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.

scholarly journals The structures of secretory and dimeric immunoglobulin A

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sonya Kumar Bharathkar ◽  
Benjamin W Parker ◽  
Andrey G Malyutin ◽  
Nandan Haloi ◽  
Kathryn E Huey-Tubman ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Heavy Chain ◽  
Binding Sites ◽  
Immunoglobulin A ◽  
Secretory Component ◽  
Antigen Binding ◽  
Effector Functions ◽  
Cryo Electron Microscopy ◽  
Mucosal Antibody ◽  
Steric Accessibility

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.

scholarly journals The Structures of Secretory and Dimeric Immunoglobulin A

2020 ◽  
Author(s):  
Sonya Kumar Bharathkar ◽  
Benjamin W. Parker ◽  
Andrey G. Malyutin ◽  
Nandan Haloi ◽  
Kathryn E. Huey-Tubman ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Heavy Chain ◽  
Binding Sites ◽  
Immunoglobulin A ◽  
Secretory Component ◽  
Antigen Binding ◽  
Effector Functions ◽  
Cryo Electron Microscopy ◽  
Mucosal Antibody ◽  
Steric Accessibility

AbstractSecretory (S) Immunoglobulin (I) 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.

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 Detection of cross-reactive immunoglobulin A against the severe acute respiratory syndrome-coronavirus-2 spike 1 subunit in saliva

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0249979
Author(s):  
Keiichi Tsukinoki ◽  
Tatsuo Yamamoto ◽  
Keisuke Handa ◽  
Mariko Iwamiya ◽  
Juri Saruta ◽  
...  
Keyword(s):  
Breast Milk ◽  
Immunoglobulin A ◽  
Cross Reactivity ◽  
University Hospital ◽  
Enzyme Linked Immunosorbent Assay ◽  
Angiotensin Converting Enzyme 2 ◽  
Mucosal Surfaces ◽  
Polymerase Chain ◽  
The Cross ◽  
Age Range

Abundant secretory immunoglobulin A (SIgA) in the mucus, breast milk, and saliva provides immunity against infection of mucosal surfaces. Pre-pandemic breast milk samples containing SIgA have been reported to cross-react with SARS-CoV-2; however, it remains unknown whether SIgA showing the cross-reaction with SARS-CoV-2 exists in saliva. We aimed to clarify whether SIgA in saliva cross-reacts with SARS-CoV-2 spike 1 subunit in individuals who have not been infected with this virus. The study involved 137 (men, n = 101; women, n = 36; mean age, 38.7; age range, 24–65 years) dentists and doctors from Kanagawa Dental University Hospital. Saliva and blood samples were analyzed by polymerase chain reaction (PCR) and immunochromatography for IgG and IgM, respectively. We then identified patients with saliva samples that were confirmed to be PCR-negative and IgM-negative for SARS-CoV-2. The cross-reactivity of IgA-positive saliva samples with SARS-CoV-2 was determined by enzyme-linked immunosorbent assay using a biotin-labeled spike recombinant protein (S1-mFc) covering the receptor-binding domain of SARS-CoV-2. The proportion of SARS-CoV-2 cross-reactive IgA-positive individuals was 46.7%, which correlated negatively with age (r = –0.218, p = 0.01). The proportion of IgA-positive individuals aged ≥50 years was significantly lower than that of patients aged ≤49 years (p = 0.008). SIgA was purified from the saliva of patients, which could partially suppress the binding of SARS-CoV-2 spike protein to the angiotensin converting enzyme-2 receptor. This study demonstrates the presence of SARS-CoV-2 cross-reactive SIgA in the saliva of individuals who had never been infected with the virus, suggesting that SIgA may help prevent SARS-CoV-2 infection.

scholarly journals CRISPR-targeted display of functional T cell receptors enables engineering of enhanced specificity and prediction of cross-reactivity

2020 ◽  
Author(s):  
Rodrigo Vazquez-Lombardi ◽  
Johanna S. Jung ◽  
Florian Bieberich ◽  
Edo Kapetanovic ◽  
Erik Aznauryan ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Poor Correlation ◽  
Naturally Occurring ◽  
Human T Cell ◽  
And Function ◽  
Exquisite Specificity ◽  
Human T Cell Line ◽  
Cancer Testis

ABSTRACTT cell receptor (TCR) gene therapy is a promising cell therapy approach for the treatment of cancer. However, most naturally occurring TCRs display low affinities to their peptide-MHC targets, and engineering of TCRs for enhanced affinity is complicated by the risk of introducing cross-reactivity and the poor correlation between affinity and function. Here we report the establishment of the TCR-accepting T cell (TnT) platform through five sequential CRISPR-Cas9 genome editing steps of a human T cell line, and demonstrate its application for functional engineering of TCRs and prediction of cross-reactivity. Using the TnT platform, we profile the mutational landscapes of tumor-specific TCRs at high-throughput to reveal a substantial discordance between antigen binding and antigen-induced signaling. Furthermore, we combine CRISPR-targeting, functional selection and deep sequencing to screen TCR mutagenesis libraries and identify variants with enhanced recognition of the cancer-testis antigen MAGE-A3. Finally, functional cross-reactivity profiling using TnT cells was able to accurately predict off-targets and identify engineered TCRs with exquisite specificity to MAGE-A3. Thus, the TnT platform represents a valuable technology for the engineering of TCRs with enhanced functional and safety profiles.

scholarly journals Non‐specific lipid‐transfer proteins: Allergen structure and function, cross‐reactivity, sensitization, and epidemiology

2021 ◽  
Vol 11 (3) ◽  
Author(s):  
Isabel J. Skypala ◽  
Ricardo Asero ◽  
Domingo Barber ◽  
Lorenzo Cecchi ◽  
Arazeli Diaz Perales ◽  
...  
Keyword(s):  
Cross Reactivity ◽  
Structure And Function ◽  
Lipid Transfer ◽  
Lipid Transfer Proteins ◽  
Allergen Structure ◽  
And Function ◽  
Specific Lipid

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.

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