IgG4 antibodies from patients with asymptomatic bancroftian filariasis inhibit the binding of IgG1 and IgG2 to C1q in a Fc-Fc-dependent mechanism

Ulrich F Prodjinotho,Achim Hoerauf,Tomabu Adjobimey

doi:10.1007/s00436-019-06451-2

Abstract

A striking feature of lymphatic filariasis (LF) is the clinical heterogeneity among exposed individuals. While endemic normals (EN) remain free of infection despite constant exposure to the infective larvae, a small group of patients, generally microfilaria free (Mf-) develops severe pathology (CP) such as lymphedema or hydrocele. Another group of infected individuals remains asymptomatic while expressing large amounts of microfilariae (Mf+). This Mf+ group is characterized by an immune-suppressed profile with high levels of anti-inflammatory cytokines and elevated IgG4. This particular immunoglobulin is unable to activate the complement. The complement system plays a critical role in both innate and adaptive immunity. However, its importance and regulation during LF is not fully understood. Using affinity chromatography and solid-phase-enzyme-immunoassays, we investigated the ability of antibody isotypes from LF clinical groups to bind C1q, the first element of the complement’s classical pathway. The results indicate that while C1q is similarly expressed in all LF clinical groups, IgG1–2 in the plasma from Mf+ individuals presented significantly lower affinity to C1q compared to EN, Mf−, and CP. In addition, selective depletion of IgG4 significantly enhanced the affinity of IgG1–2 to C1q in Mf+ individuals. Strikingly, no effect was seen on the ability of IgG3 to bind C1q in the same conditions. More interestingly, papain-generated IgG4-Fc-portions interacted with Fc portions of IgG1–2 as revealed by far-western blot analysis. These data suggest that while being unable to bind C1q, IgG4 inhibits the first steps of the complement classical pathway by IgG1 or IgG2 via Fc-Fc interactions.

Highlights

Lymphatic filariasis (LF) is a major public health concern in tropical and subtropical countries
To find out whether differences exist in the affinity of the antibody isotypes from the plasma of Endemic normals (EN), Mf+, Mf−, and chronic pathology patients (CP) individuals to C1q, we investigated the capacity of each IgG subclass antibodies, IgE, and IgM in the plasma of individuals of the clinical groups to interact with C1q
Since pro-inflammatory antibodies in Mf+ displayed a reduced capacity to interact with C1q and because previous data have suggested anti-inflammatory properties for IgG4, we investigated whether IgG4 antibodies are involved in the low affinity of IgG1and IgG2 to C1q in Mf+ individuals

Summary

Introduction

Lymphatic filariasis (LF) is a major public health concern in tropical and subtropical countries. A variety of clinical phenotypes are present. Endemic normals (EN) are clinically asymptomatic and presented no sign of infection, while asymptomatic microfilaraemics (Mf+) present circulating microfilaria but no sign of overt disease. Chronic pathology patients (CP) present severe disease manifestations such as hydrocoele, lymphedema, or elephantiasis (Babu and Nutman 2012; Simonsen et al 2013). These outcomes are tightly linked to the host’s immune reactivity. Th2-type immunity involves a cellular mobilization with an appropriate humoral response that includes secreted

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Conclusion