OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
- MeSH
- alely MeSH
- autoprotilátky genetika imunologie MeSH
- běloši genetika MeSH
- dospělí MeSH
- genotyp MeSH
- haplotypy MeSH
- HLA-DRB1 řetězec genetika imunologie MeSH
- hlavní histokompatibilní komplex genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- myozitida genetika imunologie MeSH
- polymorfismus genetický MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Genetic susceptibility for sarcoidosis and Löfgren's syndrome (LS) has been associated with prognosis. Human leukocyte antigen (HLA)-DRB1*03 is over-represented in LS, and is associated with a good prognosis, whereas HLA-DRB1*15-positive patients have a more chronic course of sarcoidosis. These HLA-DRB1 types can be easily tagged by single nucleotide polymorphisms (SNPs). Our aim was to evaluate the association between these tag SNPs and bronchoalveolar lavage (BAL) characteristics. In 29 patients, both complete HLA-DRB1* locus genotyping and SNP tagging was performed in parallel. HLA-DRB1 type was inferred from the presence of *03 tag rs2040410 allele A and referred to as *03. HLA-DRB1*15 was inferred from the presence of tag SNP rs3135388 allele A and referred to as *15. For BAL analysis, 122 patients with LS and 165 patients with non-LS sarcoidosis were included. BAL lymphocyte subsets were analyzed by flow cytometry. The presence of tag SNPs completely corresponded with HLA-DRB1*03/*15 genotypes in all 29 patients in whom both HLA-DRB1* genotyping and SNP tagging was performed. In all patients together, *03+ /*15- patients showed a higher CD4+ /CD8+ ratio than *03- /*15+ (P = 0·004) and *03- /*15- (P = 0·001). LS patients with *03+ /*15- had a lower BAL lymphocyte count compared to *03- /*15+ patients (P = 0·011). Non-LS sarcoidosis patients with *03+ /*15- patients showed a decreased CD103+ CD4+ /CD4+ ratio compared to *03- /*15+ patients (P = 0·045) and *03- /*15- patients (P = 0·018). We found that HLA-DRB1*03 and HLA-DRB1*15 can be approximated by genotyping of tag SNPs and corresponds with the degree of lymphocytosis and cell phenotypes in BAL in both LS and non-LS sarcoidosis patients.
- MeSH
- alely * MeSH
- bronchoalveolární laváž MeSH
- CD4-pozitivní T-lymfocyty * imunologie patologie MeSH
- CD8-pozitivní T-lymfocyty * imunologie patologie MeSH
- dospělí MeSH
- genotypizační techniky MeSH
- HLA-DRB1 řetězec * genetika imunologie MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- plicní sarkoidóza * genetika imunologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
BACKGROUND AND OBJECTIVES: Alloimmune antibodies against red-blood-cell (RBC) antigens induced in susceptible individuals (responders) by transfusion, pregnancy or transplantation may have serious clinical consequences. The aim of this study was to investigate association of alloimmunization against selected RBC antigens with HLA-Class II. MATERIALS AND METHODS: A total of 230 responders (106 monoresponders and 124 multiresponders) were enrolled into the study. HLA-DRB1 and HLA-DQB1 variants were determined by PCR-SSO and their frequencies compared between the patients (patient subgroups) and 375 ethnically and regionally matched controls. RESULTS: Development of multiple RBC antibodies was associated with HLA-DRB1*15 and HLA-DQB1*06 allelic groups in the patients, with the relationship being particularly apparent in those with anti-C+D antibodies. Furthermore, DRB1*13 and DQB1*06 were more frequent in multiresponders with anti-E+c antibodies and DRB1*03 and DQB1*02 in those with anti-E+Cw. CONCLUSION: For the first time, we confirmed the association of HLA-DRB1*15 with RBC antibody multiresponder status and found HLA-Class II associations for three frequent RBC antibody combinations. Our data support the concept that HLA restriction plays an important role in the response to RBC alloantigens.
- MeSH
- alely MeSH
- dospělí MeSH
- erytrocyty imunologie MeSH
- frekvence genu MeSH
- genotyp MeSH
- haplotypy MeSH
- HLA-DQ beta řetězec genetika imunologie MeSH
- HLA-DRB1 řetězec genetika imunologie MeSH
- isoprotilátky krev MeSH
- lidé MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Terapeutický efekt nepříbuzenské transplantace krvetvorných buněk (TKB) je nejvíce určován genetickou – HLA – neshodou mezi příjemcem a dárcem. Ta umožňuje jak u malignit žádoucí reakci štěpu proti leukemii (GVL – graft versus leukemia effect) snižující riziko relapsu, tak reakci štěpu proti hostiteli (GVHD-graft versus host disease) zvyšující mortalitu. Práce se snaží shrnout současný pohled na celkový význam HLA shody a interpretovat kvalitativní a kvantitativní efekt neshod v individuálních HLA genech na výsledek TKB od dospělého nepříbuzného dárce a to především u maligních onemocnění. Standardem je v současnosti snaha nalézt dárce alelicky shodného minimálně v HLA-A,-B,-C a–DRB1, protože izolovaná neshoda v každém z těchto genů zvyšuje mortalitu o přibližně 10 % a vícečetné neshody mají dokonce synergický negativní vliv. Efekt neshody je však významně ovlivněn stadiem základního onemocnění, protože u vysoce rizikových nemocných je v důsledku akcentované GVL reakce mnohem méně významný či dokonce zanedbatelný. S možnou výjimkou HLA-C lokusu u transplantace periferními krvetvornými buňkami jsou neshody na alelické i antigenní úrovni zřejmě srovnatelně tolerované. Je-li nutné akceptovat neshodného dárce, pak u kostní dřeně je lépe vyhnout se neshodám v HLA-A či DRB1, u periferních krvetvorných buněk je nejhůře tolerovanou „antigenní“ neshoda v HLA-C. Mimo HLA shodu existuje celá řada faktorů na straně dárce, které ovlivňují výsledek TKB a zde nutno zdůraznit především včasnost provedení transplantace, protože rychlost nalezení nepříbuzného dárce a neprodlené provedení TKB je takřka stejně důležité jako stupeň shody.
The therapeutic effect of unrelated donor stem cell transplantation (SCT) is predominantly determined by genetic non-identity – HLA-mismatch – between recipient and donor. This facilitates both the desirable graft versus leukaemia (GVL) effect, which reduces the risk of relapse in malignancies as well as the graft-versus-host disease (GVHD), which increases mortality. This paper attempts to summarize the current view on the overall significance of HLA match and to interpret the qualitative and quantitative effect of mismatches in individual HLA genes on the outcome of SCT from an unrelated adult donor, particularly in malignant diseases. The current standard involves an effort to find an allele-level matched donor at least in HLA-A,-B,-C,-DRB1, because isolated mismatch in each of these genes increases mortality by approximately 10% and multiple mismatches actually have a negative synergistic effect. However, the consequences of incompatibility are significantly influenced by disease stage, as in high-risk patients these are much less significant or even negligible because of the accentuated GVL response. With the possible exception of the HLA-C locus, mismatches either on allelic or antigenic level seem to be comparably tolerated in peripheral blood stem cell transplantation. If it is necessary to accept a mismatched donor, then in the case of bone marrow it is best to avoid mismatches in HLA-A and DRB1, while in the case of peripheral blood stem cells the worst tolerated “antigenic” mismatch involves HLA-C. Apart from HLA match, there are many factors on the donor side that affect SCT outcome. These especially include timely transplantation, as the speed of finding an unrelated donor and SCT within the shortest possible time are almost as important as the degree of HLA-compatibility.
- Klíčová slova
- krvetvorné buňky,
- MeSH
- časové faktory MeSH
- dárci krve MeSH
- dospělí MeSH
- HLA antigeny genetika imunologie MeSH
- HLA-A antigeny genetika imunologie MeSH
- HLA-B antigeny genetika imunologie MeSH
- HLA-C antigeny genetika imunologie MeSH
- HLA-DRB1 řetězec genetika imunologie MeSH
- homologní transplantace MeSH
- krevní a lymfatické nemoci terapie MeSH
- lidé MeSH
- nepříbuzný dárce * MeSH
- reakce štěpu proti hostiteli genetika imunologie MeSH
- reakce štěpu proti leukémii imunologie MeSH
- rizikové faktory MeSH
- testování histokompatibility * metody MeSH
- transplantace kmenových buněk * MeSH
- výběr dárců MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
