RESUMO
IgA Nephropathy (IgAN) is the commonest primary glomerular disease around the world and represents a significant cause of end-stage renal disease. IgAN is characterized by mesangial deposition of IgA-immune complexes and mesangial expansion. The pathophysiological process includes an abnormally glycosylated IgA1, which is an antigenic target. Autoantibodies specifically recognize galactose-deficient IgA1 forming immune complexes that are amplified in size by the soluble IgA Fc receptor CD89 leading to deposition in the mesangium through interaction with non-classical IgA receptors. The local production of cytokines promotes local inflammation and complement system activation, besides the stimulation of mesangial proliferation. The spectrum of clinical manifestations is quite variable from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. Despite all the advances, the pathophysiology of the disease is still not fully elucidated. The mucosal immune system is quoted to be a factor in triggering IgAN and a "gut-kidney axis" is proposed in its development. Furthermore, many recent studies have demonstrated that food intake interferes directly with disease prognosis. In this review, we will discuss how mucosal immunity, microbiota, and nutritional status could be interfering directly with the activation of intrinsic pathways of the mesangial cells, directly resulting in changes in their function, inflammation and development of IgAN.
RESUMO
On September 27-29, 2018, the International Symposium on IgA Nephropathy, organized by the International IgA Nephropathy Network, was held in Buenos Aires, Argentina, celebrating the 50th anniversary of the first description of IgA nephropathy by Berger and Hinglais in 1968. The meeting was attended by over 200 scientists and clinicians from 26 different countries across the globe. We report some key insights drawn from the meeting-including the molecular pathogenesis, genetics, pathology, and therapeutics of IgA nephropathy.
Assuntos
Congressos como Assunto , Glomerulonefrite por IGA , Nefrologia/história , Aniversários e Eventos Especiais , Argentina , História do Século XX , Humanos , Imunoglobulina A/imunologia , Glomérulos Renais/imunologiaRESUMO
Sepsis, a leading cause of death worldwide, involves exacerbated proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here, we used a phage display library to identify two peptides in Escherichia coli that interact with host innate receptors. One of these peptides, encoded by the wzxE gene of E. coli K-12, was involved in the transbilayer movement of a trisaccharide-lipid intermediate in the assembly of enterobacterial common antigen. Peptide-receptor interactions induced CD16-mediated inhibitory immunoreceptor tyrosine-based activating motif signaling, blocking the production of ROS and bacterial killing. This CD16-mediated inhibitory signaling was abrogated in a WzxE(-/-) mutant of E. coli K-12, restoring the production of ROS and bacterial killing. Taken together, the two novel CD16 ligands identified negatively regulate bacterial killing and inflammation. Our findings may contribute toward the development of new immunotherapies for E. coli-mediated infectious diseases and inflammation.
Assuntos
Antígenos de Bactérias/imunologia , Infecções por Escherichia coli/imunologia , Proteínas de Escherichia coli/imunologia , Proteínas de Membrana Transportadoras/imunologia , Fagocitose , Receptores de IgG/imunologia , Animais , Escherichia coli , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biblioteca de Peptídeos , Fagócitos/imunologia , Sepse/prevenção & controle , Transdução de SinaisRESUMO
Sepsis is a devastating disease that can affect humans at any time between neonates and the elderly and is associated with mortality rates that range from 30 to 80%. Despite intensive efforts, its treatment has remained the same over the last few decades. Fc receptors regulate multiple immune responses and have been investigated in diverse complex diseases. FcγRIIA (CD32A) is an immunoreceptor, tyrosine-based activation motif-bearing receptor that binds immunoglobulin G and C-reactive protein, important opsonins in host defense. We conducted a study of 702 patients (184 healthy individuals, 171 non-infected critically ill patients, and 347 sepsis patients) to investigate if genetic polymorphisms in the CD32A coding region affect the risk of septic shock. All individuals were genotyped for a variant at position 131 of the FcγRIIA gene. We found that allele G, associated with the R131 genotype, was significantly more frequent in septic patients than in the other groups (p = 0.05). Our data indicate that FcγRIIA genotyping can be used as a marker of genetic susceptibility to sepsis.
Assuntos
Predisposição Genética para Doença/genética , Receptores de IgG/genética , Sepse/genética , Estado Terminal , Feminino , Marcadores Genéticos/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Sepse/microbiologiaRESUMO
Focal and segmental glomerulosclerosis (FSGS) is one of the most important renal diseases related to end-stage renal failure. Bradykinin has been implicated in the pathogenesis of renal inflammation, whereas the role of its receptor 2 (B2RBK; also known as BDKRB2) in FSGS has not been studied. FSGS was induced in wild-type and B2RBK-knockout mice by a single intravenous injection of Adriamycin (ADM). In order to further modulate the kinin receptors, the animals were also treated with the B2RBK antagonist HOE-140 and the B1RBK antagonist DALBK. Here, we show that the blockage of B2RBK with HOE-140 protects mice from the development of FSGS, including podocyte foot process effacement and the re-establishment of slit-diaphragm-related proteins. However, B2RBK-knockout mice were not protected from FSGS. These opposite results were due to B1RBK expression. B1RBK was upregulated after the injection of ADM and this upregulation was exacerbated in B2RBK-knockout animals. Furthermore, treatment with HOE-140 downregulated the B1RBK receptor. The blockage of B1RBK in B2RBK-knockout animals promoted FSGS regression, with a less-inflammatory phenotype. These results indicate a deleterious role of both kinin receptors in an FSGS model and suggest a possible cross-talk between them in the progression of disease.
Assuntos
Glomerulosclerose Segmentar e Focal/patologia , Receptores da Bradicinina/fisiologia , Animais , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Glomerulosclerose Segmentar e Focal/metabolismo , Camundongos , Camundongos Knockout , Receptores da Bradicinina/efeitos dos fármacos , Receptores da Bradicinina/genéticaRESUMO
Both systemic and organ-specific autoimmune diseases are major manifestations of IgA deficiency (IgAD), the most common primary immunodeficiency. In addition, to discuss the clinical findings of IgAD patients, we proposed a hypothesis to explain the high association with autoimmune phenomena. Based on observations, interactions of monomeric IgA with FcalphaRI result in a partial phosphorylation of FcRgamma-associated FcalphaRI, notably in the immunoreceptor tyrosine-based activation motif (ITAM) inducing the recruitment of the SHP-1 tyrosine phosphatase. This leads to deactivation of several activating pathways of the immune system including immunoreceptors that bear ITAM motif and ITAM-independent receptors. Consequently, inflammatory reactions and auto-immune process would be prevented.
Assuntos
Autoimunidade , Deficiência de IgA/genética , Deficiência de IgA/imunologia , Adenocarcinoma/etiologia , Adenocarcinoma/imunologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Brasil , Humanos , Deficiência de IgA/complicações , Deficiência de IgA/epidemiologia , Imunidade nas Mucosas , Modelos Imunológicos , Infecções Oportunistas/imunologia , Prevalência , Receptores Fc/genética , Receptores Fc/imunologia , Tolerância a Antígenos Próprios , Transdução de Sinais , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/imunologiaRESUMO
BACKGROUND: Fc gamma RIIa is a low affinity receptor that has two co-dominantly expressed alleles, R131 and H131, which differ in their ability to bind immunoglobulin G (IgG) subclasses. Cells expressing H131 bind more efficiently complexed IgG2 and IgG3 than those expressing the R131 variant. The Fc gamma RIIa polymorphism has been shown to be associated with lupus nephritis. Here we evaluated the relevance of Fc gamma RIIa gene polymorphism in the development of lupus immune complex (IC)-mediated nephritis by comparing the genotype and allelic distribution of this receptor in lupus nephritis to ethnically matched healthy controls in Brazilians. METHODS: 119 systemic lupus erythematosus (SLE) patients and 48 healthy volunteers were recruited. Fc gamma RIIa genotyping was performed by PCR with allele-specific primers to distinguish between the two allelic forms (H131 and R131). RESULTS: Comparison of Fc gamma RIIa genotypes distribution in SLE patients with nephritis and in controls showed a significant increase in Fc gamma RIIa-R131 homozygosity (P < or = 0.02). The genotype distribution in lupus nephritis (45% with Fc gamma RIIa-R/R131, 30% with H/R131 and 25% with H/H131) was distinct from that observed in controls (21% with Fc gamma RIIa-R/R131, 52% with H/R131 and 27% with H/H131). In contrast, there was no difference in the distribution of Fc gamma RIIa genotypes in lupus without nephritis and controls (P = 0.3). Reinforcing the relevance of Fc gamma RIIa polymorphism in IC-mediated nephritis, patients with renal failure had an over-representation of the R131 allele (70%) when compared with normal controls (47%) (P = 0.06). CONCLUSIONS: The skewed distribution of Fc gamma RIIa genotypes with the predominance of homozygous R/R131 genotype observed in lupus nephritis emphasizes its importance as a heritable risk factor for IC-mediated renal injury in Brazilian lupus patients.