Analysis of cytotoxic T lymphocyte associated antigen 4 gene polymorphisms in patients with ulcerative colitis

BACKGROUND AND AIM: Ulcerative colitis (UC) is a multifactorial disease associated with dysregulated immunity. Recently, cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms have been reported in association with several autoimmune diseases in several populations. In the present study, the possible implication of the CTLA-4 gene as a risk factor for UC in the Iranian population was investigated. METHODS: One hundred UC patients and 100 healthy subjects were studied. CTLA-4 exon 1 position 49 (A/G: codon 17: Thr/Ala) polymorphisms were investigated by polymerase chain reaction single strand confirmation polymorphism method. Four of the patients and one of the healthy controls were excluded from the study because of incomplete DNA extraction. RESULTS: The allele frequencies of A and G in 96 patients (A: 66.1%; G: 33.9%) were not significantly different from the 99 control subjects (A: 63.1%; G: 36.9%, P > 0.05). No significant differences in the distribution of genotype frequencies were observed between A + 49G gene polymorphisms and UC in the Iranian population (P > 0.05). CONCLUSION: CTLA-4 polymorphism is not associated with UC in the Iranian population.     

Epidemiology. Ethnic differences in systemic sclerosis

To review the differences in the epidemiology, clinical manifestations, and severity of systemic sclerosis in different ethnic groups. This review considers only limited and diffuse forms of systemic sclerosis. The most relevant articles about ethnic differences in systemic sclerosis were selected. The information is presented in three sections: differences in the epidemiology of systemic sclerosis between ethnic groups; differences in clinical manifestations between ethnic group, and factors that may explain these differences. Of the different ethnic groups studied, whites have less incidence and prevalence of systemic sclerosis. Whites also have less frequency of inflammatory manifestations, and have a higher frequency of limited skin disease compared with other ethnic groups. These differences may result in the better survival of whites compared with no whites. The origin of these differences has not been discovered so far. Is probable that genetic and environmental factors may play a role in the expression of disease, producing the differences found among the ethnic groups.     

Large granular lymphocyte leukaemia associated with systemic sclerosis

SIR, Large granular lymphocytes (LGL) are a morphologicallydistinct lymphoid subset constituting 10–15% of normalperipheral blood mononuclear cells. LGL leukaemia (LGLL) isa rare disorder characterized by the clonal proliferation ofLGL [1] of either T cell (CD3⁺) or NK (CD3^–) lineage.CD3⁺ LGLL represents 85% of cases of LGLL and is often associatedwith neutropenia, various autoimmune disorders and biologicalimmune abnormalities [2]. We report a patient with clonal proliferation of LGL who developedseveral autoimmune     

克罗恩病患者血清可溶性细胞毒T淋巴细胞相关抗原4水平高表达及其临床意义

目的 研究可溶性细胞毒T淋巴细胞相关抗原4(sCTLA4)在克罗恩病(CD)患者血清中的表达状况,分析sCTLA4水平与红细胞沉降率(ESR)和C反应蛋白(CRP)的关系及其临床意义,探讨CTLA4基因-1661A/G和-1722T/C多态性与CD的相关性.方法 收集126例CD患者和300名健康对照者,酶联免疫吸附实验测定血清sCTLA4水平.全自动红细胞沉降系统分析仪测定ESR水平.速率散射比浊法测定CRP水平.DNA测序技术检测CTLA4基因-1661A/G和-1722T/C多态性.结果 CD患者血清中sCTLA4水平为(18.70±3.72)ng/ml,明显高于健康对照者[(1.72±0.32)ng/ml,P＜0.01].活动期CD患者血清sCTLA4水平为(19.83±4.35)ng/ml,比缓解期CD患者[(18.02±3.14)ng/ml,P=0.015]增高.CD患者血清sCTLA4水平与ESR和CRP水平呈正相关(r=0.267,P=0.003;r=0.524,P＜0.01).疾病行为影响CD患者血清sCTLA4水平,狭窄型CD患者血清sCTLA4水平高于非狭窄非穿透型和穿透型CD患者,差异均有统计学意义(P值分别=0.021和0.015).CD组和健康对照组中CTLA4基因-1661A/G,-1722T/C等位基因及基因型频率差异无统计学意义(P＞0.05).结论 CD患者血清sCTLA4水平增高,增高的sCTLA4水平不仅与疾病活动状态及狭窄型疾病行为相关,且与CRP正相关,提示sCTLA4分子在CD免疫学发病中可能起重要作用.

Abstract：

Objective To investigate the expression of serum soluble cytotoxic T lymphocyte associated antigen 4 (sCTLA4), the association of sCTLA4 level with erythrocyte sedimentation rate (ESR) and C reactive protein (CRP), as well as its role in patients with Crohn's disease (CD). The relationship-1661A/G and -1722T/C polymorphisms of CTLA4 gene and between disease susceptibility and phenotype of CD was analyzed. Methods A total of 126 CD patients and 300 healthy controls were enrolled in the study. Serum sCTLA4 level was determined by enzyme-linked immunosorbent assay. The concentrations of ESR and CRP were analyzed by automatic ESR Analyzer SRS 100/Ⅱ and rate nephelometry, respectively. The polymorphisms of CTLA4-1661A/G and -1722 T/C were genotyped by DNA sequencing. Results Serum sCTLA4 level was higher in CD patients than in healthy controls [(18. 70±3. 72) ng/ml vs (1.72±0. 32) ng/ml, P＜0. 01)]. Among CD patients, sCTLA4 level was higher in patients with active disease when compared to those with inactive disease [(19.83±4.35) ng/ml vs (18. 02±3.14) ng/ml, P=0. 015)]. sCTLA4 level was positively correlated with ESR and CRP levels (r=0. 267, P=0. 003; r=0. 524 P ＜0.01, respectively). In CD patients, serum sCTLA4 level was significantly higher in those with stricturing disease behavior than that in those without stricturing and penetrating or with penetrating disease behavior (P= 0.021; P=0. 015, respectively). Detection of CTLA4 -1661A/G and -1722T/C polymorphisms showed no significant difference between CD patients and healthy controls. Conclusions The high level of serum sCTLA4 in CD patients is correlated with disease activity, CRP levels and disease behavior. It suggests that sCTLA4 may play an important role in pathogenesis of CD.     

Cytotoxic T lymphocyte antigen 4 (CTLA-4) dimorphism in patients with systemic lupus erythematosus

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is conferred not only by various genes within the major histocompatibility complex (MHC) region, but also by several other non-MHC linked genes. The negatively signalling molecule CTLA-4 is involved in establishing and maintaining of peripheral T cell tolerance, which controls T cell activation and reactivity. Its attenuating action helps to prevent an inappropriate initiation of T cell responses to self antigens and to terminate ongoing T cell responses. We tested if there was an association between CTLA-4 and SLE, a disease with B and T cell hyperreactivity and impaired peripheral T cell tolerance. METHODS: Using the polymerase chain reaction--restriction fragment length polymorphism method with Bbv I digestion, we assessed an exon 1 transition dimorphism (49 A/G) of the CTLA-4 gene in 102 SLE patients and in 76 healthy controls. RESULTS: The distribution of CTLA-4 exon 1 genotypes in the SLE group was significantly different from that in the controls (chi 2 = 6.178, p < 0.05). 17.6% of the SLE patients were G/G homozygotes compared to 5.3% of the controls; 36.3% were A/G heterozygotes vs 40.8% of controls; and 46.1% were A/A homozygotes vs 53.9% of the controls. The frequency of the G allele was significantly higher in SLE patients (35.8%) than in controls (25.7%; chi 2 = 4.142, p = 0.042). CONCLUSION: Our results indicate that the non-MHC linked CTLA-4 gene could confer susceptibility in SLE, as it does in various other autoimmune diseases (Hashimoto thyroiditis, Graves' disease, IDDM).     

Ethnic disparities among patients with pulmonary hypertension associated with systemic sclerosis

OBJECTIVE: To examine a cohort of patients with systemic sclerosis (SSc) and pulmonary hypertension (PH) for ethnic disparities in clinical presentation, disease detection, or management. METHODS: Encounters of patients with SSc seen at the Medical University of South Carolina were recorded in a computerized database from November 1997 through January 2004. Patients were evaluated for discrepancy in disease manifestation and treatment. Evaluation criteria included patient ethnicity (by self report), age, disease duration from onset of first non-Raynaud's symptom, presence or absence of PH, incidence of diastolic dysfunction and left ventricular hypertrophy among patients with PH, severity of interstitial lung disease, and treatment course. RESULTS: African Americans were more likely than Caucasians to have diffuse cutaneous SSc (dcSSc) (69.9% vs 42.9%, p < 0.001) and they presented with PH (defined as right ventricular systolic pressure > 40 mm Hg by echocardiogram or mean pulmonary artery pressure > 25 mm Hg by right heart catheterization (RHC) at a younger age (60.9 yrs vs 49.0 yrs, p < 0.001). There were no ethnic disparities in time from onset of the first non-Raynaud's symptom to detection of PH, method of PH detection, or treatment modalities. Patients with PH were more likely to have diastolic dysfunction than those without PH (52.3% vs 35.9%, p = 0.011). CONCLUSION: In this cohort of patients, African Americans were more likely to have dcSSc. Among patients with PH, African Americans presented at a younger age than their Caucasian counterparts. Incidence of diastolic dysfunction was higher in the PH population. There were no significant ethnic disparities in time of progression to PH or in treatment modalities employed in our cohort.     

原发性胆汁性胆管炎患者血浆细胞毒性T淋巴细胞相关蛋白4基因多态性分析

目的 探讨原发性胆汁性胆管炎(PBC)患者血浆细胞毒性T淋巴细胞相关蛋白4(CTLA-4)基因多态性变化。方法 2015年9月～2020年12月我院诊治的PBC患者30例和同期健康体检者35例,采用聚合酶链反应-限制性片段长度多态性检测血浆CTLA－4基因rs231775、 rs4675369和rs7599230位点多态性。Logistic回归分析疾病风险关联。结果 PBC患者CTLA－4基因rs7599230位点基因型为CC型、CT型和TT型比率分别为16.7%、46.7%和36.6%,与健康人的20.0%、45.7%和34.3%比,无显著性差异(P＞0.05),等位基因C和T比率分别为40.0%和60.0%,与健康人群的42.9%和57.1%比,也无显著性差异(P＞0.05);PBC患者CTLA－4基因rs231775位点基因型为GG型和等位基因G比率分别为40.0%和61.7%,显著高于健康人的14.2%和35.7%(P＜0.05),AA基因型和等位基因A比率分别为16.7%和38.3%,显著低于健康人的42.9%和64.3%(P＜0.05);PBC患者CTLA－4基因rs4675369位点基因型为GG型和等位基因G比率分别为43.3%和65.0%,显著高于健康人的17.1%和41.4%(P＜0.05),AA基因型和等位基因A比率分别为13.4%和35.0%,显著低于健康人的34.3%和58.6%(P＜0.05);经非条件Logistic回归模型计算,校正性别和年龄,结果显示rs4675369位点GG基因型是影响PBC发生的危险基因型,其OR值为1.523((95%CI:1.113～2.085),rs231775位点GG基因型也是影响PBC发生的危险基因型,其OR值为1.636((95%CI:1.161～2.305) 。结论 CTLA-4基因rs231775和rs4675369位点GG基因型可能是PBC发生的易感基因型,值得进一步研究。     

Association of Epstein-Barr virus with systemic lupus erythematosus: effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype

OBJECTIVE: Epstein-Barr virus (EBV) is hypothesized to play a role in the development of systemic lupus erythematosus (SLE). Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is important in regulating T cell-mediated immunity, encompassing the first line of response to viral infections, and genetic variation in CTLA-4 has been associated with SLE. This study examined the seroprevalence of EBV in a population-based study of SLE patients from the southeastern United States, and potential interactions with CTLA-4 polymorphisms were assessed. METHODS: Cases comprised 230 subjects recently diagnosed as having SLE (144 African American and 86 white) from university and community-based clinics, and controls comprised 276 age-, sex-, and state-matched subjects (72 African American and 204 white) recruited from driver's license registries. Antibodies to EBV capsid antigen were determined by enzyme-linked immunosorbent assay, with results expressed as positive or negative using the international standardized ratio (ISR) (a ratio of the sample absorbance to a known standard). CTLA-4 genotypes were identified by polymerase chain reaction-based methods. RESULTS: In African Americans, EBV-IgA seroprevalence was strongly associated with SLE (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 3.0-10.6). In whites, the modest association of SLE with EBV-IgA (OR 1.6) was modified by age, in that the strongest association was observed in those older than age 50 years (OR 4.1, 95% CI 1.6-10.4). The seroprevalence of EBV-IgM and that of EBV-IgG were not associated with SLE. Higher EBV-IgG absorbance ratios were observed in SLE patients, with a significant dose response across units of the ISR in African Americans (P < 0.0001). Allelic variation in the CTLA-4 gene promoter (-1661A/G) significantly modified the association between SLE and EBV-IgA (P = 0.03), with a stronger association among those with the -1661AA genotype. CONCLUSION: These findings suggest that repeated or reactivated EBV infection, which results in increased EBV-IgA seroprevalence and higher IgG antibody titers, may be associated with SLE, and that the CTLA-4 genotype influences immune responsiveness to EBV in SLE patients. The observed patterns of effect modification by race, age, and CTLA-4 genotype should be examined in other studies and may help frame new hypotheses regarding the role of EBV in SLE etiology.     

细胞毒性T淋巴细胞相关抗原4/CT60基因多态性与溃疡性结肠炎的关系

目的探讨细胞毒性T淋巴细胞相关抗原4（CTLA4）CT00位点基因多态性与中国湖北地区汉族人溃疡性结肠炎（UC）的相关性。方法共收集64例UC患者和109例正常对照静脉血标本提取基因组DNA。采用多聚酶链反应．限制性片段长度多态性分析（PCR-RFLP）方法检测CT60G／A（rs3087243）位点的多态性，计算CTLA4的基因型和等位基因频率。结果CT60G／A基因型分布及等位基因频率，UC组与正常对照组比较差异无显著性，中国湖北地区汉族人群CTLA4CT60基因型和等位基因分布与日本人群相似。而与西班牙人群分布存在显著差异。结论CT60基因多态性与中国湖北汉族人UC易感性无关。     

Long-term immunomodulatory effects of T lymphocyte depletion in patients with systemic sclerosis

We describe 2 patients with rapidly progressing systemic sclerosis that did not respond to conventional therapy, who were treated with a 5-day regimen of T cell-specific antilymphocyte globulin. One patient had deteriorating pulmonary involvement, and the second patient had developed disabling skin disease with multiple ulcers and gangrene. Both patients showed improvement concomitant with almost complete elimination of CD4+ and CD8+ T lymphocytes. Regeneration of peripheral T cells required 60-90 days and was followed by a long-term inversion of the CD4:CD8 ratio. The persistent therapeutic effect in both patients correlated with the lack of CD4+ T cells and the predominance of CD8+ T cells. This suggests a crucial role of T cell immunity in the pathogenesis of systemic sclerosis. In vitro studies of regenerating T cells demonstrated that CD4+ helper/inducer cells were functionally competent. Alterations in the composition of the CD8+ population may explain the prolonged suppression of CD4+ T cells observed during the period of therapeutic benefit.     

Association of Epstein‐Barr virus with systemic lupus erythematosus: Effect modification by race,age, and cytotoxic T lymphocyte–associated antigen 4 genotype

Objective

Epstein‐Barr virus (EBV) is hypothesized to play a role in the development of systemic lupus erythematosus (SLE). Cytotoxic T lymphocyte–associated antigen 4 (CTLA‐4) is important in regulating T cell–mediated immunity, encompassing the first line of response to viral infections, and genetic variation in CTLA‐4 has been associated with SLE. This study examined the seroprevalence of EBV in a population‐based study of SLE patients from the southeastern United States, and potential interactions with CTLA‐4 polymorphisms were assessed.

Methods

Cases comprised 230 subjects recently diagnosed as having SLE (144 African American and 86 white) from university and community‐based clinics, and controls comprised 276 age‐, sex‐, and state‐matched subjects (72 African American and 204 white) recruited from driver's license registries. Antibodies to EBV capsid antigen were determined by enzyme‐linked immunosorbent assay, with results expressed as positive or negative using the international standardized ratio (ISR) (a ratio of the sample absorbance to a known standard). CTLA‐4 genotypes were identified by polymerase chain reaction–based methods.

Results

In African Americans, EBV‐IgA seroprevalence was strongly associated with SLE (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 3.0–10.6). In whites, the modest association of SLE with EBV‐IgA (OR 1.6) was modified by age, in that the strongest association was observed in those older than age 50 years (OR 4.1, 95% CI 1.6–10.4). The seroprevalence of EBV‐IgM and that of EBV‐IgG were not associated with SLE. Higher EBV‐IgG absorbance ratios were observed in SLE patients, with a significant dose response across units of the ISR in African Americans (P < 0.0001). Allelic variation in the CTLA‐4 gene promoter (−1661A/G) significantly modified the association between SLE and EBV‐IgA (P = 0.03), with a stronger association among those with the −1661AA genotype.

Conclusion

These findings suggest that repeated or reactivated EBV infection, which results in increased EBV‐IgA seroprevalence and higher IgG antibody titers, may be associated with SLE, and that the CTLA‐4 genotype influences immune responsiveness to EBV in SLE patients. The observed patterns of effect modification by race, age, and CTLA‐4 genotype should be examined in other studies and may help frame new hypotheses regarding the role of EBV in SLE etiology.

     

Hashimoto's thyroiditis is associated with peripheral lymphocyte activation in patients with systemic sclerosis

OBJECTIVE: To investigate whether autoimmune thyroiditis [HT] (i.e., a TH1 disease) influences the pattern of peripheral lymphocyte activation in systemic sclerosis [SSc] (commonly regarded as a TH2 disease). Twenty SSc patients, 6 with (SSc+HT+) and 14 without HT (SSc+HT-) and 20 controls were investigated for the intracellular content of IFN-gamma and IL-4 in unstimulated and stimulated (25 ng/ml PMA and 1 microg/ml ionomycin) CD4+ and CD8+ T lymphocytes. Results Under basal conditions the percentages of CD4+IFN-gamma, CD4+IL-4+ and CD8+IFN-gammawere significantly higher in the patients than the control subjects, no significant differences being detectable between the two patient subgroups. Upon PMA stimulation, the 20 SSc patients showed a higher percentage of CD4+IFN-gamma+ and CD8+IFN-gamma+ than the control subjects. In particular, the 14 SSc+HT- patients showed a higher number of CD4+IFN-y+ and CD4+IL-4+ cells, while the SSc+HT+ patients showed higher percentage of CD8+IFN-gamma+ cells. The latter patients showed a reduced percentage of CD4+IL-4+ cells and an increased percentage of CD8+IFN-y+ in comparison with the SSc+HT- patients. Type-1 activation in the peripheral blood of SSc patients has been already pointed out by other authors and ourselves. This study shows that such activation mainly affects SSc patients with coexistent HT.     

Multiple sclerosis associated with systemic sclerosis

Multiple sclerosis (MS) has been increasingly reported in association with other autoimmune diseases not primary affected the nervous system. The coexistence of MS and systemic sclerosis (SSc) has been rarely described. We report here the case of a 46-year-old female patient with longstanding MS since the age of 26, who developed SSc 12 years later. Her MS was of the relapsing-remitting type, but the definite diagnosis was not made until the age of 33. MS diagnosis was based on medical history, magnetic resonance imaging (MRI) studies and positive cerebrospinal fluid analysis. One year after the diagnosis of MS, she developed Raynaud’s phenomenon, skin tightness and hypopigmented patches, suggestive of scleroderma. Further investigation with laboratory studies, including serology, hand and chest X-rays, and chest computerized tomography scan confirmed the SSc diagnosis. Our report highlights the interesting association between MS and SSc that may be due to an overlapping pathogenetic mechanism for both processes.     

Cytotoxic T lymphocyte antigen 4 gene polymorphism associated with ST-segment elevation acute myocardial infarction.

BACKGROUND: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a particularly important molecule in down-regulating T-cell expansion and cytokine production. The purpose of the present study was to determine the frequency distribution of an A/G single nucleotide polymorphism at position 49 in exon 1 of the CTLA-4 gene, which may be a functional related-genetic risk marker for the development of ST-segment elevation (ST-se) acute myocardial infarction (AMI). METHODS AND RESULTS: A total of 503 consecutive patients, consisting of 250 ST-se AMI patients undergoing primary coronary angioplasty (group 1), 203 angina pectoris patients undergoing elective coronary angioplasty (group 2) and 50 patients with chest pain and normal coronary angiographic findings (group 3), were enrolled in the present study. The frequency of the G/G genotype was significantly higher in group 1 (53.2%) than in groups 2 (33.0%) and 3 (36.0%) (p=0.0005). In group 1, patients with a G/G genotype had significantly higher levels of high-sensitivity C-reactive protein and white blood cell counts, and much higher incidences of multi-vessel disease, greater lesion lengths, advanced congestive heart failure (>or=class 3) and 30-day mortality, than patients with G/A or A/A genotypes (p values<0.05 in all cases). Multivariate analysis of the enrolled baseline variables (age, gender, diabetes mellitus, smoking, hypertension and hypercholesterolemia) and the genotypes (G/G, A/G and A/A) demonstrated that G/G genotype is the only independent predictor of development of AMI (p<0.0001). CONCLUSION: The G/G genotype polymorphism of the CTLA-4 gene is associated with increased risk of AMI.     

A cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism is associated with autoimmune Addison's disease in English patients

OBJECTIVE: Recent studies have demonstrated an association between a microsatellite polymorphism of the CTLA-4 gene, specifically a 106 base pair allele, and both Graves' disease and autoimmune hypothyroidism. The aim of the present study was to determine whether the same polymorphism of the CTLA-4 gene was associated with autoimmune Addison's disease. DESIGN AND PATIENTS: We analysed a microsatellite polymorphism (variant lengths of a dinucleotide (AT)n repeat) within exon 3 of the CTLA-4 gene in the following groups: 21 English patients with non-associated Addison's disease, 18 with autoimmune polyglandular syndrome type 2 (APS2) and 173 healthy control subjects; 26 Norwegian patients with non-associated Addison's disease, 9 with autoimmune polyglandular syndrome type 1 (APS1), 17 with APS2 and 100 controls; 3 Finnish patients with non-associated Addison's disease, 5 with APS2 and 71 controls; 10 Estonian patients with non-associated Addison's disease, 2 with APS2 and 45 controls. MEASUREMENTS: The CTLA-4 microsatellite gene polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels. RESULTS: The frequency of the 106 base pair allele was significantly increased in the groups of English patients with either non-associated Addison's disease or APS2 (P = 0.02 and 0.04, respectively), when compared to healthy controls with no clinical evidence or family history of either Addison's disease or any other autoimmune disorder. For Norwegian patients with either non-associated Addison's disease, APS1 or APS2, there was no association (P = 0.69, 0.62 and 0.97, respectively). This was also the case for Finnish patients with either non-associated Addison's disease or APS2 (P = 0.23 and 0.28, respectively) and for Estonian patients with either non-associated Addison's disease or APS2 (P = 0.34 and 0.29, respectively). CONCLUSIONS: These results indicate that differences exist in the frequency of the 106 base pair allele in different population groups and in only the English population was the 106 base pair allele associated with Addison's disease.     

Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation

BACKGROUND: The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene encodes for a membrane bound (mCTLA-4) and a soluble (sCTLA-4) isoform, which are both involved in regulation of T cell function. The CTLA-4 +49A/G single nucleotide polymorphism (SNP) influences expression of mCTLA-4; +6230G/A SNP affects the production of sCTLA-4. AIM: To examine whether these functional SNPs influence the rate of rejection after liver transplantation. PATIENTS AND METHODS: Liver graft recipients (n = 483) were genotyped for both SNPs, and haplotypes were reconstructed. Association with rejection was tested by the log rank test using the Kaplan-Meier method with time to the first acute rejection episode as outcome. Multiple analysis of SNPs together with demographic factors was performed by Cox regression. RESULTS: Three haplotypes were observed in the cohort: +49A/+6230A, +49A/+6230G, and +49G/+6230G. The +49A/+6230G haplotype was significantly and dose dependently associated with acute rejection (p = 0.01). Of the demographic factors tested, only underlying liver disease was significantly associated with rejection. Adjusted for underlying liver disease, each additional +49A/+6230G haplotype allele resulted in a significantly higher risk of acute rejection (risk ratio 1.34 (95% confidence interval 1.04-1.72); p = 0.02). Patients who lacked this haplotype had the lowest, carriers an intermediate, and homozygotes the highest risk of acute rejection. CONCLUSION: The CTLA-4 +49A/+6230G haplotype, which encodes for normal mCTLA-4 expression but reduced sCTLA-4 production, is a co-dominant risk allele for acute rejection after clinical liver transplantation. This implies that even under immunosuppression, CTLA-4 is critically involved in the regulation of the human immune response to allogeneic grafts.     

Celiac disease associated with systemic sclerosis

Systemic scleroderma (SS) affects the connective tissue, with involvement of multiple organs. Digestive system involvement occurs in 50% of patients. SS is frequently associated with other autoimmune diseases. Celiac disease (CD) is an autoimmune disorder that affects the digestive system and is trigged by gluten intake. These two diseases share some HLA antigens. We describe the case of a woman with a diagnosis of SS who presented with weight loss. CD was diagnosed. Because the literature on this topic is scarce, this case is compared with a prior review and some similarities were found. Diagnosis of CD in patients with SS may be difficult but is essential to achieve optimal treatment response in patients with poor quality of life.     

Pulmonary hypertension associated with systemic sclerosis

Pulmonary hypertension is a rare but well known life-threatening complication of scleroderma and particularly in its limited variant, the CREST syndrome (Calcification, Raynaud phenomenon, Esophageal dysmotility, Sclerodactily, Telangiectasia). The aim of this article is to analyze the available literature and to report the experience of a center for pulmonary vascular diseases. Dyspnea is the main symptom and is frequently severe. Echocardiography is an excellent tool to detect pulmonary hypertension. However, right-heart catheterization is necessary to confirm the diagnosis of pulmonary hypertension and to test vasoreactivity with a potent vasodilator such as nitric oxide. Hemodynamic parameters are less severe in patients with connective tissue diseases perhaps because of an earlier diagnosis. A significant lower proportion of patients presents an acute vasodilator response suggesting an early constitution of irreversible pulmonary vascular lesions. Continuous intravenous epoprostenol therapy seems to be less effective as compared with patients with primitive pulmonary hypertension and does not improve survival. In our experience, immunosuppressive therapy does not improve hemodynamic or clinical data. Novel therapies including oral, sub-cutaneous or inhaled stable prostacyclin analogues and endothelin receptor antagonists are currently evaluated in large placebo-controlled trials.     

Brachial plexopathy associated with systemic sclerosis

Neurological involvement is uncommon in systemic sclerosis. Most of the reported cases concern trigeminal neuropathy or peripheral nerve entrapment. We report a third case of brachial plexopathy, presumably related to vasculitis, in a patient with systemic sclerosis, which improved after cyclophosphamide therapy. Received: 7 September 2001 / Accepted: 3 April 2002