Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells

Bidgood, Susanna R.; Tam, Jerry C. H.; McEwan, William A.; Mallery, Donna L.; James, Leo C.

doi:10.1073/pnas.1410980111

Cited by 71 publications

(75 citation statements)

References 33 publications

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“…The binding of TRIM21 itself to antibody occurs with high affinity and only a few antibodies are necessary to provoke a neutralization response11. TRIM21 has highest affinity for IgG but is also capable of binding IgM and IgA, albeit with reduced affinity (17 μM and 50 μM respectively to monomeric PRYSPRY domain)12319. Given that full-length dimeric TRIM21 increases affinity to IgG by ~375-fold, the functional affinity to IgA and IgM is likely to be submicromolar.…”

Section: Discussionmentioning

confidence: 99%

Antibody-antigen kinetics constrain intracellular humoral immunity

Bottermann

Lode

Watkinson

et al. 2016

Sci Rep

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During infection with non-enveloped viruses, antibodies stimulate immunity from inside cells by activating the cytosolic Fc receptor TRIM21. This intracellular humoral response relies on opsonized viral particles reaching the cytosol intact but the antigenic and kinetic constraints involved are unknown. We have solved the structure of a potent TRIM21-dependent neutralizing antibody in complex with human adenovirus 5 hexon and show how these properties influence immune activity. Structure-guided mutagenesis was used to generate antibodies with 20,000-fold variation in affinity, on-rates that differ by ~50-fold and off-rates by >175-fold. Characterization of these variants during infection revealed that TRIM21-dependent neutralization and NFκB activation was largely unaffected by on-rate kinetics. In contrast, TRIM21 antiviral activity was exquisitely dependent upon off-rate, with sub-μM affinity antibodies nevertheless unable to stimulate signaling because of fast dissociation kinetics. These results define the antibody properties required to elicit an efficient intracellular immune response during viral infection.

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Section: Discussionmentioning

confidence: 99%

Antibody-antigen kinetics constrain intracellular humoral immunity

Bottermann

Lode

Watkinson

et al. 2016

Sci Rep

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“…While Fc receptors are highly selective in regard to isotype and subtype binding, TRIM21 not only binds IgG but also IgM and IgA (32,35). Interestingly, the binding site for TRIM21 on IgA and IgM overlaps with that of Fc a receptor I (FcaRI), Fca/l receptor, pIgR, as well as several pathogen-produced Fc receptors (61)(62)(63)(64)(65)(66)(67)(68).…”

Section: Trim21 Has Broad Antibody Isotype Specificitymentioning

confidence: 99%

TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity

Foss

Watkinson

Sandlie

et al. 2015

Immunological Reviews

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Antibodies are key molecules in the fight against infections. Although previously thought to mediate protection solely in the extracellular environment, recent research has revealed that antibody-mediated protection extends to the cytosolic compartment of cells. This postentry viral defense mechanism requires binding of the antibody to a cytosolic Fc receptor named tripartite motif containing 21 (TRIM21). In contrast to other Fc receptors, TRIM21 shows remarkably broad isotype specificity as it does not only bind IgG but also IgM and IgA. When viral pathogens coated with these antibody isotypes enter the cytosol, TRIM21 is rapidly recruited and efficient neutralization occurs before the virus has had the time to replicate. In addition, inflammatory signaling is induced. As such, TRIM21 acts as a cytosolic sensor that engages antibodies that have failed to protect against infection in the extracellular environment. Here, we summarize our current understanding of how TRIM21 orchestrates humoral immunity in the cytosolic environment.

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“…In contrast, the binding of TRIM21 is pH independent and does not require protonation. TRIM21 is capable of binding all IgG subclasses with nM affinity (Keeble et al, 2008) and has also been shown to bind IgM (Mallery et al, 2010) and IgA (Bidgood et al, 2014), however with lower affinities of 17 and 50 μM, respectively.…”

Section: The Role Of Trim21 In Innate Immunitymentioning

confidence: 99%

Intracellular Antiviral Immunity

Bottermann

James

2018

Advances in Virus Research

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Innate immunity is traditionally thought of as the first line of defense against pathogens that enter the body. It is typically characterized as a rather weak defense mechanism, designed to restrict pathogen replication until the adaptive immune response generates a tailored response and eliminates the infectious agent. However, intensive research in recent years has resulted in better understanding of innate immunity as well as the discovery of many effector proteins, revealing its numerous powerful mechanisms to defend the host. Furthermore, this research has demonstrated that it is simplistic to strictly separate adaptive and innate immune functions since these two systems often work synergistically rather than sequentially. Here, we provide a broad overview of innate pattern recognition receptors in antiviral defense, with a focus on the TRIM family, and discuss their signaling pathways and mechanisms of action with special emphasis on the intracellular antibody receptor TRIM21.

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Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells

Cited by 71 publications

References 33 publications

Antibody-antigen kinetics constrain intracellular humoral immunity

Antibody-antigen kinetics constrain intracellular humoral immunity

TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity

Intracellular Antiviral Immunity

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