AIM： To examine an association between the cytotoxic Tlymphocyte antigen 4 （CTLA4） gene that plays a role in downregulation of T-cell activation and inflammatory bowel disease consisting of ulcerative colitis （UC...AIM： To examine an association between the cytotoxic Tlymphocyte antigen 4 （CTLA4） gene that plays a role in downregulation of T-cell activation and inflammatory bowel disease consisting of ulcerative colitis （UC） and Crohn＇s disease （CD） in the Japanese.METHODS： We studied 108 patients with UC, 79 patients with CD, and 200 sex-matched healthy controls, with respect to three single nucleotide polymorphisms （SNPs） in CTLA4, such as C-318T in the promoter region, A＋49 Gin exon 1 and G＋6230A in the 3＇ untranslated region （3＇-UTR） by a PCR-restriction fragment length polymorphism method, and to an （AT）, repeat polymorphism in 3＇-UTR by fragment analysis with fluorescence-labeling on denaturing sequence gels. Frequency of alleles and genotypes and their distribution were compared statistically between patients and controls and among subgroups of patients, using X^2 and Fisher exact tests.RESULTS： The frequency of ＂A/A＂ genotype at the G＋6230A SNP site was statistically lower in UC patients than in controls （3.7% vs 11.0%, P = 0.047, odds ratio （OR） = 0.311）. Moreover, the frequency of ＂G/G＂ genotype at the A＋49G SNP site was significantly higher in CD patients with fistula （48.6%） than those without it （26.2%）（P = 0.0388, OR=2.67）.CONCLUSION： The results suggest that CTLA4 located at 2q33 is a determinant of UC and responsible for fistula formation in CD in the Japanese.展开更多
Mixed hemopoietic chimerism is capable of inducing donor specific tolerance, thus eliminating the chronic immunosuppressive therapy following organ trans- plantation. As yet no safe and effective tolerance protocol is...Mixed hemopoietic chimerism is capable of inducing donor specific tolerance, thus eliminating the chronic immunosuppressive therapy following organ trans- plantation. As yet no safe and effective tolerance protocol is available for clinical implementation. Here we describe an alternative nonmyeloablative based strategy of using a single injection of recombination adenovirus vector encoding CTLA4-FasL fusing gene and donor bone marrow cells to promote durable mixed macrochimerism (>20% on 140 d). Chimeras exhibited robust donor-specific tolerance, as evi- denced by acceptance of fully allogeneic skin grafts (the mean survival time (MST)>200 d) and rejection of third- party skin grafts in a normal manner (MST<10 d). In this model, the frequencies of helper T lymphocyte precursor (HTLp) and cytotoxic T lymphocyte precursor (CTLp) were greatly reduced on day 14 after transplantation, suggesting that CTLA4-FasL led to rapid systemic peripheral tolerance to facilitate the bone marrow engraftment, while both HTLp and CTLp remained at low level only in recipient mice with mixed chimerism on day 140 after transplantation, demon- strating that long-term skin grafts tolerance was associated with stable mixed chimerism, and central deletion of donor specific T cell may be the main mechanism for tolerance maintenance.展开更多
The precise etiology and reasons for the increase in incidence of autoimmune disorders still remain unclear, and although both genetic and environmental factors have been proven to shape individual predisposition, it ...The precise etiology and reasons for the increase in incidence of autoimmune disorders still remain unclear, and although both genetic and environmental factors have been proven to shape individual predisposition, it is not known which of the factors, if not both, is responsible for the boom observed during the last decades. In order to establish whether a higher frequency of autoimmune-predisposing alleles may explain this increase we took advantage of ancient DNA methodology to establish the genetic predisposition, conferred by cytotoxic T lymphocyte associated antigen-4 （CTLA4） ＋49A/G and human leukocyte antigens （HLA） DQBI^57, in population inhabiting Poland in the Middle Ages. After successful typing of 42 individuals from a 12th-14th＇s century archeological burial site, we found that frequencies of the predisposing alleles in the medieval population were higher than they are at present, suggesting thus that the recently observed incidence increase results most probably from factors of other than genetic nature.展开更多
Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we...Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response.We investigated 3 distinct polymorphic sites(t49A>G,CT60 G>A and e318C>T)of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology.A significant positive association with AIH susceptibility was found for the GG genotype in t49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls(28%vs 9%,pZ0.003,ORZ3.93[1.56e9.88]).The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients.CTLA4 genotyping in position318 did not show any statistically significant difference in genotype or allele distribution.The CTLA4 gene polymorphism in position t49 is associated to AIH susceptibility in the Tunisian population.Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.展开更多
文摘AIM： To examine an association between the cytotoxic Tlymphocyte antigen 4 （CTLA4） gene that plays a role in downregulation of T-cell activation and inflammatory bowel disease consisting of ulcerative colitis （UC） and Crohn＇s disease （CD） in the Japanese.METHODS： We studied 108 patients with UC, 79 patients with CD, and 200 sex-matched healthy controls, with respect to three single nucleotide polymorphisms （SNPs） in CTLA4, such as C-318T in the promoter region, A＋49 Gin exon 1 and G＋6230A in the 3＇ untranslated region （3＇-UTR） by a PCR-restriction fragment length polymorphism method, and to an （AT）, repeat polymorphism in 3＇-UTR by fragment analysis with fluorescence-labeling on denaturing sequence gels. Frequency of alleles and genotypes and their distribution were compared statistically between patients and controls and among subgroups of patients, using X^2 and Fisher exact tests.RESULTS： The frequency of ＂A/A＂ genotype at the G＋6230A SNP site was statistically lower in UC patients than in controls （3.7% vs 11.0%, P = 0.047, odds ratio （OR） = 0.311）. Moreover, the frequency of ＂G/G＂ genotype at the A＋49G SNP site was significantly higher in CD patients with fistula （48.6%） than those without it （26.2%）（P = 0.0388, OR=2.67）.CONCLUSION： The results suggest that CTLA4 located at 2q33 is a determinant of UC and responsible for fistula formation in CD in the Japanese.
基金supported by the National Natural Science Foundation of China(Grant No.39830340).
文摘Mixed hemopoietic chimerism is capable of inducing donor specific tolerance, thus eliminating the chronic immunosuppressive therapy following organ trans- plantation. As yet no safe and effective tolerance protocol is available for clinical implementation. Here we describe an alternative nonmyeloablative based strategy of using a single injection of recombination adenovirus vector encoding CTLA4-FasL fusing gene and donor bone marrow cells to promote durable mixed macrochimerism (>20% on 140 d). Chimeras exhibited robust donor-specific tolerance, as evi- denced by acceptance of fully allogeneic skin grafts (the mean survival time (MST)>200 d) and rejection of third- party skin grafts in a normal manner (MST<10 d). In this model, the frequencies of helper T lymphocyte precursor (HTLp) and cytotoxic T lymphocyte precursor (CTLp) were greatly reduced on day 14 after transplantation, suggesting that CTLA4-FasL led to rapid systemic peripheral tolerance to facilitate the bone marrow engraftment, while both HTLp and CTLp remained at low level only in recipient mice with mixed chimerism on day 140 after transplantation, demon- strating that long-term skin grafts tolerance was associated with stable mixed chimerism, and central deletion of donor specific T cell may be the main mechanism for tolerance maintenance.
基金Project (No. 3 P05E 055 25) supported by the Ministry of Education and Science of Poland
文摘The precise etiology and reasons for the increase in incidence of autoimmune disorders still remain unclear, and although both genetic and environmental factors have been proven to shape individual predisposition, it is not known which of the factors, if not both, is responsible for the boom observed during the last decades. In order to establish whether a higher frequency of autoimmune-predisposing alleles may explain this increase we took advantage of ancient DNA methodology to establish the genetic predisposition, conferred by cytotoxic T lymphocyte associated antigen-4 （CTLA4） ＋49A/G and human leukocyte antigens （HLA） DQBI^57, in population inhabiting Poland in the Middle Ages. After successful typing of 42 individuals from a 12th-14th＇s century archeological burial site, we found that frequencies of the predisposing alleles in the medieval population were higher than they are at present, suggesting thus that the recently observed incidence increase results most probably from factors of other than genetic nature.
基金supported by the Northern Portugal Regional Operational Programme(NORTE 2020)the Portugal 2020 Partnership Agreement,through the European Regional Development Fund(FEDER)(NORTE-01-0145-FEDER-000013)the Fundacao para a Ciencia e Tecnologia(FCT)(IF/00735/2014 to AC and SFRH/BPD/96176/2013 to CC).
文摘Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response.We investigated 3 distinct polymorphic sites(t49A>G,CT60 G>A and e318C>T)of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology.A significant positive association with AIH susceptibility was found for the GG genotype in t49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls(28%vs 9%,pZ0.003,ORZ3.93[1.56e9.88]).The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients.CTLA4 genotyping in position318 did not show any statistically significant difference in genotype or allele distribution.The CTLA4 gene polymorphism in position t49 is associated to AIH susceptibility in the Tunisian population.Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.
