The inflammatory function of human IgA - PubMed (original) (raw)

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The inflammatory function of human IgA

Ivo S Hansen et al. Cell Mol Life Sci. 2019 Mar.

Abstract

The prevailing concept regarding the immunological function of immunoglobulin A (IgA) is that it binds to and neutralizes pathogens to prevent infection at mucosal sites of the body. However, recently, it has become clear that in humans IgA is also able to actively contribute to the initiation of inflammation, both at mucosal and non-mucosal sites. This additional function of IgA is initiated by the formation of immune complexes, which trigger Fc alpha Receptor I (FcαRI) to synergize with various other receptors to amplify inflammatory responses. Recent findings have demonstrated that co-stimulation of FcαRI strongly affects pro-inflammatory cytokine production by various myeloid cells, including different dendritic cell subsets, macrophages, monocytes, and Kupffer cells. FcαRI-induced inflammation plays a crucial role in orchestrating human host defense against pathogens, as well as the generation of tissue-specific immunity. In addition, FcαRI-induced inflammation is suggested to be involved in the pathogenesis of various chronic inflammatory disorders, including inflammatory bowel disease, celiac disease, and rheumatoid arthritis. Combined, IgA-induced inflammation may be used to either promote inflammatory responses, e.g. in the context of cancer therapy, but may also provide new therapeutic targets to counteract chronic inflammation in the context of various chronic inflammatory disorders.

Keywords: Autoimmunity; Cytokines; FcαRI; Inflammation; Myeloid cells.

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Conflict of interest statement

D.L.P.B. is an employee of UCB.

Figures

Fig. 1

Fig. 1

The human Fc receptor family. a IgA molecules consist of two domains, which are linked by a hinge region. IgA2 molecules have a shorter hinge region than IgA1, leading to a more Y-shaped conformation. The antigen-binding domain (Fab) binds to antigens, while the crystallizable fragment (Fc) domain can be recognized by Fc receptors. Furthermore, one molecule is made up of two identical heavy chains (in blue) and two identical light chains (in green). IgA molecules can be expressed as dimers when the Fc domains are connected to each other by a joining (J) chain. b Human FcRs are divided according to their binding capability to antibody subtype, FcγR, FcεR, and FcαR. FcγRs can be further subdivided into three types: FcγRI, FcγRII, and FcγRIII, which can be grouped based on their binding affinity to IgG (with FcγRI being the only high-affinity receptor). FcαRI is genetically located on a distinct location apart from the other receptors. The human FcR family differs quite significantly from the mouse FcR family

Fig. 2

Fig. 2

Tissue-specific FcαRI-mediated control of cytokine production in homeostasis and infection. FcαRI mediates both inflammatory and immunosuppressive responses in a cell-type and tissue-specific manner. FcαRI directs cytokine production under different conditions. Homeostasis: in non-mucosal tissues, monomeric IgA recognition by FcαRI during homeostasis leads to inhibition of pro-inflammatory cytokine production through ITAMi-mediated SHP-1 recruitment. In intestinal immunity, CD103+ DCs tolerogenic conditioning leads to activation through PRRs, which results into induction of regulatory T cells and IL-10 production. Infection: bacterial infection IgA immune complex formation is recognized by FcαRI leading to cross-talk with PRRs and pro-inflammatory cytokine production in Kupffer cells, monocytes, and macrophages through Syk and PI3K-mediated up-regulation of transcription resulting in distinct expression of cytokines. Upon intestinal infection, IgA opsonization provides a second signal through FcαRI activating Syk, PI3K, and TBK1-IKKε, which increases the glycolytic flux and fatty acid synthesis (FAS) that results in an inflammatory response mediated by increased mRNA translation and caspase-1 activation

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