Background —In β-thalassemia major, heart failure primarily affecting left ventricular systolic function is the most common complication and cause of death. Apart from iron deposition, it has been recently reported that myocarditis might be another contributing factor in the pathogenesis of acute or chronic heart failure, acting possibly through an autoimmune mechanism. In an attempt to assess the role of immunogenetic factors in the development of heart failure associated with β-thalassemia major, we studied the frequency of major histocompatibility antigens/alleles A, B, DR, and DQ in homozygous β-thalassemic patients with and without heart failure primarily affecting the left ventricle. Methods and Results —Forty-five consecutive unrelated Greek patients with homozygous β-thalassemia and left-sided chronic heart failure were studied. Fifty-eight unrelated Greek patients with homozygous β-thalassemia without heart failure and 130 unrelated Greek healthy controls were also studied. In all subjects, class I HLA-A and -B typing was performed by the complement-mediated lymphocytotoxicity assay, whereas class II HLA-DR and -DQ typing was performed by polymerase chain reaction. HLA-DRB1*1401 allele frequency was significantly increased in patients with β-thalassemia major without left-sided heart failure compared with those with heart failure (corrected P [ P c ]=0.02, odds ratio 0.1) and healthy controls ( P c =0.001). HLA-DQA1*0501 allele frequency was increased in patients with heart failure compared with patients without heart failure ( P c =0.04, odds ratio 14) and healthy controls ( P c =0.004). Conclusions —Differences exist in the immunogenetic profile between homozygous β-thalassemic patients with and without left-sided heart failure, raising the possibility that genetically defined immune mechanisms may play an important role in the pathogenesis of heart failure in β-thalassemia.

Objectives: We assessed the role of the immunogenetic background in the development and recurrence of acute idiopathic pericarditis (AIP). Methods: Fifty-five patients with a first episode of AIP were followed for 23.8 ± 6.3 months and recurrences were recorded. The control group consisted of 246 healthy individuals. In all subjects, genomic human leukocyte antigen (HLA) typing was performed. Moreover, circulating lymphocyte subpopulations were studied in 44 randomly selected patients and in 20 controls. Results: An increased frequency of HLA-A*02, -Cw*07 and -DQB1*0202 alleles, and a decreased frequency of the -DQB1*0302 allele was detected in patients with AIP. The recurrence rate was 40% and time to recurrence was 202.8 ± 164.1 days. In patients with idiopathic recurrent pericarditis (RP), increased frequencies of HLA-A*02, -Cw*07 and -DQB1*0202 alleles were found. Notably, no patient with RP exhibited HLA-DRB1*04 and -DQB1*0302 alleles. Patients with RP exhibited lower CD4+/CD45RA+ naïve T cells (p = 0.03) than controls, and higher CD8+DR+ activated T cells (p = 0.01) than patients without recurrence and controls. Conclusions: HLA alleles may confer either susceptibility or resistance to AIP and RP. Circulating T-cell subpopulations may also predict RP. A combination of the above parameters might help to better define patients prone to recurrence.

Objective: It was the aim of this study to evaluate the safety of the optimized cryptic peptide TERT_572Y in pretreated patients with advanced cancer. Methods: Nineteen patients with progressive and chemotherapy-refractory tumors received escalated doses (2–6 mg) of 2 subcutaneous injections of the optimized TERT_572Y peptide followed by 4 subcutaneous injections of the native TERT₅₇₂ peptide every 3 weeks. Both TERT peptides were coinjected with adjuvant Montanide ISA51. Toxicity was evaluated every 3 weeks and peptide-specific CD8+ cells were detected by flow cytometry using TERT_572Y tetramers. Results: Fourteen out of 19 patients completed the vaccination program. No grade III/IV toxicity was observed. Grade I anemia was observed in 4 patients and local skin reaction at the injection site in 11 patients. Other nonhematologic toxicities were mild, and no late toxicity was observed after a median postvaccination follow-up period of 10.7 months. There was no dose-limiting toxicity. Peripheral blood TERT_572Y-specific CD8+ lymphocytes were detected in 13 out of 14 evaluable patients after 2 injections with the optimized TERT_572Y peptide. There was no complete or partial response, but 4 patients (21%) with persistent TERT_572Y-specific CD8+ experienced stable disease for a median of 10.5 months. Conclusion: TERT_572Y peptide vaccine is well tolerated and effective in eliciting specific TERT_572Y CD8+ lymphocytes in pretreated cancer patients, demonstrating that cryptic peptides could be used in cancer immunotherapy.

was identified as a candidate gene for DBA and mutations in this gene have been described in 25% of DBA patients. 2,3 However, the mechanism by which mutations in RPS19 can lead to DBA remains unclear.RPS19 is a structural component of a small ribosomal subunit and is known to have two other functions. First, RPS19 homodimers are released by apoptotic cells and act as a chemotactic factor for monocytes during macrophage-dependent apoptotic cell clearance. 4 Second, RPS19, together with ribosomal proteins S3a, S13, S16, and S24, participates in the binding of eukaryotic initiation factor 2 (eIF-2) to ribosomes. 5 eIF-2 plays a central role in the initiation of translation, and its function is controlled in an erythroid-specific manner by heme-regulated kinase. 6 To investigate the possibility that DBA phenotype might result from mutations in ribosomal proteins involved in eIF-2 binding, we sequenced cDNAs for RPS3a, S13, S16, and S24 in 14 patients from the Czech National DBA Registry. Five of these patients have been previously shown to carry a mutation in the RPS19 gene. 7 After obtaining informed consent, total RNA was isolated from peripheral blood mononuclear cells, and reverse transcription was performed using an oligo(dT) primer. Primers specific for full-length coding regions of RPS3a, S13, S16, and S24 were used for PCR amplification. PCR products were sequenced on an automated genetic analyzer, and resulting sequences were evaluated for the presence of mutations.In all DBA patients tested, no mutations in RPS3a, S13, S16, and S24 were found on the cDNA level. We therefore conclude that these four of the five ribosomal proteins important for eIF-2 binding to ribosomes are not involved in DBA pathogenesis.

The association of certain HLA-DRB1 alleles in Green rheumatoid arthritis (RA) patients with several features of the disease, the gender of the patient and the age at onset was investigated. This case control study includes 86 Greek RA patients and 130 healthy controls unrelated to the patients. HLA typing was performed by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide (SSO) probes. HLA-DR4 was significantly increased in RA patients. The alleles *0101, *0401, *0405 and *1001 were associated with a higher risk of RA. The *0408 allele was absent from our patients. Sixty-five per cent of RA patients carried the 'sharp epitope' (SE) compared with 31.5% of controls. The risk for RA in individuals carrying a single allele positive for SE was 2.85 times higher, and for those carrying two alleles positive for SE 8.57 times higher, than in SE-negative individuals. The risk was higher in those carrying the *0401 allele, followed by *0405 and *0101, while the genotype *0401/*0404 was absent. Alleles positive for SE comprise a predisposing factor for RA at an early age, particularly in men, and are associated with positive rheumatoid factor, nodules and erosions.

Our results do not support the notion that noninherited maternal antigens have a role in susceptibility to RA in the offspring.

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