BACKGROUND: C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear. METHODS: Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant's association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population. RESULTS: Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome. CONCLUSIONS: Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.
Complement C3b Inactivator Proteins , Glomerulonephritis, IGA , Blood Proteins , Complement C3/genetics , Complement C3/metabolism , Complement C3b Inactivator Proteins/genetics , Complement C3b Inactivator Proteins/metabolism , Complement Factor H/genetics , DNA Copy Number Variations , Disease Susceptibility , Glomerulonephritis, IGA/genetics , Glomerulonephritis, IGA/metabolism , Humans , Prognosis
Background: Seronegative celiac disease (CD) poses a diagnostic challenge. Aims: Characterize and identify differences between seronegative and seropositive CD. Patients and methods: Retrospective cohort study examining adult patients diagnosed with CD (1980-2017). Clinical, analytical, histological, genetic and immunophenotypic data were compiled. Seronegative CD was defined as a anti-tissue transglutaminase type 2 IgA and endomysial antibodies (EMA) negative and HLA-DQ2 and/or DQ8 positive, showing clinical signs of CD plus an abnormal duodenal biopsy, and responding to a gluten-free diet (GFD). Factors associated with seronegative CD were identified through binomial logistic regression. Results: Of 315 CD patients, 289 were seropositive (91.7%) and 26 seronegative (8.3%). Among the seronegative patients, higher prevalence was observed for autoimmune thyroiditis (26.9% vs. 9.7%, p = .016), HLA-DQ8 heterozygosity (23.1% vs. 2.5%, p Ë .001) and Marsh I lesion (34.6% vs. 3.7%, p Ë .001). The two groups showed similar flow cytometry-determined duodenal immunophenotypes and rates of refractory CD. Conclusions: Seronegative CD differs mostly in genetic (more HLA-DQ8) and histologic (milder atrophy) features as compared with seropositive. Intestinal intraepithelial immunophenotype by flow cytometry, similar in both modalities, is a useful tool to diagnose seronegative CD.
Celiac Disease/genetics , Celiac Disease/pathology , Duodenum/pathology , Lymphocytes/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Atrophy , Autoantibodies/blood , Biopsy , Celiac Disease/diagnosis , Celiac Disease/diet therapy , Diet, Gluten-Free , Duodenal Diseases/diagnosis , Duodenal Diseases/genetics , Duodenal Diseases/pathology , Female , Flow Cytometry , GTP-Binding Proteins/blood , HLA-DQ Antigens/genetics , Humans , Immunoglobulin A/immunology , Intestinal Mucosa/pathology , Logistic Models , Male , Middle Aged , Protein Glutamine gamma Glutamyltransferase 2 , Retrospective Studies , Transglutaminases/blood , Young Adult
No disponible
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Cathartics/administration & dosage , Cathartics/adverse effects , Kidney Diseases/chemically induced , Kidney Diseases/diagnosis , Phosphates/adverse effects , Administration, Oral , Colonoscopy , Phosphates/administration & dosage , Preoperative Care
Cathartics/adverse effects , Colonoscopy , Kidney Diseases/chemically induced , Phosphates/adverse effects , Administration, Oral , Aged , Aged, 80 and over , Cathartics/administration & dosage , Female , Humans , Kidney Diseases/diagnosis , Male , Middle Aged , Phosphates/administration & dosage , Preoperative Care
No disponible
Humans , Female , Middle Aged , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Scleroderma, Systemic/complications , Scleroderma, Systemic/diagnosis , /therapeutic use , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/physiopathology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , /metabolism , Dyslipidemias/complications , Dyslipidemias/diagnosis , Dyslipidemias , Radiography, Thoracic/instrumentation , Radiography, Thoracic/methods , Radiography, Thoracic/trends
Large granular lymphocyte leukemia is a rare entity belonging to same spectrum of diseases than Felty's syndrome, which might occur in patients with long-standing rheumatoid arthritis. It is clinically characterized by persistent neutropenia and recurrent bacterial infections associated with the presence in both peripheral blood and bone marrow of clonal expansion of atypic lymphocytes with a cytotoxic T cell phenotype, or less frequently an NK-cell phenotype, as well as splenomegaly. It is more frequently diagnosed in seropositive rheumatoid arthritis, with significant structural damage, extra-articular manifestations and persistently elevated values of ESR, despite them havubg low inflammatory joint activity. We report the case of a 70 year old male with a long-standing rheumatoid arthritis, who developed septic shock secondary to prosthetic hip infection by Salmonella spp. He showed persistent neutropenia, and an aberrant monoclonal T cell population was detected in both peripheral blood and bone marrow, consistent with large granular lymphocyte leukemia.
Arthritis, Rheumatoid/complications , Leukemia, Large Granular Lymphocytic/diagnosis , Aged , Humans , Leukemia, Large Granular Lymphocytic/etiology , Male
