IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
- MeSH
- celogenomová asociační studie MeSH
- IgA nefropatie * farmakoterapie genetika diagnóza MeSH
- imunoglobulin A genetika MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
IgA nefropatie je v současné době nejvíce studovanou glomerulonefritidou. Je definována průkazem převažujících nebo s jinými imunoglobuliny „kodominujících“ depozit imunoglobulinu A1 v mezangiu glomerulů. Depozita IgA1 nejpravděpodobněji pocházejí z cirkulujících imunitních komplexů, může ale jít i o agregaci IgA1 pozměněné struktury či o vazbu na receptory pro IgA1 na mezangiálních buňkách. Příčinou tvorby imunitních komplexů odpovědných za IgA nefropatii je nedostavěný O-glykosidický řetězec imunoglobulinu A1, na jehož konci v důsledku anomálií glykosyltransferáz chybí galaktóza. Na tento cukerný antigen se váží přirozeně se vyskytující protilátky třídy IgG nebo IgA1. V klinickém obrazu rozeznáváme časné stadium obvykle se vyznačující erytrocyturií a proměnlivé stadium pozdní, dané buď klinickou remisí, nebo perzistencí erytrocyturie či u jedné třetiny pacientů narůstající proteinurií, zvýšeným krevním tlakem a klesající funkcí ledvin. Prognózu IgA nefropatie nedovedeme v časném stadiu odhadnout ani z klinické prezentace ani z morfologického nálezu ani z množství odchylně glykosylovaného IgA1 v cirkulaci. Spolehlivým ukazatelem závažné prognózy je teprve pozdní stadium se stoupající proteinurií a hypertenzí a v biopsii s atrofií tubulů a intersticiální sklerózou. Hlavním trendem v léčbě IgA nefropatie je důraz na podávání inhibitorů ACE/sartanů, které sami podáváme již při mikroalbuminurii. Jestliže při této léčbě proteinurie nepoklesne pod 1 g/24 h, je lékem volby prednison. Nové poznatky o patogeneze choroby nabízejí možnosti zásahu na úrovni tvorby nefritogenních imunitních komplexů blokádou dnes již známé antigenní determinanty na imunoglobulinu A1 a/nebo na základě kompetitivní inhibice přirozeně se vyskytujících příslušných protilátek.
IgA nephropathy is currently the most frequently investigated glomerulonephritis. The disease is defined by the presence of dominant or co-dominant deposits of IgA1 in the glomerular mesangium. Circulating immune complexes are most likely the source of the deposited IgA1. However, it is also possible that the aggregates of structurally altered IgA1 or enhanced binding to IgA receptors expressed on mesangial cells lead to deposition. The cause of the formation of immune complexes responsible for IgA nephropathy lies in the incomplete O-linked oligosaccharide side chains, which, due to the deficiency of corresponding glycosyltransferases, lack terminal galactose residues leading to the exposure of N-acetylgalactosamine. Naturally occurring antibodies of the IgG or IgA1 isotype bind to this sugar antigen. In the clinical course, we differentiate between the early stage usually characterized by hematuria, and a variable late stage characterized either by a clinical remission, by persistence of hematuria, or by increasing proteinuria and blood pressure and decreasing renal function in one third of the patients. In the early stage, it is difficult to predict the prognosis of IgA nephropathy, either on the basis of clinical presentation and morphological findings, or according to the level of galactose-deficient IgA1 in the circulation. The reliable criteria of serious prognosis emerge only in the later stages of the disease and include proteinuria, hypertension, and histologically apparent tubular atrophy and interstitial sclerosis. The dominant trend in the treatment of IgA nephropathy is the emphasis on administration of ACE inhibitors/sartans, which are introduced into the treatment at the time of microalbuminuria. If proteinuria does not decrease below 1 g/24 h, treatment with prednisone is justifiable. New findings concerning the molecular/cellular mechanism involved in the pathogenesis of IgA nephropathy suggest the possible therapeutical interference with the generation of nephritogenic immune complexes by a selective blocking of the IgA1 molecules with altered glycan structures using monovalent reagents.
- MeSH
- galaktosa MeSH
- genetická predispozice k nemoci MeSH
- glukokortikoidy MeSH
- glykosylace MeSH
- IgA nefropatie * diagnóza etiologie patofyziologie terapie vrozené MeSH
- imunoglobulin A genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- oligosacharidy MeSH
- proteinurie diagnóza MeSH
- sérum MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
PURPOSE: The aim of our retrospective study was to clarify fertility, pregnancy complications and outcomes in common variable immunodeficiency (CVID) females. METHODS: Retrospective data were obtained from three Czech referral centres. The data were compared with data obtained from the Czech National Registry of Reproduction Health. RESULTS: Our cohort of patients comprised 54 women with 115 pregnancies; 88 pregnancies in 50 females were finished with live births (77 %). In only 8 women (15%) was the diagnosis of CVID established before the first pregnancy. Replacement immunoglobulin therapy was performed in 10 patients without any moderate or severe adverse effects. Compared with the Czech population, the CVID patients suffered significantly more frequently from the threat of preterm labour (p < 0.0001), vaginal bleeding (p = 0.0001), eclampsia/preeclampsia (p = 0.009) and a higher number of stillbirths (p < 0.0001). Furthermore, the frequency of babies with low birth weight (less than 2500 g) born to the CVID patients was increased compared with the normal population (p < 0.0001). Serum IgG, IgA and IgM determination was done in 57 children of 50 mothers showing 13 cases of IgA deficiency (23%). There was no significant difference among the non-symptomatic, symptomatic untreated and symptomatic treated females in any of the determined gynaecological complications. The number of unsuccessful pregnancies was higher in the symptomatic untreated women. CONCLUSIONS: Fertility in CVID patients is not decreased, and their pregnancies could be considered more risky compared with those of the general population.
- MeSH
- běžná variabilní imunodeficience komplikace imunologie MeSH
- děložní krvácení etiologie MeSH
- dítě MeSH
- dospělí MeSH
- imunoglobulin A genetika MeSH
- kohortové studie MeSH
- komplikace těhotenství imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předčasná porodní činnost etiologie MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- těhotenství imunologie MeSH
- výsledek těhotenství MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- těhotenství imunologie MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- B-buněčný lymfom komplikace genetika imunologie patologie MeSH
- dospělí MeSH
- exprese genu MeSH
- fosfatidylinositol-3-kinasy třídy I genetika imunologie MeSH
- genetická predispozice k nemoci MeSH
- heterozygot MeSH
- imunoglobulin A genetika imunologie MeSH
- imunoglobulin G genetika imunologie MeSH
- imunoglobulin M genetika imunologie MeSH
- lidé MeSH
- mladiství MeSH
- mutace MeSH
- přesmyk imunoglobulinových tříd MeSH
- syndromy imunologické nedostatečnosti komplikace genetika imunologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
The human UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 2 (GalNAc-T2) is one of the key enzymes that initiate synthesis of hinge-region O-linked glycans of human immunoglobulin A1 (IgA1). We designed secreted soluble form of human GalNAc-T2 as a fusion protein containing mouse immunoglobulin light chain kappa secretory signal and expressed it using baculovirus and mammalian expression vectors. The recombinant protein was secreted by insect cells Sf9 and human HEK 293T cells in the culture medium. The protein was purified from the media using affinity Ni-NTA chromatography followed by stabilization of purified protein in 50mM Tris-HCl buffer at pH 7.4. Although the purity of recombinant GalNAc-T2 was comparable in both expression systems, the yield was higher in Sf9 insect expression system (2.5mg of GalNAc-T2 protein per 1L culture medium). The purified soluble recombinant GalNAc-T2 had an estimated molecular mass of 65.8kDa and its amino-acid sequence was confirmed by mass-spectrometric analysis. The enzymatic activity of Sf9-produced recombinant GalNAc-T2 was determined by the quantification of enzyme-mediated attachment of GalNAc to synthetic IgA1 hinge-region peptide as the acceptor and UDP-GalNAc as the donor. In conclusion, murine immunoglobulin kappa secretory signal was used for production of secreted enzymatically active GalNAc-T2 in insect baculovirus expression system.
- MeSH
- aktivace enzymů MeSH
- Baculoviridae genetika metabolismus MeSH
- genetické vektory genetika metabolismus MeSH
- HEK293 buňky MeSH
- hmyz genetika metabolismus MeSH
- imunoglobulin A genetika metabolismus MeSH
- imunoglobuliny - kappa-řetězce chemie genetika MeSH
- klonování DNA MeSH
- kultivační média metabolismus MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- myši MeSH
- N-acetylgalaktosaminyltransferasy biosyntéza genetika izolace a purifikace MeSH
- plazmidy genetika metabolismus MeSH
- proteiny - lokalizační signály MeSH
- rekombinantní fúzní proteiny biosyntéza genetika izolace a purifikace MeSH
- rozpustnost MeSH
- sekvence aminokyselin MeSH
- stabilita proteinů MeSH
- tandemová hmotnostní spektrometrie MeSH
- transfekce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- srovnávací studie MeSH
Interleukin-10 (IL-10) is an immunoregulatory cytokine, usually considered to mediate the downregulation of the inflammatory response in rheumatoid arthritis (RA). Some effects of IL-10 are not anti-inflammatory; for example, the activation of B cells to promote autoantibody production. Allelic polymorphisms located in the promoter region of the IL-10 gene may contribute to the regulation of autoantibodies production. To examine the putative association between the -1082 G/A polymorphism in the promoter region of the IL-10 gene and the susceptibility to disease onset and severity of RA, a total of 144 patients with RA diagnosed according to the revised criteria of the American College of Rheumatology for RA were consecutively recruited into the study. Radiographic progression of RA was scored according to the Sharp/van der Heijde method. Serum levels of rheumatoid factors (RFs) were measured by enzyme-linked immunosorbent assay. Polymerase chain reaction amplification was used for the analysis of the promoter polymorphism of the IL-10 gene. We observed significant differences in genotype distribution of the -1082 G/A polymorphism between IgM RF, IgA RF, and IgG RF positive/negative subgroups of RA patients, with higher prevalence of the GG genotype within IgM RF (Pg = 0.006), IgA RF (Pg = 0.05), and IgG RF (Pg = 0.007) negative RA patients. Results obtained in this study provide the evidence of an association between the -1082 G/A polymorphism in the IL-10 gene promoter and the production of RFs in RA patients.
- MeSH
- dospělí MeSH
- frekvence genu MeSH
- imunoglobulin A genetika MeSH
- imunoglobulin G genetika MeSH
- imunoglobulin M genetika MeSH
- interleukin-10 genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- promotorové oblasti (genetika) genetika MeSH
- revmatoidní artritida genetika imunologie MeSH
- revmatoidní faktor genetika imunologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
IgA nephropathy (IgAN) is a complex trait determined by genetic and environmental factors. Most IgAN patients exhibit a characteristic undergalactosylation of the O-glycans of the IgA1 hinge region, which promotes formation and glomerular deposition of immune complexes. It is not known whether this aberrant glycosylation is the result of an acquired or inherited defect, or whether the presence of aberrant IgA1 glycoforms alone can produce IgAN. A newly validated lectin enzyme-linked immunosorbent assay (ELISA) was used to determine the serum level of galactose-deficient IgA1 (Gd-IgA1) in a cohort of 89 IgAN patients and 266 of their relatives. High Gd-IgA1 levels (> or =95th percentile for controls) were observed in all 5 available patients with familial IgAN, in 21 of 45 (47%) of their at-risk relatives (assuming autosomal dominant inheritance), and in only 1 of 19 (5%) of unrelated individuals who married into the family. This provides evidence that abnormal IgA1 glycosylation is an inherited rather than acquired trait. Similarly, Gd-IgA1 levels were high in 65 of 84 (78%) patients with sporadic IgAN and in 50 of 202 (25%) blood relatives. Heritability of Gd-IgA1 was estimated at 0.54 (P = 0.0001), and segregation analysis suggested the presence of a major dominant gene on a polygenic background. Because most relatives with abnormal IgA1 glycoforms were asymptomatic, additional cofactors must be required for IgAN to develop. The fact that abnormal IgA1 glycosylation clusters in most but not all families suggests that measuring Gd-IgA1 may help distinguish patients with different pathogenic mechanisms of disease.
