Head and neck squamous cell carcinoma (HNSCC) includes diverse cancers arising in the oral cavity, oropharynx, and larynx, with the main risk factors being environmental exposures such as tobacco, alcohol, and human papillomavirus (HPV) infection. The genetic factors contributing to susceptibility across different populations and tumour subsites remain incompletely understood. Here we show, through a genome-wide association and fine mapping study of over 19,000 HNSCC cases and 38,000 controls from multiple ancestries, 18 genetic risk variants and 11 signals from fine mapping of the human leukocyte antigen (HLA) region, all previously unreported. rs78378222, a regulatory variant for TP53 is associated with a 40% reduction in overall HNSCC risk. We also identify gene-environment interactions, with BRCA2 and ADH1B variants showing effects modified by smoking and alcohol use. Subsite-specific analysis of the HLA region reveals distinct immune-related associations across HPV-positive and HPV-negative tumours. These findings refine the genetic architecture of HNSCC and highlight mechanisms linking inherited variation, immunity, and environmental exposures.

• MeSH
• alkoholdehydrogenasa genetika   MeSH
• celogenomová asociační studie MeSH
• dlaždicobuněčné karcinomy hlavy a krku * genetika   MeSH
• genetická predispozice k nemoci MeSH
• HLA antigeny genetika   MeSH
• infekce papilomavirem genetika   komplikace   MeSH
• interakce genů a prostředí MeSH
• jednonukleotidový polymorfismus MeSH
• kouření škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory hlavy a krku * genetika   MeSH
• pití alkoholu MeSH
• protein BRCA2 genetika   MeSH
• rizikové faktory MeSH
• spinocelulární karcinom * genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ADH1B protein, human MeSH Prohlížeč
• alkoholdehydrogenasa MeSH
• BRCA2 protein, human MeSH Prohlížeč
• HLA antigeny MeSH
• nádorový supresorový protein p53 MeSH
• protein BRCA2 MeSH
• TP53 protein, human MeSH Prohlížeč

Natural killer (NK) cells are vital in the antiviral response regulated by inhibitory and activating receptors, including NKG2 and KIR families, which bind HLA-I. While the adaptive features of NK cells in response to human cytomegalovirus (hCMV) have been well described, their behavior during Epstein-Barr virus (EBV) infection and the influence of KIR-HLA combinations in healthy carriers of these viruses remains unclear. We performed high-resolution HLA genotyping, phenotypic profiling of NK cell subsets, and serological testing for hCMV and EBV-specific IgG in 85 healthy adult donors. hCMV-seropositive individuals exhibited significant expansions of NKG2C+ and HLA-DR+ NK cell subsets, with the proportion of NKG2C+ cells strongly correlating with hCMV-IgG titers. In contrast, EBV infection was associated with increased frequencies of terminally differentiated CD56dim, NKG2A-, CD57+ NK cells and elevated expression of inhibitory KIRs, but not NKG2C or HLA-DR. EBV-IgG titers correlated with CD57 and KIR2DS4 levels. Among KIR2DS4-expressing donors, carriage of at least one HLA-C2 allele was associated with elevated EBV-IgGs. The precise analysis of KIR2DL2/DL3, KIR2DS4, and KIR2DL1 revealed dependencies on EBV-IgG titers, with no associations with hCMV. These findings highlight the differential impacts of hCMV and EBV on NK cells and underscore the relevance of HLA-KIR landscapes in shaping antiviral immunity.

• Klíčová slova
• EBV, HLA, KIR, NK cells, NKG2, antiviral immunity, hCMV,
• MeSH
• buňky NK * imunologie   virologie   MeSH
• cytomegalovirové infekce * imunologie   virologie   MeSH
• Cytomegalovirus * imunologie   MeSH
• dospělí MeSH
• fenotyp MeSH
• genotyp MeSH
• HLA antigeny genetika   MeSH
• imunoglobulin G krev   MeSH
• infekce virem Epsteina-Barrové * imunologie   virologie   MeSH
• lektinové receptory NK-buněk - podrodina C MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• protilátky virové krev   MeSH
• receptory KIR genetika   imunologie   MeSH
• virus Epsteinův-Barrové * imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HLA antigeny MeSH
• imunoglobulin G MeSH
• lektinové receptory NK-buněk - podrodina C MeSH
• protilátky virové MeSH
• receptory KIR MeSH

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are rare autoimmune disorders. Genetic association studies have highlighted the role of human leukocyte antigen (HLA) polymorphisms in IIM. We aimed to characterise the nonadditive effects (dominance and interaction) of HLA alleles on IIM risk. METHODS: This study included a total of 3206 IIM cases and 11,697 controls of European ancestry. HLA alleles were imputed using a multiancestry HLA reference panel. Logistic regressions were conducted to estimate the nonadditive effects of HLA alleles. Clinical subgroup analysis, calculation of phenotypic variance explained, and stepwise conditional analyses were conducted to further characterise these effects. RESULTS: We identified significant nonadditive effects in 5 HLA genes, particularly in the core alleles of ancestral haplotype 8.1 (8.1 AH), including HLA-B*08:01 (P = 3.93 × 10-13), HLA-C*07:01 (P = 3.14 × 10-8), HLA-DQA1*05:01 (P = 3.03 × 10-9), HLA-DQB1*02:01 (P = 3.53 × 10-23), and HLA-DRB1*03:01 (P = 8.47 × 10-21). Notable risk difference between heterozygotes and homozygotes was observed in IIM, such as HLA-DRB1*03:01 (homozygote odds ratio [OR], 2.17; heterozygote OR, 3.13). In the interaction model, HLA-DQA1 and HLA-DRB1 showed specific significant allelic interactions. The nonadditive effect model explained a larger proportion of phenotypic variance than the model with additive effects alone. Conditional analysis indicated the independent nonadditive effect of HLA-DRB1*03:01 in 8.1 AH and amino acid residue Arg-74 in HLA-DRB1. CONCLUSIONS: This study identified significant nonadditive effects within the HLA region of IIM. A genetic risk model including nonadditive effects could provide more accurate individual risk estimates. These findings highlight a complex role of HLA heterozygosity in the development of IIM and support further research into HLA nonadditive effects with clinical relevance.

• MeSH
• alely MeSH
• běloši genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• haplotypy MeSH
• heterozygot MeSH
• HLA antigeny * genetika   MeSH
• HLA-DQ alfa řetězec genetika   MeSH
• HLA-DRB1 řetězec genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myozitida * genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HLA antigeny * MeSH
• HLA-DQ alfa řetězec MeSH
• HLA-DQA1 antigen MeSH Prohlížeč
• HLA-DRB1 řetězec MeSH

UNLABELLED: Patients with dry eye syndrome form a significant proportion of those treated in everyday ophthalmology practice. Diabetes mellitus is a major risk factor for the development of dry eye syndrome. Changes in tear film homeostasis, chronic inflammation and subsequent corneal nerve fiber pathology play a key role in its progression. The aim of this study was to describe the status of modern biomarkers of ocular surface damage in patients with type 1 diabetes and asses their utility in early diagnosis of dry eye syndrome. MATERIAL AND METHODS: In total the pilot study included 19 patients with type 1 diabetes (T1D) and 15 patients in the control group. All patients underwent a detailed ocular surface examination, sample collection for matrix metalloproteinase-9 (MMP-9) laboratory analysis and epithelial HLA-DR expression evaluation, and in-vivo corneal confocal microscopy. RESULTS: T1D patients showed statistically significantly reduced corneal nerve fiber length (p = 0.0482). The differences between the groups in terms of osmolarity, corneal sensitivity, Oxford score, tear break-up time and MMP-9 level were not statistically significant (p = 0.8272, p = 0.6029, p = 0.3507, p = 0.7561 and p = 0.0826 respectively). HLA-DR expression was examined in 10 T1D patients and 8 patients in the control group. Both groups showed minimal or no expression (p > 0.9999). CONCLUSION: The previously published literature supports our finding of corneal nerve fiber length reduction in T1D patients compared to controls. However, we did not find any significant changes in standard or modern ocular surface markers (MMP-9 levels, HLA-DR expression) measured in patients with dry eye syndrome.

• Klíčová slova
• Confocal microscopy, HLA-DR, MMP-9, biomarker, cardiovascular disease, diabetes mellitus, dry eye disease,
• MeSH
• biologické markery analýza   MeSH
• časná diagnóza MeSH
• diabetes mellitus 1. typu * komplikace   MeSH
• dospělí MeSH
• HLA-DR antigeny analýza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• matrixová metaloproteinasa 9 analýza   MeSH
• mladý dospělý MeSH
• pilotní projekty MeSH
• rohovka inervace   MeSH
• slzy MeSH
• syndromy suchého oka * diagnóza   etiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• HLA-DR antigeny MeSH
• matrixová metaloproteinasa 9 MeSH

The association of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects after allogeneic stem-cell transplantation (SCT) is well-established but was not confirmed in the modern era and following post-transplant cyclophosphamide (PTCy). We assessed GVHD/ GVL association in AML patients following HLA-matched SCT with standard calcineurin-based (n = 12,653, 57% with additional in-vivo T-cell depletion) or PTCy-based (n = 508) GVHD prophylaxis. Following standard prophylaxis, acute GVHD grade II-IV and III-IV, chronic GVHD, and extensive chronic GVHD rates were 23.8%, 7.5%, 37.0%, and 16.3%, respectively. Acute GVHD grade II and III-IV were associated with lower relapse [hazard-ratio (HR) 0.85, P = 0.002; HR 0.76, P = 0.003, respectively)], higher non-relapse mortality (NRM) (HR 1.5, P < 0.001; HR 6.21, P < 0.001) and lower overall survival (OS) (HR 1.49, P < 0.001; HR 6.1, P < 0.001). Extensive chronic GVHD predicted lower relapse (HR 0.69, P < 0.001), higher NRM (HR 2.83, P < 0.001), and lower OS (HR 2.74, P < 0.001). Following PTCy, GVHD rates were 22.8%, 6.2%, 35.5%, and 17.7%, respectively. Acute GVHD was not associated with relapse (HR 1.37, P = 0.15) but predicted higher NRM (HR 3.34, P < 0.001) and lower OS (HR 1.92, P = 0.001). Chronic GVHD was not prognostic for these outcomes. In conclusion, GVHD and GVL are strongly associated with contemporary SCT. However, following PTCy, GVHD is not associated with reduced relapse.

• MeSH
• akutní myeloidní leukemie * terapie   MeSH
• cyklofosfamid * terapeutické užití   MeSH
• dospělí MeSH
• HLA antigeny imunologie   MeSH
• homologní transplantace MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc štěpu proti hostiteli * etiologie   prevence a kontrola   MeSH
• reakce štěpu proti leukémii * MeSH
• senioři MeSH
• testování histokompatibility MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyklofosfamid * MeSH
• HLA antigeny MeSH
• imunosupresiva MeSH

• Klíčová slova
• Association (4), Chest X-ray stage(8), Clinical phenotype(5), Extrapulmonary manifestation(6), HLA(2), Sarcoidosis (1), Single nucleotide polymorphism(3), Treatment requirement(7),
• MeSH
• dospělí MeSH
• fenotyp * MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• HLA antigeny genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• sarkoidóza * genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• Geografické názvy
• Řecko MeSH
• Názvy látek
• HLA antigeny MeSH

BACKGROUND: Live donor kidney transplantation is considered the optimal choice for renal replacement therapy, providing established benefits, such as superior patient survival and improved quality of life. However, immunological challenges, including ABO blood group incompatibility and, particularly, donor-specific HLA antibodies, may impact long-term outcomes considerably or even prevent safe direct transplantation with the intended donor. METHODS: In this review, the authors discuss kidney paired donation (KPD) as a viable strategy to overcome immunological barriers to living donation through organ exchanges. We thereby lay special focus on the Czech-Austrian transnational KPD program. RESULTS: While the benefits of KPD programs are well established for adult recipients, recent data suggest that this may hold true also for pediatric patients. Complex algorithms, considering factors like the intricate patterns of HLA sensitization, play a pivotal role in predicting suitable matches, but for pediatric patients also non-immunological factors including age and weight match may play a role. As pool size proves crucial for program efficacy, several countries in Europe have now initiated transnational collaborations to maximize match rates. Among those, the Czech-Austrian transnational joint program, established in 2015 and now expanded to a cooperation with the Israel transplant program to further increase transplant rates, represents a successful example. CONCLUSION: KPD programs, with their innovative approaches and international partnerships, hold promise for enhancing outcomes and addressing the increasing demand for kidney transplantation.

• Klíčová slova
• ABO incompatibility, HLA incompatibility, kidney paired donation, kidney transplantation,
• MeSH
• dítě MeSH
• dospělí MeSH
• HLA antigeny imunologie   MeSH
• lidé MeSH
• transplantace ledvin * MeSH
• žijící dárci * MeSH
• získávání tkání a orgánů * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH
• Evropa MeSH
• Názvy látek
• HLA antigeny MeSH

There is a paucity of information on how to select the most appropriate unrelated donor (UD) in hematopoietic stem cell transplantation (HSCT) using posttransplant cyclophosphamide (PTCy). We retrospectively analyzed the characteristics of 10/10 matched UDs (MUDs) and 9/10 mismatched UDs (MMUDs) that may affect transplant outcomes in patients with acute myeloid leukemia (AML) in first or second complete remission (CR1 or CR2). The primary end point was leukemia-free survival (LFS). Overall, 1011 patients were included with a median age of 54 years (range, 18-77). Donors had a median age of 29 years (range, 18-64); 304 (30%) were females, of which 150 (15% of the whole group) were donors to male recipients, and 621 (61%) were MUDs; 522 (52%) had negative cytomegalovirus (CMV-neg) serostatus, of which 189 (19%) were used for CMV-neg recipients. Donor age older than 30 years had a negative impact on relapse (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.06-1.8), LFS (HR, 1.4; 95% CI, 1.12-1.74), overall survival (HR 1.45; 95% CI, 1.14-1.85) and graft-versus-host disease (GVHD) free, relapse-free survival (HR, 1.29; 95% CI, 1.07-1.56). In addition, CMV-neg donors for CMV-neg recipients were associated with improved LFS (HR, 0.74; 95% CI, 0.55-0.99). The use of MMUD and female donors for male recipients did not significantly impact any transplant outcomes. For patients undergoing HSCT from a UD with PTCy for AML, donor age <30 years significantly improves survival. In this context, donor age might be prioritized over HLA match considerations. In addition, CMV-neg donors are preferable for CMV-neg recipients. However, further research is needed to validate and refine these recommendations.

• MeSH
• akutní myeloidní leukemie * terapie   mortalita   MeSH
• cyklofosfamid terapeutické užití   MeSH
• dospělí MeSH
• HLA antigeny imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc štěpu proti hostiteli etiologie   MeSH
• nepříbuzný dárce * MeSH
• přežití bez známek nemoci MeSH
• retrospektivní studie MeSH
• senioři MeSH
• testování histokompatibility MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyklofosfamid MeSH
• HLA antigeny MeSH

A comprehensive knowledge of human leukocyte antigen (HLA) molecular variation worldwide is essential in human population genetics research and disease association studies and is also indispensable for clinical applications such as allogeneic hematopoietic cell transplantation, where ensuring HLA compatibility between donors and recipients is paramount. Enormous progress has been made in this field thanks to several decades of HLA population studies allowing the development of helpful databases and bioinformatics tools. However, it is still difficult to appraise the global HLA population diversity in a synthetic way. We thus introduce here a novel approach, based on approximately 2000 data sets, to assess this complexity by providing a fundamental synopsis of the most frequent HLA alleles observed in different regions of the world. This new knowledge will be useful not only as a fundamental reference for basic research, but also as an efficient guide for clinicians working in the field of transplantation.

• Klíčová slova
• CWD catalogues, HLA allele frequencies, HLA biostatistical tools, HLA databases, HLA population genetics, HLA workshops,
• MeSH
• alely * MeSH
• frekvence genu MeSH
• HLA antigeny * genetika   imunologie   MeSH
• lidé MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• HLA antigeny * MeSH

AIM: Cutaneous T-cell lymphomas (CTCL) can be described as chronic skin inflammation lesions with the content of malignant T cells and they are considered to be T-cell-mediated skin diseases. CD147 is recognized as a 58-kDa cell surface glycoprotein of the immunoglobulin superfamily; it can induce the synthesis of MMPs (matrix metalloproteinases) on the surface of tumor cells where it was originally identified. It can also function in adjacent tumor fibroblasts using CD147-CD147 interactions. The polymorphism rs8259 T/A is situated in the untranslated region (3'UTR) of the CD147 gene. HLA DRB1*1501 takes part in the process of presentation and recognition of different antigens to T cells. It can be expressed by antigen-presenting cells-macrophages, dendritic cells, and B cells. The aim of the study is to test genotype-phenotype associations of both polymorphisms including therapy in a large cohort of CTCL patients. MATERIALS AND METHODS: A final total of 104 CTCL patients were enrolled in the study. For the first remission at the clinic department, they were treated by means of local skin-directed therapy, phototherapy, and systemic therapy. Genomic DNA was isolated from peripheral blood leukocytes. A standard technique using proteinase K was applied. The polymorphisms rs8259 T/A (CD147 gene) and rs3135388 (HLA DRB1*1501) were detected through standard PCR-restriction fragment length polymorphism methods. RESULTS: The severity of the disease (patients with parapsoriasis, stages IA and IB, vs patients with stages IIB, IIIA, and IIIB) was associated with the CD147 genotype: the AA variant was 3.38 times more frequent in more severe cases, which reflects the decision on systemic therapy (p = 0.02, specificity 0.965). The AA genotype in the CD147 polymorphism was 12 times more frequent in patients who underwent systemic therapy of CTCL compared to those not treated with this therapy (p = 0.009, specificity 0.976). The same genotype was also associated with radiotherapy-it was observed 14 times more frequently in patients treated with radiotherapy (p = 0.009, specificity 0.959). In patients treated with interferon α therapy, the AA genotype was observed to be 5.85 times more frequent compared to the patients not treated with interferon therapy (p = 0.03, specificity 0.963). The HLA DRB1*1501 polymorphism was associated with local skin-directed therapy of CTCL. The CC genotype of the polymorphism was observed to be 3.57 times more frequent in patients treated with local therapy (p = 0.008, specificity 0.948). When both polymorphisms had been calculated together, even better results were obtained: the AACC double genotype was 11 times more frequent in patients with severe CTCL (p = 0.009, specificity 0.977). The TACT double genotype was associated with local skin-directed therapy (0.09 times lower frequency, p = 0.007, sensitivity 0.982). The AACC genotype was 8.9 times more frequent in patients treated by means of systemic therapy (p = 0.02, specificity 0.976) and as many as 18.8 times more frequent in patients treated with radiotherapy (p = 0.005, specificity 0.969). Thus, the AACC double genotype of CD147 and DRB1*1501 polymorphisms seems to be a clinically highly specific marker of severity, systemic therapy and radiotherapy of patients with T-cell lymphoma. CONCLUSION: Although genotyping results were not known during the treatment decision and could not modify it, the clinical decision on severity and therapy reflected some aspects of the genetic background of this complicated T-cell-associated disease very well.

• Klíčová slova
• CD147, CTCL, HLA DRB1*1501,
• MeSH
• genetické markery MeSH
• HLA-DRB1 řetězec genetika   MeSH
• kožní T-buněčný lymfom * farmakoterapie   genetika   MeSH
• lidé MeSH
• lymfom T-buněčný * MeSH
• nádory kůže * farmakoterapie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• genetické markery MeSH
• HLA-DRB1 řetězec MeSH