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

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.

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Structure of the secretory immunoglobulin A core

Science ◽

10.1126/science.aaz5807 ◽

2020 ◽

Vol 367 (6481) ◽

pp. 1008-1014 ◽

Cited By ~ 20

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.

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Reduction in the Quantity of the Polymeric Immunoglobulin Receptor Is Sufficient to Account for the Low Concentration of Intestinal Secretory Immunoglobulin A in a Weanling Mouse Model of Wasting Protein-Energy Malnutrition

Journal of Nutrition ◽

10.1093/jn/127.3.427 ◽

1997 ◽

Vol 127 (3) ◽

pp. 427-435 ◽

Cited By ~ 22

Author(s):

Choi-Lan Ha ◽

Bill Woodward

Keyword(s):

Mouse Model ◽

Protein Energy Malnutrition ◽

Immunoglobulin A ◽

Polymeric Immunoglobulin Receptor ◽

Secretory Immunoglobulin A ◽

Immunoglobulin Receptor ◽

Low Concentration ◽

Protein Energy ◽

Weanling Mouse ◽

Secretory Immunoglobulin

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Column enzyme immunoassay for secretory immunoglobulin A in serum.

Clinical Chemistry ◽

10.1093/clinchem/29.1.151 ◽

1983 ◽

Vol 29 (1) ◽

pp. 151-153 ◽

Cited By ~ 11

Author(s):

R Yamamoto ◽

S Kimura ◽

S Hattori ◽

Y Ishiguro ◽

K Kato

Keyword(s):

Enzyme Immunoassay ◽

Sodium Carbonate Solution ◽

Solid Phase ◽

Immunoglobulin A ◽

Enzyme Reaction ◽

Secretory Component ◽

Secretory Immunoglobulin A ◽

Serum Samples ◽

Sepharose 4B ◽

Secretory Immunoglobulin

Abstract This enzyme immunoassay for specific measurement of secretory immunoglobulin A concentrations in human serum involves use of a small chromatographic column as a solid-phase. Serum samples are incubated for 2 h with beta-D-galactosidase-labeled antibody to secretory component, then passed through a 0.1-mL Sepharose 4B column containing antibodies to human immunoglobulin A. After the column is washed to remove the unbound label, the buffer in the column is replaced by a solution of o-nitrophenyl-beta-D-galactoside (a beta-D-galactosidase substrate) and incubated at 25 degrees C overnight. The enzyme reaction is stopped by washing the column with sodium carbonate solution, and the absorbance of the eluate is measured at 420 nm. The concentration of secretory immunoglobulin A can be determined with a minimum detectable sensitivity of 3 mg/L, without interference from free immunoglobulin A and secretory component in the same samples.

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Clearance of Citrobacter rodentium Requires B Cells but Not Secretory Immunoglobulin A (IgA) or IgM Antibodies

Infection and Immunity ◽

10.1128/iai.72.6.3315-3324.2004 ◽

2004 ◽

Vol 72 (6) ◽

pp. 3315-3324 ◽

Cited By ~ 137

Author(s):

Christian Maaser ◽

Michael P. Housley ◽

Mitsutoshi Iimura ◽

Jennifer R. Smith ◽

Bruce A. Vallance ◽

...

Keyword(s):

B Cells ◽

Host Defense ◽

Immunoglobulin A ◽

Mucosal Inflammation ◽

Secretory Immunoglobulin A ◽

J Chain ◽

Crypt Hyperplasia ◽

Deficient Mice ◽

Secretory Antibodies ◽

Secretory Immunoglobulin

ABSTRACT Citrobacter rodentium, a murine model pathogen for human enteropathogenic Escherichia coli, predominantly colonizes the lumen and mucosal surface of the colon and cecum and causes crypt hyperplasia and mucosal inflammation. Mice infected with C. rodentium develop a secretory immunoglobulin A (IgA) response, but the role of B cells or secretory antibodies in host defense is unknown. To address this question, we conducted oral C. rodentium infections in mice lacking B cells, IgA, secreted IgM, polymeric Ig receptor (pIgR), or J chain. Normal mice showed peak bacterial numbers in colon and feces at 1 week and bacterial eradication after 3 to 4 weeks. B-cell-deficient mice were equally susceptible initially but could not control infection subsequently. Tissue responses showed marked differences, as infection of normal mice was accompanied by transient crypt hyperplasia and mucosal inflammation in the colon and cecum at 2 but not 6 weeks, whereas B-cell-deficient mice had few mucosal changes at 2 weeks but severe epithelial hyperplasia with ulcerations and mucosal inflammation at 6 weeks. The functions of B cells were not mediated by secretory antibodies, since mice lacking IgA or secreted IgM or proteins required for their transport into the lumen, pIgR or J chain, cleared C. rodentium normally. Nonetheless, systemic administration of immune sera reduced bacterial numbers significantly in normal and pIgR-deficient mice, and depletion of IgG abrogated this effect. These results indicate that host defense against C. rodentium depends on B cells and IgG antibodies but does not require production or transepithelial transport of IgA or secreted IgM.

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