The role of HLA DQ2 and DQ8 in dissecting celiac-like disease in common variable immunodeficiency.

OBJECTIVES: Gastrointestinal manifestations are frequent in patients with common variable immunodeficiency (CVID), and some of the patients present with celiac-like features. Diagnosing celiac disease (CD) in CVID however is challenging, as autoantibody detection and histopathology of the small intestine cannot reliably discriminate between classic CD and a celiac-like disease in these individuals. For the development of classic gluten-sensitive CD a certain HLA haplotype involving the loci DQA1* and DQB1* and encoding two different HLA DQ heterodimers is the prerequisite. We aimed to determine the frequency of these haplotypes in CVID patients with suspected CD. Furthermore, we report on autoimmune manifestations and the lymphocyte phenotype in these patients. METHODS: By retrospective analysis data on gastrointestinal symptoms, diet, concurrent autoimmune diseases, and routine laboratory values were collected. CVID patients were classified according to their B-cell phenotype. Expression of HLA-DQA1* and HLA-DQB1* alleles were determined by genetic analysis. RESULTS: Twenty out of 250 CVID patients presented with a clinical phenotype resembling celiac disease. Four (20%) out of these CVID patients carried the CD-associated HLA DQ2.5 or DQ8 heterodimer, while HLA DQ2.5 was present in 100% of a CD control cohort. Gluten-free diet (GFD) resulted in a clinical and histological response in two out of four patients with HLA high-risk alleles for CD. The response could not be assessed in the remaining two patients, as these patients did not adhere sufficiently long to GFD. The percentage of autoimmune manifestations other than CD was high (50%) in CVID patients presenting with a CD-like enteropathy, and most of these patients had an expansion of B-cells with low expression of CD21 (CD21low B-cells). CONCLUSIONS: In CVID patients with suspected celiac disease typing of the HLA loci DQA1 and DQB1 can help to identify those that have a genetic susceptibility for CD. In CVID patients with a celiac-like phenotype but negative for CD-associated HLA-DQ markers, an autoimmune enteropathy (AIE) as part of an extended autoimmune dysregulation needs to be considered. This has important implications for further diagnostics and therapy of these patients.

Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with a poor prognosis and limited therapeutic options. Therefore, the development of novel therapeutic strategies is of high priority. alpha-Fetoprotein (AFP) is overexpressed in the majority of HCCs. Priming of immune responses against AFP results in significant protective antitumoral T cell responses in the mouse model. Little information is available about the hierarchy, breadth, frequency, and peripheral versus intrahepatic distribution of AFP-specific CD8(+) T cell responses in patients with HCC. To address these important issues we comprehensively analyzed CD8(+) T cell responses against full-length AFP in peripheral blood, tumor liver tissue, and nontumor liver tissue from patients with HCC using overlapping AFP peptides. The AFP-specific CD8(+) T cell response was also tested in peripheral blood and liver from patients chronically infected with hepatitis C virus (HCV) and compared to the HCV-specific CD8(+) T cell response. The majority of patients with HCC showed AFP-specific responses, with many responses directed against previously unreported epitopes. These responses were primarily detectable in the HCC tissue and mainly targeted the C-terminus of AFP. Interestingly, AFP-specific T cells were not only found in patients with HCC but also in patients with chronic HCV infection, other liver diseases, and less frequently in healthy subjects. CONCLUSION: In patients with HCC, a high frequency of AFP-specific CD8(+) T cells directed against different epitopes suggest that AFP has a strong and broad immunogenicity. Further, CD8(+) T cells specific for the self-antigen AFP are present in the normal T cell repertoire and are not centrally or peripherally deleted. Our results provide support for strategies to boost AFP-specific CD8(+) T cell responses in patients with HCC but also demonstrate a diversity of immune responses that may be needed for protection.

The phosphodiesterase-5-inhibitor udenafil lowers portal pressure in compensated preascitic liver cirrhosis. A dose-finding phase-II-study.

BACKGROUND: Phosphodiesterase-5-inhibitors may lower portal pressure. AIMS: To investigate the effect of the phosphodiesterase-5-inhibitor udenafil on hepatic and systemic haemodynamics in liver cirrhosis. METHODS: In an open-label phase-II-study, patients with liver cirrhosis Child A/B and hepatic venous pressure-gradient ≥ 12 mmHg received 12.5mg/day, 25mg/day, 50mg/day, 75 mg/day (n = 5, each), or 100mg/day (n = 10) udenafil p.o. for one week. On days 0 and 6, hepatic venous pressure-gradient was measured prior to and one hour after drug ingestion. Endpoints were reduction of hepatic venous pressure-gradient from day 0 pre to day 6 post intake and reduction in the acute setting. Pharmacokinetics were measured in the two lowest dosage groups. RESULTS: Combining the 75 and 100mg/day groups hepatic venous pressure-gradient reduction after drug intake was 19.9% (p = 0.0006) on day 0. From day 0 pre-dose to day 6 post-dose hepatic venous pressure-gradient decreased by 15.7% (p = 0.040) and in 5/15 patients by ≥ 20% or to <12 mmHg. In the 100mg/day group, mean arterial pressure decreased from 98.9 mmHg by 6.2 mmHg (p = 0.037) from day 0 pre-dose to day 6 post-dose. Heart rates or electrocardiograms were unchanged. Udenafil was eliminated with t1/2 = 25 h. CONCLUSIONS: Oral application of 75-100mg of the phosphodiesterase-5-inhibitor udenafil lowers portal pressure in the acute setting by about 20% without relevant systemic cardiovascular side effects.