A TNF-α Promoter Polymorphism Is Associated with Juvenile Onset Psoriasis and Psoriatic Arthritis

Tumor necrosis factor-α is considered to be one of the important mediators in the pathogenesis of psoriasis. A strong association of juvenile onset psoriasis with the major histocompatibility complex encoded HLA-Cw6 antigen has been reported but it is unclear whether Cw6 itself or a closely linked gene is involved in the pathogenesis. This study has focused on the association of promoter polymorphisms of the major histocompatibility complex encoded tumor necrosis factor-α gene with psoriasis and psoriatic arthritis. Tumor necrosis factor-α promoter polymorphisms were sought by sequence-specific oligonucleotide hybridization and by direct sequencing in Caucasian patients with juvenile onset psoriasis and with psoriatic arthritis and in healthy controls. A mutation at position −238 of the tumor necrosis factor-α promoter was present in 23 of 60 patients (38%; p < 0.0001; Pcorr < 0.008) with juvenile onset psoriasis and in 20 of 62 patients (32%; p < 0.0003; Pcorr < 0.03) with psoriatic arthritis, compared with seven of 99 (7%) Caucasian controls. There was a marked increase of homozygotes for this mutation in the psoriasis group. Another mutation at position −308 was found in similar proportions of patients and controls. Our study shows a strong association of the tumor necrosis factor-α promoter polymorphism at position −238 with psoriasis and psoriatic arthritis. Our findings suggest that this promoter polymorphism itself or a gene in linkage disequilibrium with tumor necrosis factor-α predispose to the development of psoriasis

Transcription factors of T and B lymphocytes--basic research and clinical perspectives for gastroenterology

Tissue specific regulation of gene expression by transcription factors is a fascinating new field in molecular immunology. This review summarizes data on specific regulation of promoters and enhancers by nuclear trans-acting factors in lymphocytes. The structural classes of transcription factors are described and basic methods for detection and analysis of transcription factors are detailed. Furthermore, the most important trans-acting factors of T and B lymphocytes (e.g. NF-kB, NF-AT and STAT families) and their functional importance are described. Several methods for specific down-regulation of transcription factors are shown that may be relevant to treatment of human disease. The data are discussed with regard to their potential clinical relevance for gastroenterology

Constitutive and inducible protein/DNA interactions of the interferon-gamma promoter in vivo in [corrected] CD45RA and CD45R0 T helper subsets

Interferon-gamma (IFN-gamma) is a key cytokine of T lymphocytes with major regulatory functions in the immune system. To determine and compare protein/DNA interactions at the native IFN-gamma locus in T cells, we analyzed the human IFN-gamma promoter by ligation-mediated polymerase chain reaction (LM-PCR) techniques. Accordingly, Jurkat T cells and primary CD45RA and CD45R0 CD4+ T cell subsets isolated from peripheral blood using immunomagnetic beads were cultured and analyzed by LM-PCR. Constitutive and inducible protein/DNA interactions of the IFN-gamma promoter in vivo were detected in all T cells tested. Interestingly, an inducible footprint between -183 and -196 was consistently observed in Jurkat T cells and CD45RA and CD45R0 T helper subsets upon stimulation with phorbol 12-myristate 13-acetate+phytohemagglutinin (PMA+PHA) that was highly sensitive to treatment with corticosteroids. This novel target site, denoted the C-site, was shown by several criteria, including cell distribution studies, stimulation experiments, supershift assays, and cross-competition electrophoretic mobility shift assays to bind the transcription factor AP-1. Mutation of the C-site that prevented AP-1 binding to this site was sufficient strikingly to reduce inducible promoter activity in primary CD45R0 T cells. In summary, the data demonstrate that IFN-gamma gene transcription in primary T cells is regulated in vivo at the level of constitutive and inducible protein/DNA interactions. We propose a model where basal transcription is maintained by binding of various transcription factors to the IFN-gamma promoter, whereas PMA+PHA-inducible IFN-gamma transcription in CD45R0 T cells is associated with binding of AP-1 to the C-site

Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice

Chronic intestinal inflammation induced by 2,4,6,-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn's disease. Here, we show that the transcription factor NF-kappa B p65 was strongly activated in TNBS-induced colitis and in colitis of interleukin-10-deficient mice. Local administration of p65 antisense phosphorothioate oligonucleotides abrogated clinical and histological signs of colitis and was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. The data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and suggest a potential therapeutic utility of p65 antisense oligonucleotides as a novel molecular approach for the treatment of patients with Crohn's disease

Active hepatitis B vaccination of dialysis patients and medical staff

AbstractActive hepatitis B vaccination of dialysis patients and medical staff. One hundred six patients with terminal renal insufficiency and 29 medical personnel were given three doses of hepatitis B vaccine at an interval of 0, 1, and 6 months (Merck, Sharp and Dohme, West Point, Pennsylvania, part of a joint study no. 649). Chronic hemodialysis patients (N = 99) received 40 µg vaccine (V) i.m. Uremic patients, who were just about to start chronic dialysis treatment (N = 7), were given 40 µg V, and at the first vaccination 3ml hyperimmune globulin (HBIG) in addition. The medical personnel was alternately vaccinated with 20 µg V (N = 8), 40 µg (N = 11), 40 µg V, and 3ml HBIG at the first vaccination (N = 10). After 12 months, 50% of the male dialysis patients, 66% of the female dialysis patients, and 95% of the medical staff developed anti-HBs antibodies. The anti-HBs titer of the dialysis patients was ten times lower than in the medical staff. The simultaneous passive immunization did not lead to any impairment of the anti-HBs titer in the dialysis patients and staff. The type of renal disease, length of time on dialysis, hematocrit, and immunoglobulin concentration did not influence the rate of immunization. After 12 months, 43 patients without antibody response were vaccinated a fourth time. Sixteen of these patients then developed anti-HBs, improving the immunization rate from 56.5 to 71.7%. A fifth vaccination only led to seroconversion, when brief or borderline anti-HBs could already be demonstrated previously. In dialysis patients who fail to develop anti-HBs after three doses of vaccine, a fourth vaccination is recommended after 12 months.Vaccination contre l'hépatite B active de malades hémodialysés et du personnel medical. Un cent et six malades en insuffisance rénale terminale et 29 personnels médicaux ont reçu trois doses de vaccin antihépatite B à un intervalle de 0, 1, et 6 mois (Merck, Sharp et Dohme, partie d'une étude coopérative no. 649). Les hémodialysés chroniques (N = 99) ont reçu 40 µg de vaccin (V), i.m. Les malades urémiques, qui étaient juste au moment de commencer l'hémodialyse chronique (N = 7), ont reçu 40 µg de V, et à la première injection 3 ml de globulines hyperimmunes (HBIG) en plus. Le personnel médical était vacciné alternativement avec 20 µg de V (N = 8), 40 µg (N = 11), 40 µg de V, et 3 ml de HBIG à la première vaccination (N = 10). Au bout de 12 mois, 50% des hommes dialyses, 66% des femmes dialysées, et 95% du personnel médical ont développé des anticorps anti-HBs. Le titre des anti-HBs chez les hémodialysés était dix fois plus faible que dans le personnel médical. L'immunisation passive simultanée n'a pas entraîné de diminution du titre des anti-HBs chez les hémodialysés ou le personnel. Le type de maladie rénale, le temps passé en hémodialyse, l'hématocrite, et la concentration d'immunoglobulines n'ont pas influencé la vitesse d'immunisation. Après 12 mois, 43 malades sans réponse anticorps ont été vaccinés une quatrième fois. Seize de ces malades ont alors développé des anti-HBs, améliorant le taux d'immunisation de 56,5 à 71,7%. Une cinquième vaccination n'a entraîné qu'une sérocon-version, lorsque des anti-HBs passagers ou limites pouvaient déjà auparavant être démontrés. Chez les dialyses qui n'ont pas développé d'anti-HBs après trois doses de vaccin, une quatrième vaccination est recommandée après 12 mois