A proliferation-inducing ligand (APRIL) is a key member of the tumor necrosis factor superfamily of cytokines and plays a central role in B-cell survival, proliferation, and Ig class switching. Recently, there has been increasing interest in the role of APRIL and the related cytokine B-cell activating factor in several glomerular diseases, because of their importance in the above processes. The therapeutic inhibition of APRIL represents a potentially attractive immunomodulatory approach that may abrogate deleterious host immune responses in autoimmune diseases while leaving other important functions of humoral immunity intact, such as memory B-cell function and responses to vaccination, in contrast to B-cell-depleting strategies. In this review, we describe the physiological roles of APRIL in B-cell development and their relevance to glomerular diseases, and outline emerging clinical trial data studying APRIL inhibition, with a focus on IgA nephropathy where the clinical development of APRIL inhibitors is in its most advanced stage.

• MeSH
• B-lymfocyty * imunologie   účinky léků   MeSH
• glomerulus imunologie   patologie   účinky léků   MeSH
• IgA nefropatie * imunologie   farmakoterapie   MeSH
• lidé MeSH
• protein TALL-2 * antagonisté a inhibitory   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

IgA nefropatie je nejčastější primární glomerulonefritida. V patogenezi onemocnění hrají zásadní roli imunitní komplexy, složené z galaktózy-deficitního IgA1 a autoprotilátek, které aktivují komplement a vyvolávají imunitní zánět glomerulů, progredující renální insuficienci až selhání ledvin. V současné době jsou léčebné možnosti u tohoto onemocnění limitované. Nepochybně potřebujeme cílenou léčbu, která ovlivní tvorbu patogenních protilátek obsahujících Gd-IgA1 a imunokomplexů. Tento článek shrnuje nové léčebné možnosti, které zasahují na úrovni vlastní patogeneze IgAN, ovlivňují komplementem zprostředkovaný zánět, tvorbu galaktóza-deficitního IgA1 i patogenních protilátek deplecí B a CD38 pozitivních plazmatických buněk.

IgA nephropathy is the most common primary glomerulonephritis worldwide. Immune complexes, composed of galactose-deficient IgA1 and Gd-IgA1 autoantibodies, are deposited in the mesangial area of the glomeruli where they induce complement-mediated inflammation. This may result in the reduced kidney function which can progress to end stage kidney disease. Treatment options are very limited. Treatments which directly affect the formation of pathogenic Gd-IgA1 antibodies and anti-Gd-IgA1 antibody-containing immune complexes are needed. This article reviews potential therapies that may affect the main axis of pathogenesis of IgA nephropathy. New treatment options are aimed at the immunopathogenesis of IgAN including depletion or modulation of Gd-IgA1 producing B cells, plasma cells, alternate and/or lectin pathway of complement.

• MeSH
• glifloziny farmakologie   terapeutické užití   MeSH
• hormony kůry nadledvin farmakologie   terapeutické užití   MeSH
• IgA nefropatie * diagnóza   farmakoterapie   imunologie   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• komplement - faktor B antagonisté a inhibitory   MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• progrese nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and a common cause of end-stage renal disease. Evaluation of a kidney biopsy is necessary for diagnosis, with routine immunofluorescence microscopy revealing dominant or co-dominant IgA immunodeposits usually with complement C3 and sometimes IgG and/or IgM. IgA nephropathy reduces life expectancy by more than 10 years and leads to kidney failure in 20-40% of patients within 20 years of diagnosis. There is accumulating clinical, genetic, and biochemical evidence that complement plays an important role in the pathogenesis of IgA nephropathy. The presence of C3 differentiates the diagnosis of IgA nephropathy from the subclinical deposition of glomerular IgA. Markers for the activation of the alternative and mannan-binding lectin (MBL) pathways in renal-biopsy specimens are associated with disease activity and portend a worse renal outcome. Complement proteins in the circulation have also been evaluated in IgA nephropathy and found to be of prognostic value. Recently, genetic studies have identified IgA nephropathy-associated loci. Within these loci are genes encoding products involved in complement regulation and interaction with immune complexes. Put together, these data identify the complement cascade as a rational treatment target for this chronic kidney disease. Recent case reports on the successful use of humanized anti-C5 monoclonal antibody eculizumab are consistent with this hypothesis, but a better understanding of the role of complement in IgA nephropathy is needed to guide future therapeutic interventions.

• MeSH
• chronická renální insuficience imunologie   MeSH
• glomerulonefritida imunologie   MeSH
• IgA nefropatie imunologie   MeSH
• imunoglobulin A imunologie   MeSH
• komplement C3 imunologie   MeSH
• komplement C5 imunologie   MeSH
• ledviny imunologie   MeSH
• lidé MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, has serious outcomes with end-stage renal disease developing in 30-50% of patients. The diagnosis requires renal biopsy. Due to its inherent risks, non-invasive approaches are needed. METHODS: We evaluated 91 Czech patients with biopsy-proven IgAN who were assessed at time of diagnosis for estimated glomerular filtration rate (eGFR), proteinuria, microscopic hematuria, and hypertension, and then followed prospectively. Serum samples collected at diagnosis were analyzed for galactose-deficient IgA1 (Gd-IgA1) using new native-IgA1 and established neuraminidase-treated-IgA1 tests, Gd-IgA1-specific IgG autoantibodies, discriminant analysis and logistic regression model assessed correlations with renal function and Oxford classification (MEST score). RESULTS: Serum levels of native (P <0.005) and neuraminidase-treated (P <0.005) Gd-IgA1 were associated with the rate of eGFR decline. A higher relative degree of galactose deficiency in native serum IgA1 predicted a faster eGFR decline and poor renal survival (P <0.005). However, Gd-IgA1 has not differentiated patients with low vs. high baseline eGFR. Furthermore, patients with high baseline eGFR that was maintained during follow-up were characterized by low serum levels of Gd-IgA1-specific IgG autoantibodies (P = 0.003). CONCLUSIONS: Including levels of native and neuraminidase-treated Gd-IgA1 and Gd-IgA1-specific autoantibodies at diagnosis may aid in the prognostication of disease progression in Czech patients with IgAN. Future tests will assess utility of these biomarkers in larger patients cohorts from geographically distinct areas.

• MeSH
• autoprotilátky krev   imunologie   MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• galaktosa krev   imunologie   MeSH
• IgA nefropatie krev   diagnóza   imunologie   mortalita   MeSH
• imunoglobulin A krev   imunologie   MeSH
• lidé MeSH
• následné studie MeSH
• progrese nemoci MeSH
• prospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Current studies have shown that the Th17/Treg immune balance may be involved in the occurrence of IgAN, but the exact mechanism is still unclear. Indoleamine 2,3-dioxygenase (IDO) is an enzyme that catalyses degradation of tryptophan (Trp) through the kynurenine (Kyn) pathway; it can control inflammation and immune response by inducing Trp starvation. IDO may be a key molecule in regulating the Th17/Treg immune balance. However, it is not clear whether IDO is involved in the IgAN disease occurrence by regulating the Th17/Treg immune balance. In this study, an IgAN mouse model was established. The mice were intraperitoneally inoculated with IDO inhibitor 1-MT or agonist ISS-ODN to observe whether the IDO signalling pathway participates in the occurrence and development of IgAN by regulating the Th17/Treg immune balance. The results showed that IDO inhibitor 1-MT significantly increased renal injury and glomerular IgA accumulation and up-regulated Th17/Treg and Th17-related cytokine expression in IgAN mice, while ISS-ODN significantly decreased renal injury and glomerular IgA accumulation, down-regulated Th17/Treg expression and inhibited Th17-related cytokine expression in IgAN mice. In conclusion, IDO was involved in the occurrence and progress of IgAN by regulating the Th17/ Treg balance.

• MeSH
• buňky Th17 imunologie   MeSH
• cytokiny metabolismus   MeSH
• IgA nefropatie enzymologie   imunologie   MeSH
• imunita * MeSH
• indolamin-2,3,-dioxygenasa metabolismus   MeSH
• ledviny zranění   metabolismus   patologie   MeSH
• myši inbrední BALB C MeSH
• regulační T-lymfocyty imunologie   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m(2), to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8-2.4) mg/dl, and proteinuria was 2.1 (0.6-5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.

• MeSH
• dospělí MeSH
• IgA nefropatie komplikace   farmakoterapie   imunologie   patofyziologie   MeSH
• imunologické faktory terapeutické užití   MeSH
• ledviny patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• proteinurie etiologie   MeSH
• rituximab terapeutické užití   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
• randomizované kontrolované studie MeSH

• Klíčová slova
• TRF-budesonid,
• MeSH
• budesonid aplikace a dávkování   farmakologie   MeSH
• glukokortikoidy aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• hodnoty glomerulární filtrace imunologie   účinky léků   MeSH
• IgA nefropatie * farmakoterapie   imunologie   patofyziologie   MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé MeSH
• proteinurie diagnóza   farmakoterapie   MeSH
• renin-angiotensin systém účinky léků   MeSH
• střevní sliznice imunologie   účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH

IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis in the world. The disease is characterized by the presence of IgA-containing immune complexes in the circulation and in mesangial deposits with ensuing glomerular injury. Although in humans there are two IgA subclasses, only IgA1 molecules are involved. The exclusivity of participation of IgA1 in IgAN prompted extensive structural and immunological studies of the unique hinge region (HR) of IgA1, which is absent in otherwise highly homologous IgA2. HR of IgA1 with altered O-glycans serves as an antigen recognized by autoantibodies specific for aberrant HR glycans leading to the generation of nephritogenic immune complexes. However, there are several unresolved questions concerning the phylogenetic origin of human IgA1 HR, the structural basis of its antigenicity, the origin of antibodies specific for HR with altered glycan moieties, the regulatory defects in IgA1 glycosylation pathways, and the potential approaches applicable to the disease-specific interventions in the formation of nephritogenic immune complexes. This review focuses on the gaps in our knowledge of molecular and cellular events that are involved in the immunopathogenesis of IgAN.

• MeSH
• IgA nefropatie imunologie   MeSH
• imunoglobulin A imunologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Autoantibodies against galactose-deficient IgA1 drive formation of pathogenic immune complexes in IgA nephropathy. IgG autoantibodies against galactose-deficient IgA1 in patients with IgA nephropathy have a specific amino-acid sequence, Y1CS3, in the complementarity-determining region 3 of the heavy chain variable region compared with a Y1CA3 sequence in similar isotype-matched IgG from healthy controls. We previously found that the S3 residue is critical for binding galactose-deficient IgA1. To determine whether this difference is due to a rare germline sequence, we amplified and sequenced the corresponding germline variable region genes from peripheral blood mononuclear cells of seven patients with IgA nephropathy and six healthy controls from whom we had cloned single-cell lines secreting monoclonal IgG specific for galactose-deficient IgA1. Sanger DNA sequencing revealed that complementarity-determining region 3 in the variable region of the germline genes encoded the Y1C(A/V)3 amino-acid sequence. Thus, the A/V>S substitution in the complementarity-determining region 3 of anti-galactose-deficient-IgA1 autoantibodies of the patients with IgA nephropathy is not a rare germline gene variant. Modeling analyses indicated that the S3 hydroxyl group spans the complementarity-determining region 3 loop stem, stabilizing the adjacent β-sheet and stem structure, important features for effective binding to galactose-deficient IgA1. Understanding processes leading to production of the autoantibodies may offer new approaches to treat IgA nephropathy.

• MeSH
• autoprotilátky genetika   MeSH
• galaktosa nedostatek   MeSH
• IgA nefropatie enzymologie   genetika   imunologie   MeSH
• imunoglobulin A * MeSH
• lidé MeSH
• mutace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

In this grant proposal the properties of high molecular weight immune complexes isolated from IgA nephropathy (IgAN) and Henoch-Schoenlein purpura nephritis (HSPN) patients? sera will be analyzed. They are main etiopathological factor of both diseases. These IC consist of polymeric IgA1 with aberrantly glycosylated hinge region, which is recognized by glycan-specific natural antibodies, predominantly of the IgG isotype. We propose do prepare several recombinant proteins and synthetic peptides containinghinge region with similar glycosylation aberrancy as in IgAN and test them as the competitors during above IC formation. IC from IgAN and HSPN patients? sera will be isolated, dissociated under low pH, and after pH normalization and competitor additionthe re-formatted IC will be physico-chemically characterized and their ability to stimulate proliferation of mesangial cells will be determined.

V projektu budou studovány vlastnosti velkých imunitních komplexů (IK) izolovaných ze sér pacientů s IgA nefropatií (IgAN) a nefritídou u Henoch-Schoenleinovy purpury (HSPN), které jsou etiopatologickým faktorem obou chorob. Tyto IK jsou tvořeny polymerním IgA1 na jehož pantovou oblast jsou navázány abnormální oligosacharidy, které vážou přirozené, cukerně specifické protilátky (nejčastěji IgG). Navrhujeme připravit několik monovalentních rekombinantních proteinů a syntetických peptidů obsahujících pantovou oblast lidského IgA1 obdobně glykosylovanou jako u IgAN, které budou testovány in vitro jako kompetitory tvorby výše zmíněných patologických IK. IK budou po izolaci charakterizovány, rozpuštěny (snížením pH) a v přítomnosti jednotlivých kompetitorůbudou po zvýšení pH7,4 opět reformovány. Nově vzniklé IK budou fyzikálně-chemicky charakterizovány a bude sledována jejich schopnost aktivovat lidské mesangiální buňky in vitro.

• MeSH
• blokátory receptoru 1 pro angiotenzin II MeSH
• glykosylace MeSH
• glykosyltransferasy MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• IgA nefropatie imunologie   MeSH
• IgA vaskulitida imunologie   MeSH
• imunokomplex MeSH
• imunosupresiva terapeutické užití   MeSH
• nízkoproteinová dieta MeSH
• oligosacharidy s větvenými řetězci MeSH
• renin antagonisté a inhibitory   MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• nefrologie
• biologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR