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International Journal of Molecular... Jul 2021IgA, previously called Henoch-Schönlein vasculitis, is an essential immune component that drives the host immune response to the external environment. As IgA has the... (Review)
Review
IgA, previously called Henoch-Schönlein vasculitis, is an essential immune component that drives the host immune response to the external environment. As IgA has the unique characteristic of a flexible response to broad types of microorganisms, it sometimes causes an autoreactive response in the host human body. IgA vasculitis and related organ dysfunction are representative IgA-mediated autoimmune diseases; bacterial and viral infections often trigger IgA vasculitis. Recent drug developments and the presence of COVID-19 have revealed that these agents can also trigger IgA vasculitis. These findings provide a novel understanding of the pathogenesis of IgA vasculitis. In this review, we focus on the characteristics of IgA and symptoms of IgA vasculitis and other organ dysfunction. We also mention the therapeutic approach, biomarkers, novel triggers for IgA vasculitis, and epigenetic modifications in patients with IgA vasculitis.
Topics: Animals; Biomarkers; Epigenesis, Genetic; Humans; Immunoglobulin A; Vasculitis
PubMed: 34299162
DOI: 10.3390/ijms22147538 -
Cell Proliferation Sep 2022Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate...
BACKGROUND
Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway.
METHODS
We established a TP-treated IgAN mouse model and produced IgA1-induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3-Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p-p38 MAPK/p38 MAPK following TP treatment.
RESULTS
Administering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1-induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN.
CONCLUSION
TP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway.
Topics: Animals; Autophagy; CARD Signaling Adaptor Proteins; Cell Division; Cell Proliferation; Cells, Cultured; Diterpenes; Epoxy Compounds; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Mice; Phenanthrenes; p38 Mitogen-Activated Protein Kinases
PubMed: 35733381
DOI: 10.1111/cpr.13278 -
Journal of the American Society of... May 2022IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered...
BACKGROUND
IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered O-glycans (Gd-IgA1) and anti-glycan antibodies in the kidney mesangium. The mesangial IgA deposits and serum IgA1 contain predominantly light (L) chains, but the nature and origin of such IgA remains enigmatic.
METHODS
We analyzed L chain expression in peripheral blood B cells of 30 IgAN patients, 30 healthy controls (HCs), and 18 membranous nephropathy patients selected as disease controls (non-IgAN).
RESULTS
In comparison to HCs and non-IgAN patients, peripheral blood surface/membrane bound (mb)-Gd-IgA1 cells from IgAN patients express predominantly L chains. In contrast, total mb-IgA, mb-IgG, and mb-IgM cells were preferentially positive for kappa () L chains, in all analyzed groups. Although minor in comparison to L chains, L chain subsets of mb-IgG, mb-IgM, and mb-IgA cells were significantly enriched in IgAN patients in comparison to non-IgAN patients and/or HCs. In contrast to HCs, the peripheral blood of IgAN patients was enriched with mb-Gd-IgA1, CCR10, and CCR9 cells, which preferentially home to the upper respiratory and digestive tracts. Furthermore, we observed that mb-Gd-IgA1 cell populations comprise more CD138 cells and plasmablasts (CD38) in comparison to total mb-IgA cells.
CONCLUSIONS
Peripheral blood of IgAN patients is enriched with migratory mb-Gd-IgA1 B cells, with the potential to home to mucosal sites where Gd-IgA1 could be produced during local respiratory or digestive tract infections.
Topics: Female; Galactose; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male
PubMed: 35115327
DOI: 10.1681/ASN.2021081086 -
Cells Apr 2022Chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF) are distinct respiratory diseases that share features such as the obstruction of small... (Review)
Review
Chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF) are distinct respiratory diseases that share features such as the obstruction of small airways and disease flare-ups that are called exacerbations and are often caused by infections. Along the airway epithelium, immunoglobulin (Ig) A contributes to first line mucosal protection against inhaled particles and pathogens. Dimeric IgA produced by mucosal plasma cells is transported towards the apical pole of airway epithelial cells by the polymeric Ig receptor (pIgR), where it is released as secretory IgA. Secretory IgA mediates immune exclusion and promotes the clearance of pathogens from the airway surface by inhibiting their adherence to the epithelium. In this review, we summarize the current knowledge regarding alterations of the IgA/pIgR system observed in those major obstructive airway diseases and discuss their implication for disease pathogenesis.
Topics: Humans; Immunoglobulin A; Immunoglobulin A, Secretory; Pulmonary Disease, Chronic Obstructive; Receptors, Polymeric Immunoglobulin; Respiratory System
PubMed: 35456002
DOI: 10.3390/cells11081324 -
Scandinavian Journal of Immunology Apr 2023Virus neutralization at respiratory mucosal surfaces is important in the prevention of infection. Mucosal immunity is mediated mainly by extracellular secretory... (Review)
Review
Virus neutralization at respiratory mucosal surfaces is important in the prevention of infection. Mucosal immunity is mediated mainly by extracellular secretory immunoglobulin A (sIgA) and its role has been well studied. However, the protective role of intracellular specific IgA (icIgA) is less well defined. Initially, in vitro studies using epithelial cell lines with surface expressed polymeric immunoglobulin receptor (pIgR) in transwell culture chambers have shown that icIgA can neutralize influenza, parainfluenza, HIV, rotavirus and measles viruses. This effect appears to involve an interaction between polymeric immunoglobulin A (pIgA) and viral particles within an intracellular compartment, since IgA is transported across the polarized cell. Co-localization of specific icIgA with influenza virus in patients' (virus culture positive) respiratory epithelial cells using well-characterized antisera was initially reported in 2018. This review provides a summary of in vitro studies with icIgA on colocalization and neutralization of the above five viruses. Two other highly significant respiratory infectious agents with severe global impacts viz. SARS-2 virus (CoViD pandemic) and the intracellular bacterium-Mycobacterium tuberculosis-are discussed. Further studies will provide more detailed understanding of the mechanisms and kinetics of icIgA neutralization in relation to viral entry and early replication steps with a specific focus on mucosal infections. This will inform the design of more effective vaccines against infectious agents transmitted via the mucosal route.
Topics: Humans; Immunoglobulin A; Antibodies, Monoclonal; COVID-19; Cell Line; Immunity, Mucosal; Vaccines; Immunoglobulin A, Secretory; Receptors, Polymeric Immunoglobulin
PubMed: 36597220
DOI: 10.1111/sji.13253 -
International Immunology Nov 2021Dysbiosis is alterations in the microbial composition compared with a healthy microbiota and often features a reduction in gut microbial diversity and a change in... (Review)
Review
Dysbiosis is alterations in the microbial composition compared with a healthy microbiota and often features a reduction in gut microbial diversity and a change in microbial taxa. Dysbiosis, especially in the gut, has also been proposed to play a crucial role in the pathogenesis of a wide variety of diseases, including inflammatory bowel disease, colorectal cancer, cardiovascular disease, obesity, diabetes and multiple sclerosis. A body of evidence has shown that intestinal polymeric immunoglobulin A (IgA) antibodies are important to regulate the gut microbiota as well as to exclude pathogenic bacteria or viral infection such as influenza and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) at mucosal sites. Since the 1970s, trials for oral administration of therapeutic IgA or IgG have been performed mainly to treat infectious enteritis caused by pathogenic Escherichia coli or Clostridium difficile. However, few of them have been successfully developed for clinical application up to now. In addition to the protective function against intestinal pathogens, IgA is well known to modulate the gut commensal microbiota leading to symbiosis. Nevertheless, the development of therapeutic IgA drugs to treat dysbiosis is not progressing. In this review, the advantages of therapeutic IgA antibodies and the problems for their development will be discussed.
Topics: Animals; Bacteria; Dysbiosis; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Immunoglobulin A; Immunomodulating Agents; Inflammatory Bowel Diseases; Intestines; Species Specificity
PubMed: 34492105
DOI: 10.1093/intimm/dxab066 -
Mucosal Immunology Jan 2020The human intestine is densely colonized with commensal microbes that stimulate the immune system. While secretory Immunoglobulin (Ig) A is known to play a crucial role... (Review)
Review
The human intestine is densely colonized with commensal microbes that stimulate the immune system. While secretory Immunoglobulin (Ig) A is known to play a crucial role in gut microbiota compartmentalization, secretory IgM, and systemic IgG have recently been highlighted in host-microbiota interactions as well. In this review, we discuss important aspects of secretory IgA biology, but rather than focusing on mechanistic aspects of IgA impact on microbiota, we stress the current knowledge of systemic antibody responses to whole gut microbiota, in particular their generation, specificities, and function. We also provide a comprehensive picture of secretory IgM biology. Finally, therapeutic and diagnostic implications of these novel findings for the treatment of various diseases are outlined.
Topics: Animals; Gastrointestinal Microbiome; Homeostasis; Host Microbial Interactions; Humans; Immunity, Mucosal; Immunoglobulin A; Immunoglobulin A, Secretory; Intestinal Mucosa; Symbiosis
PubMed: 31413347
DOI: 10.1038/s41385-019-0192-y -
Advances in Clinical and Experimental... Apr 2020Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is the most common form of systemic vasculitis in children. Although the first... (Review)
Review
Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is the most common form of systemic vasculitis in children. Although the first case of IgAV was described more than 200 years ago, its etiology still remains unclear. Nephrological symptoms are observed in 30-50% of children during the course of the disease, and in up to 91% of cases within 6 weeks of the onset of the first symptoms. Whereas other organ manifestations of IgAV are mostly benign and self-limiting, nephritis may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Appropriate treatment commenced early enough can stop the disease progression. However, even in severe cases there are no evidence-based guidelines, which makes the therapeutic decisions more difficult. In this article, which is the most up-to-date overview regarding IgAV, we discuss the disease's pathogenesis, the clinical forms of renal involvement in the course of the disease, the risk factors for adverse prognosis and treatment options in accordance with current recommendations.
Topics: Child; Humans; IgA Vasculitis; Immunoglobulin A; Kidney; Nephritis; Vasculitis
PubMed: 32356414
DOI: 10.17219/acem/112566 -
ELife Oct 2020Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody, which binds pathogens and commensal microbes. SIgA is a polymeric antibody, typically containing...
Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody, which binds pathogens and commensal microbes. SIgA is a polymeric antibody, typically containing two copies of IgA that assemble with one joining-chain (JC) to form dimeric (d) IgA that is bound by the polymeric Ig-receptor ectodomain, called secretory component (SC). Here, we report the cryo-electron microscopy structures of murine SIgA and dIgA. Structures reveal two IgAs conjoined through four heavy-chain tailpieces and the JC that together form a β-sandwich-like fold. The two IgAs are bent and tilted with respect to each other, forming distinct concave and convex surfaces. In SIgA, SC is bound to one face, asymmetrically contacting both IgAs and JC. The bent and tilted arrangement of complex components limits the possible positions of both sets of antigen-binding fragments (Fabs) and preserves steric accessibility to receptor-binding sites, likely influencing antigen binding and effector functions.
Topics: Animals; Cell Line; Cryoelectron Microscopy; Humans; Immunoglobulin A; Immunoglobulin A, Secretory; Mice; Models, Molecular; Protein Conformation; Secretory Component
PubMed: 33107820
DOI: 10.7554/eLife.56098 -
Frontiers in Immunology 2023Significant progress has been made in the elucidation of human antibody repertoires. Furthermore, non-canonical functions of antibodies have been identified that reach... (Review)
Review
Significant progress has been made in the elucidation of human antibody repertoires. Furthermore, non-canonical functions of antibodies have been identified that reach beyond classical functions linked to protection from pathogens. Polyclonal immunoglobulin preparations such as IVIG and SCIG represent the IgG repertoire of the donor population and will likely remain the cornerstone of antibody replacement therapy in immunodeficiencies. However, novel evidence suggests that pooled IgA might promote orthobiotic microbial colonization in gut dysbiosis linked to mucosal IgA immunodeficiency. Plasma-derived polyclonal IgG and IgA exhibit immunoregulatory effects by a diversity of different mechanisms, which have inspired the development of novel drugs. Here we highlight recent insights into IgG and IgA repertoires and discuss potential implications for polyclonal immunoglobulin therapy and inspired drugs.
Topics: Humans; Immunoglobulins, Intravenous; Immunoglobulin G; Antibody Diversity; Immunologic Deficiency Syndromes; Immunization, Passive; Immunoglobulin A
PubMed: 37063852
DOI: 10.3389/fimmu.2023.1166821