首先进行多重聚合酶链反应．序列特异性引物（PCR-sequence specific primer，PCR-SSP）分析。然后对Rh盒子基因进行特异性测序分析，同时对Rh盒子基因的扩增产物采用聚合酶链反应-限制性片段长度多态性（restrict fragment length polymorphism，RFLP）方法进行RHD基因的纯合性测定。结果46例（62％）样品在多重PCR-SSP分析中显示缺失RHD基因，在PCR-RFLP分析中显示为纯合的RHD基因阴性。22例（30％）样品显示存在RHD基因，其中19例显示为杂合的RHD基因，3例显示为纯合的RHD基因。5例（7％）样品缺失RHD基因，但PCR．RFLP分析显示存在1个RHD基因，进一步的分析表明它们至少存在RHD基因第1和10外显子。1例（1％）样品显示存在RHD基因，但缺失第6外显子。对27例在多重PCR分析中显示缺失RHD基因的RhD阴性样品的杂化Rh盒子基因进行DNA测序分析，表明中国人存在与白人相一致的杂化Rh盒子基因序列。结论RHD基因缺失是引起中国汉族人PhD阴性表型形成的主要分子机理。中国人RHD基因缺失发生于与白人相一致的断点区域。     

Activation-induced cytidine deaminase: structure-function relationship as based on the study of mutants

Activation-induced cytidine deaminase (AID; gene symbol AICDA) is the key molecule required to induce immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation (SHM) of the variable regions of Ig genes. Its deficiency causes a form of hyper-IgM (HIGM) syndrome. The study of natural AID mutants associated with HIGM as well as engineered mutants led to the characterization of the active domains of the protein. AID, through its cytidine deaminase activity, induces a targeted DNA lesion as an early step required for both CSR and SHM. Besides its cytidine deaminase activity, AID plays a further essential role in CSR, likely by recruiting CSR-specific cofactors by its C-terminus. A similar binding of SHM-specific cofactors to the N-terminal part is suggested by the functional characteristics of N(ter) AID artificial mutants. These data require confirmation in vivo. Finally, AID acts as a homo-, di-, or multimeric complex. Together, these data strongly suggest that AID, a master molecule for antibody diversification, exerts its activity on CSR not only as a cytidine deaminase enzyme but also as a docking protein, recruiting specific cofactors to a multimeric complex.