The L-selectin Phe206Leu gene polymorphism is not associated with visceral leishmaniasis (original) (raw)
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Genes and Immunity, 2005
Altered function of selectin glycoprotein adhesion molecules may modulate severity and organ-specific manifestations of autoimmune and inflammatory disease via changes in leukocyte trafficking. Serum concentrations of selectin molecules have been suggested as useful biomarkers in systemic lupus erythematosus (SLE). We identified increased levels of soluble L-selectin (sL-selectin), but not soluble E-selectin (sE-selectin) in 278 European-Caucasian lupus patients compared to 230 healthy siblings (P ¼ 0.002). sL-selectin levels were markedly elevated in patients with IgG antiphospholipid autoantibodies (P ¼ 0.002), suggesting that perhaps sL-selectin defines a subgroup of lupus with vasculopathy. sL-selectin level was also influenced by two L-selectin polymorphisms: 665C4T, F206L in the epidermal growth factor-like domain (P ¼ 0.015) and rs12938 in the 3 0 -untranslated region (P ¼ 0.06). Having shown increased sL-selectin levels in lupus patients, we used genetics to investigate whether this was a secondary phenomena or the result of an underlying genetic mechanism. The inheritance of nine single-nucleotide polymorphisms (SNP) spanning the selectin locus was tested in 523 UK simplex SLE families. No association with SLE, or related phenotypes, was evident with any single SNP, or haplotype in family-based tests of association. Selectin polymorphisms are, therefore, unlikely to be independent factors in SLE susceptibility.
Human Immunology, 2006
Celiac disease (CD) follows an autoimmune course in which both genetic and environmental factors contribute to its development. A strong association with HLA class II molecules, predominantly HLA-DQ2, has been reported in most ethnic groups with CD. The aim of this study was to determine if genetic polymorphisms in L-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) have any correlation with CD. We investigated 5 mutations, namely F206L in L-selectin, S128R and L554F in E-selectin, and G241R and K469E in ICAM-1, in 37 North Indian pediatric patients with CD. A significant increase in allele frequencies of 128R of E-selectin and the associated genotype SR was observed in patients. No significant differences were observed in the F206L polymorphism of L-selectin, or the G241R and E469K polymorphisms in the ICAM-1 gene in CD. This study illustrates that selectin gene polymorphism might contribute to the genetic background of CD and invites further investigation relevant to understanding the mechanisms underlying the immunopathogenesis of this autoimmune disease.
Neurological Research, 2021
ABSTRACT Objectives: Natalizumab (NTZ), a treatment indicated for patients with highly active Relapsing – Remitting Multiple Sclerosis (RRMS), is known to induce increased relative frequency of lymphocytes. Progressive Multifocal Leukoencephalitis (PML) is a rare but serious adverse event related to NTZ. Moreover, reduced L-selectin (CD62L) expression in T-cells in cryopreserved samples of patients with RRMS under NTZ has been proposed as a biomarker of pre-PML state. We explore the association between L-selectin expression in T-cells and hematological parameters in freshly processed samples of patients with RRMS under NTZ. Methods: We studied L-selectin expression in patients with: RRMS under NTZ (n=34), fingolimod (FTY, n=14), interferon-beta (IFNβ, n=22), glatiramer acetate (GA, N=17); in 9 patients with secondary progressive (SP) MS and in 6 healthy controls. Twenty-two patients under NTZ and 6 patients under FTY were followed for 18 months. One NTZ-treated patient developed PML during the study. Results: Patients under NTZ exhibited increased relative frequency of lymphocytes (40.02±1.45) compared to patients under first–line treatment (30.57±1.68, p<0.001) and to patients with SPMS (29±1.56, p=0.02), and a lower mean L-selectin expression in (69.39±1.73) compared to patients under first–line treatment (79.1±1.17, p=0.003). A negative correlation between the relative frequency of CD4+CD62L+ T-cells and the absolute lymphocyte counts (Pearson’s r=0.367, p=0.033) was observed. Discussion: We hereby provide mechanistic insight in a possible pathway implicated in NTZ-related PML risk. These results further underline the need for thorough validation of L-selectin expression in T-cells as a potential pre-PML biomarker. GRAPHICAL ABSTRACT
Background: L-selectin gene (SELL) is a candidate gene for the development of acute coronary syndrome (ACS) that contributes to endothelial dysfunction. The −642C > T (rs2205849) and 725C > T (rs2229569) poly-morphisms have been associated with changes in gene expression, ligand affinity and increased risk of cardiovascular disease. The aim of this study was to investigate the association between the haplotypes constructed with the −642C > T and 725C > T polymorphisms of the SELL gene, the expression levels of its mRNA and the serum levels of soluble L-selectin with ACS. Methods: We recruited 615 individuals of Mexican origin matched by age, including 342 patients with ACS and 273 individuals without personal history of ischemic cardiopathy as control group (CG). Genotyping was performed by PCR-RFLP. The qPCR technique was used to analyze the expression of mRNA using TaqMan® UPL probes. The levels of soluble L-selectin were measured with ELISA. Results: The allele variants in both polymorphisms were over-represented in the CG compared to the ACS (OR range: 0.371–0.716, p < 0.006). The CT and TT haplotypes had a protective effect against the development of ACS (OR = 0.401, p < 0.0001; OR = 0.628, p < 0.0001, respectively). SELL expression was 3.076 times higher in the ACS group compared to CG (p < 0.001). The levels of soluble L-selectin were similar between ACS and CG. Conclusions: Both polymorphisms had no effect on mRNA expression and soluble protein levels. The polymorphisms −642C > T and 725C > T of the SELL gene are protective factors against the development of ACS. There is an increased gene expression of L-selectin in ACS compared to CG in the population of Western Mexico.
Impaired primary T cell responses in L-selectin-deficient mice
Journal of Experimental Medicine, 1996
L-selectin is a homing receptor that mediates the selective attachment ofleukocytes to specialized high endothelial venules. To study the potential role of L-selectin in immune responses in intact mice, we generated L-selectin-deficient mice by gene targeting. L-selectin-deficient mice are defective in cutaneous delayed-type hypersensitivity (DTH) responses when tested after conventional intervals of immunization (4 d). Primary T cell proliferative responses and cytokine production (interleukin [ILl 2, IL-4, and interferon ~) were also compromised when tested after 5 d of immunization, indicating that L-selectin is important for the immune response to antigens. In contrast, after more prolonged immunization protocols (9 d), normal responses were observed, suggesting that L-selectin-independent compensatory mechanisms exist. Interestingly, humoral responses of L-selectin-deficient mice to keyhole limpet hemocyanin are indistinguishable from wild-type control mice, implying that L-selectin plays no rate-limiting role in T cell help of B cell function. Thus, our results suggest that L-selectin plays an important role in the generation of primary T cell responses but may not be essential for humoral and memory T cell responses. L-selectin does not appear to be rate limiting for the events leading to antigen-driven neutrophil recruitment, since normal DTH responses are obtained at late time points after immunization. J. Exp.
Association between the Phe206Leu polymorphism of L-selectin and brucellosis
Journal of Medical Microbiology, 2006
Brucellosis remains a major zoonosis worldwide; therefore, better understanding of its immunology is a priority for the development of new therapeutic and vaccination strategies. Genetic factors appear to have an important role in the pathogenesis of infectious diseases such as brucellosis. Adhesion molecules, such as members of the selectin family, participate in the interaction between leukocytes and the endothelium, as well as in inflammatory cell recruitment. The impact of L-selectin polymorphisms on brucellosis has not so far been investigated. The aim of this study was to assess an L-selectin Phe206Leu (F206L) polymorphism in patients with active brucellosis, and to analyse its possible relationship with disease progression. A case-control association study was carried out on 619 subjects, including 374 patients with brucellosis and 245 age-and sex-matched healthy controls. Genomic DNA was isolated, and amplification of L-selectin genomic regions was performed by PCR incorporating sequence-specific primers (PCR-SSP) to distinguish the genotypes. The frequencies of the F206L polymorphism were studied. A significant difference in F206L polymorphism was found between patients with brucellosis and controls. The 206Leu allele was more frequent in patients than in healthy individuals (36?6 versus 28 %, P=0?003). In addition, there was an association between the presence of the 206Leu allele and a relapse of brucellosis (odds ratio 6?53, 95 % confidence interval 1?5-28?8, P=0?005). The higher frequency of L-selectin genotypes in patients with brucellosis than in control individuals, as well as the association between the 206Leu allele and the occurrence of brucellosis relapse, suggest that the F206L polymorphism could make individuals more vulnerable to brucellosis.
Could the lower frequency of CD 8 1 CD 18 1 CD 45 RO 1 lymphocytes be biomarkers of human VL ?
2009
Toward obtaining a more comprehensive understanding of factors governing activation and/or function during visceral leishmaniasis (VL), we have compared active disease (pre-treatment) versus post-chemotherapy immune response in VL patients by means of ex vivo staining with different cell markers. Our results show that during active disease, the frequency of T cells positive for CD25, CTLA-4 and CD45RO was significantly lower in VL patients compared with healthy controls, whereas cells staining positive for Annexin V and CD95 were significantly higher. In all cases, chemotherapy was able to restore these frequencies to normal levels. Interestingly, significant differences in the frequency of CD18 and in the frequency of CD45RO-positive cells were observed in the CD81 T cell subset. These two frequencies were also significantly higher in bone marrow when compared with peripheral blood, suggesting a possible compartmentalization of certain CD81 T cell populations during active disease....
Infection, Genetics and Evolution, 2012
Chromosome 6q26-27 is linked to susceptibility to visceral leishmaniasis (VL) in Brazil and Sudan. DLL1 encoding the Delta-like 1 ligand for Notch 3 was implicated as the etiological gene. DLL1 belongs to the family of Notch ligands known to selectively drive antigen-specific CD4 T helper 1 cell responses, which are important in protective immune response in leishmaniasis. Here we provide further genetic and functional evidence that supports a role for DLL1 in a well-powered population-based study centred in the largest global focus of VL in India. Twenty-one single nucleotide polymorphisms (SNPs) at PHF10/ C6orf70/DLL1/FAM120B/PSMB1/TBP were genotyped in 941 cases and 992 controls. Logistic regression analysis under an additive model showed association between VL and variants at DLL1 and FAM120B, with top associations (rs9460106, OR = 1.17, 95%CI 1.01-1.35, P = 0.033; rs2103816, OR = 1.16, 95%CI 1.01-1.34, P = 0.039) robust to analysis using caste as a covariate to take account of population substructure. Haplotype analysis taking population substructure into account identified a common 2-SNP risk haplotype (frequency 0.43; P = 0.028) at FAM120B, while the most significant protective haplotype (frequency 0.18; P = 0.007) was a 5-SNP haplotype across the interval 5 0 of both DLL1 (negative strand) and FAM120B (positive strand) and extending to intron 4 of DLL1. Quantitative RT/PCR was used to compare expression of 6q27 genes in paired pre-and post-treatment splenic aspirates from VL patients (N = 19). DLL1 was the only gene to show differential expression that was higher (P < 0.0001) in precompared to post-treatment samples, suggesting that regulation of gene expression was important in disease pathogenesis. This well-powered genetic and functional study in an Indian population provides evidence supporting DLL1 as the etiological gene contributing to susceptibility to VL at Chromosome 6q27, confirming the potential for polymorphism at DLL1 to act as a genetic risk factor across the epidemiological divides of geography and parasite species.
Molecular Biology Reports, 2012
Lymphotoxin-a (LT-a) and interleukin-1beta (IL-1b) are proinflammatory cytokines playing important roles in immunity against Leishmania infection and the outcome of the disease. As cytokine productions are under the genetic control, this study tried to find any probable relationship between these cytokine gene polymorphisms and the susceptibility to visceral leishmaniasis in Iranian pediatric patients. Ninety-five pediatric patients involved with visceral leishmaniasis and 128 non-relative healthy people, from the same area as the patients, were genotyped for LT-a (?252A/G) and IL-1b (?3953T/C and -511T/C) gene polymorphisms using polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP). There was not found any significant differences in allele and genotype frequencies of LT-a (?252A/G) and IL-1b (?3953) among the study groups. However, the frequency of IL-1b -511TT genotype was higher in the controls (P = 0.0004) while the frequency of IL-1b -511CC genotype and C allele were higher in the patients (P = 0.008 and P = 0.00006, respectively). Furthermore, IL-1b CC (-511/?3953) haplotype was more frequent in VL patients compared with the controls (P = 0.0002) and the distribution of TT haplotype was higher in the controls compared with the patients (P = 0.003). In conclusion, based on the results, IL-1b -511C allele, CC genotype and CC (-511/?3953) haplotype could be considered as the susceptibility factors for visceral leishmaniasis while IL-1b -511TT genotype, T allele and TT haplotype (-511/ ?3953) might be counted as the influential factors for resistance to the disease.
TheScientificWorldJournal, 2014
Interleukin-18 (IL-18) is a cytokine that mediates Th1 response by inducing interferon-gamma (IFN-) production in T cells and natural killer cells. Genetic polymorphisms in the IL-18 gene have been found to be associated with its expression in cancer, tuberculosis, HBV infection, and various other diseases. Lower plasma level of IL-18 in visceral leishmaniasis (VL) patients might be associated with polymorphisms in the regulating or coding region of the gene. Three single nucleotide polymorphisms (SNPs), rs1946519 (−656 G/T) and rs187238 (−137 G/C) in the promoter region and rs549908 (+105 A/C) in the codon region, were genotyped in 204 parasitological confirmed VL patients and 267 controls with no past history of VL. For each locus, polymerase chain reaction (PCR) followed by restriction digestion was performed. IL-18 expression in peripheral blood mononuclear cells (PBMC) collected from VL patients and controls was measured by quantitative real-time RT-PCR. Distribution of G allele at position −656 ( < 0.0001) and double haplotypes GGC/GGA ( = 0.05) were found to be significantly associated with controls while genotypes TT ( < 0.0001) and single haplotypes TGA ( = 0.0002), with cases. The inheritance of G allele at the position −656 might be considered as a protective allele for VL.