The autoimmune regulator gene (AIRE) is strongly associated with vitiligo.

BACKGROUND: Vitiligo is an autoimmune disorder that occurs with greatly increased frequency in the rare recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) caused by mutations of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. We have previously detected an association between alopecia areata and single nucleotide polymorphisms (SNPs) in the AIRE gene. OBJECTIVES: To report the findings of an extended study including haplotype analysis on six AIRE polymorphisms (AIRE C-103T, C4144G, T5238C, G6528A, T7215C and T11787C) in vitiligo, another APECED-associated disease. METHODS: A case-control analysis was performed. RESULTS: Results showed a strong association between AIRE 7215C and vitiligo [P = 1.36 x 10(-5), odds ratio (OR) 3.12, 95% confidence interval (CI) 1.87-5.46]. We found no significant association with the other polymorphisms individually. However, haplotype analysis revealed that the AIRE haplotype CCTGCC showed a highly significant association with vitiligo (P = 4.14 x 10(-4), OR 3.00, 95% CI 1.70-5.28). To select the most informative minimal haplotypes, we tagged the polymorphisms using SNP tag software. Using AIRE C-103T, G6528A, T7215C and T11787C as tag SNPs, the haplotype AIRE CGCC was associated with vitiligo (P = 0.003, OR 2.49, 95% CI 1.45-4.26). CONCLUSIONS: The link between vitiligo and AIRE raises the possibility that defective skin peripheral antigen selection in the thymus is involved in the changes that result in melanocyte destruction in this disorder.

Genetic analysis of autoimmune regulator haplotypes in alopecia areata.

Alopecia areata is an immune-mediated disorder, occurring with the highest observed frequency in the rare recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome caused by mutations of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. We have previously detected association between alopecia areata and a single nucleotide polymorphism (SNP) in the AIRE gene in patients without APECED, and we now report the findings of an extended examination of the association of alopecia areata with haplotype analysis including six SNPs in the AIRE gene: C-103T, C4144G, T5238C, G6528A, T7215C and T11787C. In Caucasian groups of 295 patients and 363 controls, we found strong association between the AIRE 7215C allele and AA [P = 3.8 x 10(-8), OR (95% CI): 2.69 (1.8-4.0)]. The previously reported association between AA and the AIRE 4144G allele was no longer significant on correction for multiple testing. The AIRE haplotypes CCTGCT and CGTGCC showed a highly significant association with AA [P = 6.05 x 10(-6), 9.47 (2.91-30.8) and P = 0.001, 3.51 (1.55-7.95), respectively]. To select the haplotypes most informative for analysis, we tagged the polymorphisms using SNPTag software. Employing AIRE C-103T, G6528A, T7215C and T11787C as tag SNPs, two haplotypes were associated with AA; AIRE CGCT and AIRE CGCC [P = 3.84 x 10(-7), 11.40 (3.53-36.9) and P = 3.94 x 10(-4), 2.13 (1.39-3.24) respectively]. The AIRE risk haplotypes identified in this study potentially account for a major component of the genetic risk of developing alopecia areata.

Triple therapy in cadaveric renal transplantation: role of induction cyclosporine and targeted levels to avoid rejection.

The updated data on 61 consecutive cadaveric transplants performed at our institution from 1987 to 1990 (followup 31 to 82 months, median 54 months) were analyzed with emphasis on cyclosporine monitoring and long-term results. All patients received triple therapy with cyclosporine induction, azathioprine and prednisone regardless of graft function, and they were preferentially placed on the calcium blocker nifedipine. We monitored 12-hour cyclosporine trough levels in whole blood using high performance liquid chromatography and the dose was adjusted to maintain levels at 150 ng./ml. or greater for the first 3 months. In 17 of 61 patients (28%) 22 rejection episodes occurred and 20 nephrotoxicity episodes occurred in 17 of 61 patients (28%). There was no significant difference in the mean cyclosporine levels among 32 rejection, nonrejection, nephrotoxic and nonnephrotoxic cases at any interval. Rejection occurred by 1 month in 13 (76%) and by 3 months in 15 (88%) of 17 patients. Comparisons were made in the first month to define the desirable cyclosporine levels by calculating the mean cyclosporine only within 10 to 14 days of rejection or nephrotoxicity events. The mean cyclosporine level before rejection was significantly lower than that for nephrotoxicity (188 +/- 113 versus 304 +/- 62 ng./ml., p < 0.01). The median cyclosporine level for first month rejection was also significantly lower than that for nonrejection (156 versus 218 ng./ml., p < 0.05) and it was significantly greater for nephrotoxicity versus nonnephrotoxicity (272 versus 218 ng./ml., p < 0.05). Of 13 rejections in the first month 10 (77%) were associated with mean levels of less than 210 ng./ml. Actuarial graft survival at 1, 3 and 5 years was 93.4%, 87.8% and 78.5%, respectively. The 3-year graft survival was significantly worse for patients who experienced acute rejection episodes versus those who did not (68.8% versus 96.7%, p < 0.05) but it was not different for nephrotoxic versus nonnephrotoxic groups (85.6% versus 79.6%). Long-term function was not influenced by the occurrence of acute nephrotoxicity events. These findings confirm the efficacy of triple therapy with induction cyclosporine in cadaveric transplantation, yielding improved short-term and intermediate graft survival without any adverse effects on long-term graft function. Specific cyclosporine level monitoring is invaluable, particularly initially, with high target levels of 200 ng./ml. or greater. The use of calcium blockers may have allowed higher cyclosporine dosing in the first 3 months, mitigating against cyclosporine associated chronic nephrotoxicity.

Post-transplant lymphoceles: a critical look into the risk factors, pathophysiology and management.

To define better the prevalence and pathophysiology of lymphoceles following renal transplantation, we prospectively evaluated 118 consecutive renal transplants performed in 115 patients (96 cadaveric, 22 living-related, 7 secondary and 111 primary). Ultrasonography was performed post-operatively and during rehospitalizations or whenever complications occurred. Perirenal fluid collections were identified in 43 patients (36%). Lymphoceles with a diameter of 5 cm. or greater were identified in 26 of 118 cases (22%). Eight patients (6.8%) had symptomatic lymphoceles requiring therapy. The interval for development of symptomatic lymphoceles was 1 week to 3.7 years (median 10 months). Risk factors for the development of lymphoceles were examined by univariate and multivariate analysis, and included patient age, sex, source of transplants (cadaver versus living-related donor), retransplantation, tissue match (HLA-B/DR), type of preservation, arterial anastomosis, occurrence of acute tubular necrosis-delayed graft function, occurrence of rejection, and use of high dose corticosteroids. Univariate analysis showed a significant risk for the development of lymphoceles in transplants with acute tubular necrosis-delayed graft function (odds ratio 4.5, p = 0.004), rejection (odds ratio 25.1 p < 0.001) and high dose steroids (odds ratio 16.4, p < 0.001). When applying multivariate analyses using stepwise logistic regression, only rejection was associated with a significant risk for lymphoceles (symptomatic lymphoceles--odds ratio 25.08, p = 0.0003, all lymphoceles--odds ratio 75.24, p < 0.0001). When adjusting for rejection, no other risk factor came close to being significant (least p = 0.4). Therapy included laparoscopic peritoneal marsupialization and drainage in 1 patient, incisional peritoneal drainage in 4 and percutaneous external drainage in 3 (infected). All symptomatic lymphoceles were successfully treated without sequelae to grafts or patients. We conclude that allograft rejection is the most significant factor contributing to the development of lymphoceles. Therapy of symptomatic lymphoceles should be individualized according to the presence or absence of infection.