Immunoglobulin A: magic bullet or Trojan horse?

Heineke, Marieke H.; Egmond, Marjolein van

doi:10.1111/eci.12716

Cited by 50 publications

(50 citation statements)

References 75 publications

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“…A small number of research groups have recently focused on IgA and FcαRI engagement to treat cancer . Whereas most research has focused on IgG in mAb therapy because of potent antitumor mechanisms including complement activation and natural killer cell‐mediated ADCC, IgA appears to be potent in the recruitment and activation of neutrophils via the FcαRI to kill tumors, providing an attractive target for mAb antitumor therapy .…”

Section: Antitumor Role Of Igamentioning

confidence: 99%

“…Whereas most research has focused on IgG in mAb therapy because of potent antitumor mechanisms including complement activation and natural killer cell‐mediated ADCC, IgA appears to be potent in the recruitment and activation of neutrophils via the FcαRI to kill tumors, providing an attractive target for mAb antitumor therapy . Several neutrophil IgA‐mediated antitumor functions have been described in vitro , such as ADCC, phagocytosis, immune cell recruitment, release of cytotoxic molecules and induction of necrosis . Target‐specific IgA mAbs enable formation of an immunological synapse by bringing neutrophils and target tumor cells together to enhance killing (Figure ).…”

Section: Antitumor Role Of Igamentioning

confidence: 99%

“…IgA autoantibodies have been reported as the mediator for several diseases including IgA nephropathy (elevated IgA levels), rheumatoid arthritis, coeliac disease and various IgA‐associated skin diseases reviewed by Heineke and van Egmond …”

Section: Virusesmentioning

confidence: 99%

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Serum IgA Fc effector functions in infectious disease and cancer

et al. 2020

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Immunoglobulin (Ig) A is the most abundant antibody isotype present at mucosal surfaces and the second most abundant in human serum. In addition to preventing pathogen entry at mucosal surfaces, IgA can control and eradicate bacterial and viral infections through a variety of antibody-mediated innate effector cell mechanisms. The role of mucosal IgA in infection (e.g. neutralization) and in inflammatory homeostasis (e.g. allergy and autoimmunity) has been extensively investigated; by contrast, serum IgA is comparatively understudied. IgA binding to fragment crystallizable alpha receptor plays a dual role in the activation and inhibition of innate effector cell functions. Mounting evidence suggests that serum IgA induces potent effector functions against various bacterial and some viral infections including Neisseria meningitidis and rotavirus. Furthermore, in the era of immunotherapy, serum IgA provides an interesting alternative to classical IgG monoclonal antibodies to treat cancer and infectious pathogens. Here we discuss the role of serum IgA in infectious diseases with reference to bacterial and viral infections and the potential for IgA as a monoclonal antibody therapy.

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Section: Antitumor Role Of Igamentioning

confidence: 99%

Section: Antitumor Role Of Igamentioning

confidence: 99%

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Serum IgA Fc effector functions in infectious disease and cancer

et al. 2020

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“…A polyclonal response targeting different epitopes will thus favor the generation of high avidity complexes with higher receptor‐crosslinking potential. Granulocytes can arm themselves with antibodies binding to their high‐affinity receptors, FcαRI, 27 FcγRI 28 , 29 and FcεRI, and degrade target antigen following receptor crosslinkage, phagocytosis or exocytosis.…”

Section: Fcr‐mediated Effector Functionsmentioning

confidence: 99%

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions

Prechl¹

2017

Clin & Trans Imm

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The homeostasis of antibodies can be characterized as a balanced production, target-binding and receptor-mediated elimination regulated by an interaction network, which controls B-cell development and selection. Recently, we proposed a quantitative model to describe how the concentration and affinity of interacting partners generates a network. Here we argue that this physical, quantitative approach can be extended for the interpretation of effector functions of antibodies. We define global antibody equilibrium as the zone of molar equivalence of free antibody, free antigen and immune complex concentrations and of dissociation constant of apparent affinity: [Ab]=[Ag]=[AbAg]=KD. This zone corresponds to the biologically relevant KD range of reversible interactions. We show that thermodynamic and kinetic properties of antibody–antigen interactions correlate with immunological functions. The formation of stable, long-lived immune complexes correspond to a decrease of entropy and is a prerequisite for the generation of higher-order complexes. As the energy of formation of complexes increases, we observe a gradual shift from silent clearance to inflammatory reactions. These rules can also be applied to complement activation-related immune effector processes, linking the physicochemical principles of innate and adaptive humoral responses. Affinity of the receptors mediating effector functions shows a wide range of affinities, allowing the continuous sampling of antibody-bound antigen over the complete range of concentrations. The generation of multivalent, multicomponent complexes triggers effector functions by crosslinking these receptors on effector cells with increasing enzymatic degradation potential. Thus, antibody homeostasis is a thermodynamic system with complex network properties, nested into the host organism by proper immunoregulatory and effector pathways. Maintenance of global antibody equilibrium is achieved by innate qualitative signals modulating a quantitative adaptive immune system, which regulates molecular integrity of the host by tuning the degradation and recycling of molecules from silent removal to inflammatory elimination.

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“…This consists of commensal or pathogen bacteria coating by respectively low-or high-affinity IgA, controlling their entrance across the intestinal epithelium. Nevertheless, in addition to this antiinflammatory function, dIgA and SIgA were recently described as pro-inflammatory actors in mucosa by recruiting neutrophils [12,13] or by transporting mucosal Ag to APC such as macrophages and DC in the lamina propria or Peyer's patches. In such case, inflammation can be induced after IgA recognition by receptors such as the transferrin receptor (transferrinRCD71) [1].…”

Section: Introductionmentioning

confidence: 99%

Impact of IgA isoforms on their ability to activate dendritic cells and to prime T cells

et al. 2020

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Human IgA could be from different isotypes (IgA1/IgA2) and/or isoforms (monomeric, dimeric, or secretory). Monomeric IgA mainly IgA1 are considered as an anti‐inflammatory isotype whereas dimeric/secretory IgA have clearly dual pro‐ and anti‐inflammatory effects. Here, we show that IgA isotypes and isoforms display different binding abilities to FcαRI, Dectin‐1, DC‐SIGN, and CD71 on monocyte‐derived dendritic cells (moDC). We describe that IgA regulate the expression of their own receptors and trigger modulation of moDC maturation. We also demonstrate that dimeric IgA2 and IgA1 induce different inflammatory responses leading to cytotoxic CD8+ T cells activation. moDC stimulation by dimeric IgA2 was followed by a strong pro‐inflammatory effect. Our study highlights differences regarding IgA isotypes and isoforms in the context of DC conditioning. Further investigations are needed on the activation of adaptive immunity by IgA in the context of microbiota/IgA complexes during antibody‐mediated immune selection.

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Immunoglobulin A: magic bullet or Trojan horse?

Cited by 50 publications

References 75 publications

Serum IgA Fc effector functions in infectious disease and cancer

Serum IgA Fc effector functions in infectious disease and cancer

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions

Impact of IgA isoforms on their ability to activate dendritic cells and to prime T cells

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