Filariasis asymptomatically infected donors have lower levels of disialylated IgG compared to endemic normals

Abstract

Helminths induce strong regulatory and T helper 2-type responses, whereby antibody-derived host protection and regulation are essential components. Lymphatic filariasis is an immune-mediated spectral disease that manifests as two main clinical outcomes: chronic pathology or asymptomatic infection. These outcomes depend on a multitude of factors, including parasite-induced immunoregulation and host genetic background; antibody responses contribute to this outcome. N-glycosylation of the Fc region of antibodies is a post-translational modification required for the structure and molecular function, influencing host inflammatory and regulatory responses. Altered IgG glycosylation correlates with disease, whereby decreased galactosylation is associated with inflammation while increased sialylation is associated with anti-inflammatory responses. We purified N-linked glycans from the Fc region of total IgG from Wuchereria bancrofti-infected patients characterizing the two clinical manifestations (chronic pathology and asymptomatic infection) and compared them to infection-free endemic normals. Using capillary electrophoresis, we found that there was no difference in galactosylation of total IgG between the three groups; however, asymptomatically infected patients had significantly lower levels of disialylated IgG compared to endemic normals and patients with pathology. These data suggest that while galactosylation does not contribute to disease outcome, sialylation may be involved in asymptomatic infection.

Changes in canine serum N-glycosylation as a result of infection with the heartworm parasite Dirofilaria immitis

“…FA2 has been shown to predominantly originate from IgG 40 , 41 . While a previous study has reported changes in the IgG sialylation in people infected with a related filarial nematode, W. bancrofti 36 , our analysis revealed no change in IgG N-glycan microheterogeneity in dogs with a patent D. immitis infection. We do, however, see an increased abundance of serum IgG in infected dogs that is likely responsible for at least part of the change in the relative abundances of serum N-glycans.…”

“…Further, it is noteworthy that D. immitis is closely related to O. volvulus , W. bancrofti and B. malayi , causative agents of onchocerciasis and lymphatic filariasis afflicting more than 135 million humans 33 , 34 , thus making our results relevant for a wider filariasis research community. While alterations in IgG N-glycosylation have previously been associated with leishmaniasis 35 , asymptomatic filariasis 36 and other parasitic infection in developing countries 37 to the best of our knowledge, this is the first report of drastic changes in the mammalian total serum N-glycosylation profile as a consequence of parasitic infections.…”

Clinical Severity of Visceral Leishmaniasis Is Associated with Changes in Immunoglobulin G Fc N-Glycosylation

“…In this study, distinct glycosylation features of IgG1 and IgG2 and -3 that determine the inflammatory and regulatory functions of IgG molecules and possibly cognate functions of antibodies were associated with outcomes of infections with L. infantum chagasi . Several studies have addressed the composition and role of IgG Fc N-glycans in human infectious diseases; e.g., global IgG galactosylation is significantly perturbed in patients with tuberculosis ( 25 ); patients with hepatitis C virus who develop cirrhosis present increased levels of agalactosylated IgG specific for alpha-Gal epitope [Gal-1-3Gal1-(3)4GlcNAc-R] ( 40 ); antiviral activity is modulated by natural variations in Fc glycosylation of HIV-specific antibodies ( 27 ); the opsonizing capacity of IgG for hepatitis B virus depends on the profile of Fc glycosylation, which is also associated with clinical outcomes of infection with this virus ( 41 ); and individuals asymptomatically infected with Wuchereria bancrofti had significantly lower levels of disialylated IgG than endemic controls and patients with pathology ( 42 ). However, the analytical techniques applied in those studies did not discriminate between IgG subclasses and/or registered overall glycosylation but not Fc-specific glycosylation or did not detail specific Fc glycosylation profiles.…”

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

“…The patients elicit a strong T helper (Th)1 and Th17 immune response that eliminate the microfilarial stage [5] while inducing the production of angiogenic factors like VEGF known to be associated with the development of filarial lymphedema [6]. This severe clinical profile is characterized by high antigen-specific immunoglobulin (Ig)E and low IgG4 [5] [7,8]. The third group includes asymptomatic individuals with latent infection who are free of microfilaria (Mf-) but are positive for circulating filarial antigens (CFA) [9].…”