Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes

Abstract

A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fcγ-receptor signalling. The activation of Fcγ receptors usually leads to phagocytosis. Paradoxically, the ligation of monocyte or macrophage Fcγ receptors by IgG immune complexes, rather than aiding host defences, can suppress innate immunity, increase production of interleukin 10, and bias T-helper-1 (Th1) responses to Th2 responses, leading to increased infectious output by infected cells. This intrinsic antibody-dependent enhancement (ADE) of infection modulates the severity of diseases as disparate as dengue haemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes.

Figure 1

Pathways by which toll-like-receptor signals and ligation of Fcγ receptor lead to the production of interleukin 10 (A) Toll-like receptors (TLRs) signal through the adaptor molecule myeloid differentiation primary response gene (MyD88) to activate a kinase cascade, resulting in the activation of nuclear factor κB (NFκB) and p38. This pathway leads to the activation of transcription factors that have the potential to bind to the interleukin 10 promoter. In resting cells, this promoter is inaccessible to these transcription factors because it is tightly packed in chromatin. (B) The ligation of Fcγ receptors signals through a different protein kinase, Syk, to activate extracellular signal-regulated kinase (ERK). This pathway leads to the phosphorylation of chromatin, making the promoter accessible to transcription factors. IRAK= interleukin-1 receptor associated kinase. TRAF6=TNF receptor-associated factor 6. IκK=IκB kinase. NEMO=NFκB essential modulator. PKC=protein kinase C.

Figure 2

Intrinsic ADE of dengue virus infection in THP-1 human monocytic cells Attachment and entry of infectious virus–antibody complexes into Fc receptor-bearing cells results in increased production of virus by inhibition of type I interferon and production of proinflammatory cytokines. Additionally, interleukin-10 biosynthesis is activated, stimulating members of the suppressor of cytokine signalling (SOCS) family, which results in suppression of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) signalling pathway and bias towards a Th2 response. By contrast, infection by naked virus via virus-specific receptor signals through pattern recognition receptor (PRRs) produces intracellular antiviral molecules. ADE=antibody-dependent enhancement. Th2=T helper 2. DENV=dengue virus.