Pathological manifestations in lymphatic filariasis correlate with lack of inhibitory properties of IgG4 antibodies on IgE-activated granulocytes

Abstract

Helminth parasites are known to be efficient modulators of their host’s immune system. To guarantee their own survival, they induce alongside the classical Th2 a strong regulatory response with high levels of anti-inflammatory cytokines and elevated plasma levels of IgG4. This particular antibody was shown in different models to exhibit immunosuppressive properties. How IgG4 affects the etiopathology of lymphatic filariasis (LF) is however not well characterized. Here we investigate the impact of plasma and affinity-purified IgG/IgG4 fractions from endemic normals (EN) and LF infected pathology patients (CP), asymptomatic microfilaraemic (Mf+) and amicrofilaraemic (Mf-) individuals on IgE/IL3 activated granulocytes. The activation and degranulation states were investigated by monitoring the expression of CD63/HLADR and the release of granule contents (neutrophil elastase (NE), eosinophil cationic protein (ECP) and histamine) respectively by flow cytometry and ELISA. We could show that the activation of granulocytes was inhibited in the presence of plasma from EN and Mf+ individuals whereas those of Mf- and CP presented no effect. This inhibitory capacity was impaired upon depletion of IgG in Mf+ individuals but persisted in IgG-depleted plasma from EN, where it strongly correlated with the expression of IgA. In addition, IgA-depleted fractions failed to suppress granulocyte activation. Strikingly, affinity-purified IgG4 antibodies from EN, Mf+ and Mf- individuals bound granulocytes and inhibited activation and the release of ECP, NE and histamine. In contrast, IgG4 from CP could not bind granulocytes and presented no suppressive capacity. Reduction of both the affinity to, and the suppressive properties of anti-inflammatory IgG4 on granulocytes was reached only when FcγRI and II were blocked simultaneously. These data indicate that IgG4 antibodies from Mf+, Mf- and EN, in contrast to those of CP, natively exhibit FcγRI/II-dependent suppressive properties on granulocytes. Our findings suggest that quantitative and qualitative alterations in IgG4 molecules are associated with the different clinical phenotypes in LF endemic regions.

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

“…Another interesting finding was the fact that in our model, IgG4 antibodies from Mf+ individuals presented a higher affinity to the Fc portions of IgG1–2 compared to IgG4 antibodies from Mf− and CP individuals. This finding extends our previous observation that functional differences regarding their affinity to FcγRs exist between IgG4 antibodies from LF patients of the different clinical groups (Prodjinotho et al 2017) and suggest that a similar pattern might be applicable for their affinity to Fc fragments of other antibodies.…”

“…Due to its molecular and immunological properties, IgG4 is often seen as a blocking antibody (Aalberse et al 2009; Rispens et al 2013; Rispens et al 2009; van der Neut et al 2007). Since, in LF models, IgG4 was shown to be predominant in Mf+ individuals compared to Mf−, CP, and EN (Prodjinotho et al 2017), we hypothesized that IgG4 might be the factor that inhibited the affinity of IgG1 and IgG2 to C1q. To test this hypothesis, we depleted IgG4 from the plasma of Mf+ individuals and analyzed the ability of IgG1 and IgG2 in bulk Mf+ plasma (IgG4+) and IgG4-depleted plasma (IgG4−) to interact with C1q.…”

“…Alongside these classical Th2 responses, the majority of LF patients present a strong immune-regulated profile with high levels of regulatory cells, anti-inflammatory cytokines, and elevated IgG4. This particular immunoglobulin is well known to be unable to activate the complement pathway (Adjobimey and Hoerauf 2010; Prodjinotho et al 2017). The human complement system consists of over 30 circulatory or membrane-bound plasma proteins and can be activated at the site of infection by three different pathways (classical, lectin, and alternative).…”

Trichinella spiralis Infection Mitigates Collagen-Induced Arthritis via Programmed Death 1-Mediated Immunomodulation

“…It is reported that helminth infection drives the sustained expression of T cell inhibitory receptors, which may negatively regulate proliferation and the production of pro-inflammatory cytokines by helminth antigen-specific T cells ( 38 – 40 ). Because these molecules largely function to prevent over exuberant T cell activation, their essential role in preventing parasite-induced immunopathology have been confirmed in animal studies ( 38 , 41 ). However, the impact of these parasite-induced inhibitory molecules on autoimmune pathology has not been clarified.…”

Correlation of Lyme Disease–Associated IgG4 Autoantibodies With Synovial Pathology in Antibiotic‐Refractory Lyme Arthritis

“…Additionally, in pemphigus, IgG4 autoantibodies to desmoglein play a direct role in the disruption of the epithelial cell surface, leading to the blistering lesions of the disease (37). Moreover, in lymphatic filariasis, IgG4 antibodies from asymptomatic individuals suppressed granulocytes, whereas IgG4 antibodies from symptomatic patients did not (38). Thus, under certain circumstances, the usual antiinflammatory effects of IgG4 antibodies may be altered, resulting in loss of their usual suppressive function, or these antibodies may develop a direct pathogenic role.…”