Induction of immunoglobulin G4 in human filariasis: an indicator of immunoregulation

Abstract

Filarial parasites are known to induce a large range of immunoregulatory mechanisms, including the induction of alternatively activated macrophages and regulatory T cells. These mechanisms are used to evade and down-modulate the host's immune system, to support parasite survival. Several reports have focused on some of these mechanisms, in humans and murine models, but the complex immunoregulatory networks associated with filarial infections remain unclear. Recent publications have conferred a role for regulatory T cells in the ability of helminth parasites to modulate human immune responses, such cells promoting the induction of the non-complement-fixing immunoglobulin G4 (IgG4). High plasma concentrations of IgG4 have been reported in hypo-responsive and asymptomatic cases of helminth infection. In both human lymphatic filariasis and onchocerciasis, the asymptomatic infections are characterised by high plasma concentrations of IgG4 (compared with those of IgE) and of the complement-fixing antibodies IgG1, IgG2 and IgG3. In asymptomatic filarial infection, elevations in IgG4 are also often associated with high worm loads and with high plasma levels of the immunomodulatory interleukin-10. Here, various aspects of the induction of IgG4 in humans and it roles in the immunomodulation of the human responses to filarial parasites are reviewed.

FIG

Simplified view of the induction and regulatory properties of IgG4 in human filariasis. Adult filarial parasites produce microfilariae (MF) that are responsible for the recruitment and induction of Foxp3(+) and interleukin‐10‐producing regulatory T cells (Treg), probably by the manipulation of antigen‐presenting cells (APC). Natural CD4(+)CD25(+)FOXP3(+) Treg and antigen‐induced, interleukin‐10‐producing, regulatory cells of type 1 (Tr1) interact with B cells and enhance the production of non‐cytolytic IgG4 while inhibiting the induction of other IgG and IgE. This humoral regulation contributes to the avoidance of pathology [e.g. filarial lymphoedema, onchocercal dermatitis, keratitis and tropical pulmonary eosinophilia (TPE)]. In the absence of immunoregulation, immunocompetent APC activate effector T‐cells (Th) which, in turn, induce B cells to produce cytolytic IgG1, IgG2, IgG3 and IgE. These antibodies induce various effector mechanisms (such as complement activation and antibody‐dependent cell‐mediated cytotoxicity), provoking parasite death and the release of antigens from endosymbobiotic Wolbachia. These bacterial antigens contribute to the induction of a strong immune reaction and to the subsequent development of pathology. IL‐10, Interleukin‐10; TGF‐β, tumour growth factor‐β; IL‐12, interleukin‐12; IFN‐γ, interferon‐γ; IL‐4, interleukin‐4.