scholarly journals Absence of Epithelial Immunoglobulin a Transport, with Increased Mucosal Leakiness, in Polymeric Immunoglobulin Receptor/Secretory Component–Deficient Mice

1999 ◽  
Vol 190 (7) ◽  
pp. 915-922 ◽  
Author(s):  
Finn-Eirik Johansen ◽  
Marcela Pekna ◽  
Inger Natvig Norderhaug ◽  
Bjørn Haneberg ◽  
Max Albert Hietala ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Epithelial Transport ◽  
Serum Proteins ◽  
Immunoglobulin A ◽  
Secretory Component ◽  
Epithelial Barrier Function ◽  
Immunoglobulin Receptor ◽  
Mucosal Surfaces ◽  
Gluten Sensitive Enteropathy ◽  
Mucosal Homeostasis

Mucosal surfaces are protected specifically by secretory immunoglobulin A (SIgA) and SIgM generated through external translocation of locally produced dimeric IgA and pentameric IgM. Their active transport is mediated by the epithelial polymeric Ig receptor (pIgR), also called the transmembrane secretory component. Paracellular passive external transfer of systemic and locally produced antibodies also provides mucosal protection, making the biological importance of secretory immunity difficult to assess. Here we report complete lack of active external IgA and IgM translocation in pIgR knockout mice, indicating no redundancy in epithelial transport mechanisms. The knockout mice were of normal size and fertility but had increased serum IgG levels, including antibodies to Escherichia coli, suggesting undue triggering of systemic immunity. Deterioration of their epithelial barrier function in the absence of SIgA (and SIgM) was further attested to by elevated levels of albumin in their saliva and feces, reflecting leakage of serum proteins. Thus, SIgA did not appear to be essential for health under the antigen exposure conditions of these experimental animals. Nevertheless, our results showed that SIgA contributes to maintenance of mucosal homeostasis. Production of SIgA might therefore be a variable in the initiation of human immunopathology such as inflammatory bowel disease or gluten-sensitive enteropathy.

scholarly journals Structural insights into secretory immunoglobulin A and its interaction with a pneumococcal adhesin

2020 ◽  
Author(s):  
Yuxin Wang ◽  
Guopeng Wang ◽  
Yaxin Li ◽  
Hao Shen ◽  
Huarui Chu ◽  
...  
Keyword(s):  
Specific Interaction ◽  
Immunoglobulin A ◽  
Underlying Mechanism ◽  
Secretory Component ◽  
Secretory Immunoglobulin A ◽  
Immunoglobulin Receptor ◽  
J Chain ◽  
Cryo Electron Microscopy ◽  
Structural Insights ◽  
Secretory Immunoglobulin

AbstractSecretory Immunoglobulin A (SIgA) is the most abundant antibody at the mucosal surface. SIgA possesses two additional subunits besides IgA: the joining chain (J-chain) and secretory component (SC). SC is the ectodomain of the polymeric immunoglobulin receptor (pIgR), which functions to transport IgA to the mucosa. The underlying mechanism of how the J-chain and pIgR/SC facilitates the assembly and secretion of SIgA remains to be understood. During the infection of Streptococcus pneumoniae, a pneumococcal adhesin SpsA hijacks SIgA and unliganded pIgR/SC to evade host defense and gain entry to human cells. How SpsA specifically targets SIgA and pIgR/SC also remains unclear. Here we report a cryo-electron microscopy structure of the Fc region of human IgA1 (Fcα) in complex with J-chain and SC (Fcα-J-SC), which reveals the organization principle of SIgA. We also present the structure of Fcα-J-SC in complex with SpsA, which uncovers the specific interaction between SpsA and human pIgR/SC. These results advance the molecular understanding of SIgA and shed light on the pathogenesis of S. pneumoniae.

Production and Function of Immunoglobulin A

2021 ◽  
Vol 39 (1) ◽  
pp. 695-718
Author(s):  
Timothy W. Hand ◽  
Andrea Reboldi
Keyword(s):  
Immunoglobulin A ◽  
Intestinal Bacteria ◽  
Secretory Component ◽  
Cross Reactivity ◽  
Antigen Binding ◽  
Effector Functions ◽  
Mucosal Surfaces ◽  
Enteric Infections ◽  
And Function ◽  
Exquisite Specificity

Among antibodies, IgA is unique because it has evolved to be secreted onto mucosal surfaces. The structure of IgA and the associated secretory component allow IgA to survive the highly proteolytic environment of mucosal surfaces but also substantially limit IgA's ability to activate effector functions on immune cells. Despite these characteristics, IgA is critical for both preventing enteric infections and shaping the local microbiome. IgA's function is determined by a distinct antigen-binding repertoire, composed of antibodies with a variety of specificities, from permissive polyspecificity to cross-reactivity to exquisite specificity to a single epitope, which act together to regulate intestinal bacteria. Development of the unique function and specificities of IgA is shaped by local cues provided by the gut-associated lymphoid tissue, driven by the constantly changing environment of the intestine and microbiota.

Structure of the secretory immunoglobulin A core

Science ◽  
2020 ◽  
Vol 367 (6481) ◽  
pp. 1008-1014 ◽  
Author(s):  
Nikit Kumar ◽  
Christopher P. Arthur ◽  
Claudio Ciferri ◽  
Marissa L. Matsumoto
Keyword(s):  
Immunoglobulin A ◽  
Secretory Component ◽  
Polymeric Immunoglobulin Receptor ◽  
Secretory Immunoglobulin A ◽  
First Line ◽  
Immunoglobulin Receptor ◽  
Host Protection ◽  
Luminal Side ◽  
Mucosal Pathogens ◽  
Secretory Immunoglobulin

Secretory immunoglobulin A (sIgA) represents the immune system’s first line of defense against mucosal pathogens. IgAs are transported across the epithelium, as dimers and higher-order polymers, by the polymeric immunoglobulin receptor (pIgR). Upon reaching the luminal side, sIgAs mediate host protection and pathogen neutralization. In recent years, an increasing amount of attention has been given to IgA as a novel therapeutic antibody. However, despite extensive studies, sIgA structures have remained elusive. Here, we determine the atomic resolution structures of dimeric, tetrameric, and pentameric IgA-Fc linked by the joining chain (JC) and in complex with the secretory component of the pIgR. We suggest a mechanism in which the JC templates IgA oligomerization and imparts asymmetry for pIgR binding and transcytosis. This framework will inform the design of future IgA-based therapeutics.

scholarly journals IgA: Structure, Function, and Developability

Antibodies ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 57 ◽  
Author(s):  
Patrícia de Sousa-Pereira ◽  
Jenny M. Woof
Keyword(s):  
Monoclonal Antibodies ◽  
Structure Function ◽  
Immunoglobulin A ◽  
Structural Features ◽  
The Other ◽  
Immune Defence ◽  
Major Site ◽  
Mucosal Surfaces ◽  
Serum Iga ◽  
Antibody Class

Immunoglobulin A (IgA) plays a key role in defending mucosal surfaces against attack by infectious microorganisms. Such sites present a major site of susceptibility due to their vast surface area and their constant exposure to ingested and inhaled material. The importance of IgA to effective immune defence is signalled by the fact that more IgA is produced than all the other immunoglobulin classes combined. Indeed, IgA is not just the most prevalent antibody class at mucosal sites, but is also present at significant concentrations in serum. The unique structural features of the IgA heavy chain allow IgA to polymerise, resulting in mainly dimeric forms, along with some higher polymers, in secretions. Both serum IgA, which is principally monomeric, and secretory forms of IgA are capable of neutralising and removing pathogens through a range of mechanisms, including triggering the IgA Fc receptor known as FcαRI or CD89 on phagocytes. The effectiveness of these elimination processes is highlighted by the fact that various pathogens have evolved mechanisms to thwart such IgA-mediated clearance. As the structure–function relationships governing the varied capabilities of this immunoglobulin class come into increasingly clear focus, and means to circumvent any inherent limitations are developed, IgA-based monoclonal antibodies are set to emerge as new and potent options in the therapeutic arena.

279 Changes in Mucosal Homeostasis Leading to Hypersensitivity to Mucosal Injury in NHE3 Knockout Mice

2009 ◽  
Vol 136 (5) ◽  
pp. A-54
Author(s):  
Daniel Laubitz ◽  
Claire B. Larmonier ◽  
Monica T. Midura-Kiela ◽  
Robert D. Thurston ◽  
Pawel R. Kiela ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Mucosal Injury ◽  
Mucosal Homeostasis

scholarly journals Correlations between Antibody Immune Responses at Different Mucosal Effector Sites Are Controlled by Antigen Type and Dosage

2000 ◽  
Vol 68 (7) ◽  
pp. 3830-3839 ◽  
Author(s):  
Dörthe Externest ◽  
Barbara Meckelein ◽  
M. Alexander Schmidt ◽  
Andreas Frey
Keyword(s):  
Cholera Toxin ◽  
Plasma Cells ◽  
Immunoglobulin A ◽  
Secretory Iga ◽  
Enzyme Linked Immunosorbent Assay ◽  
Routine Diagnostics ◽  
Significant Relationships ◽  
Serum Igg ◽  
Mucosal Surfaces ◽  
Secretory Immunoglobulin

ABSTRACT Monitoring specific secretory immunoglobulin A (IgA) responses in the intestines after mucosal immunization or infection is impeded by the fact that sampling of small intestinal secretions requires invasive methods not feasible for routine diagnostics. Since IgA plasma cells generated after intragastric immunization are known to populate remote mucosal sites as well, secretory IgA responses at other mucosal surfaces may correlate to those in the intestines and could serve as proxy measures for IgA secretion in the gut. To evaluate the practicability of this approach, mice were immunized intragastrically with 0.2, 2, and 20 mg of ovalbumin plus 10 μg of cholera toxin, and the antigen-specific local secretory IgA responses in duodenal, ileal, jejunal, rectal, and vaginal secretions, saliva, urine, and feces, as well as serum IgG and IgA responses were analyzed by enzyme-linked immunosorbent assay. Correlation analysis revealed significant relationships between serum IgG and IgA, urinary IgA, salivary IgA, and secretory IgA in duodenal, jejunal, ileal, and rectal secretions for the 0.2-mg but not for the 20-mg ovalbumin dose. Fecal samples were poor predictors for intestinal antiovalbumin IgA responses, and no correlations could be established for cholera toxin, neither between local anti-cholera toxin levels nor to the antiovalbumin responses. Thus, specific IgA in serum, saliva, or urine can serve as a predictor of the release of specific IgA at intestinal surfaces after intragastric immunization, but the lack of correlations for high ovalbumin doses and for cholera toxin indicates a strong dependency on antigen type and dosage for these relationships.

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