Filariasis and lymphoedema.
Among the causes of lymphoedema (LE), secondary LE due to filariasis is the most prevalent. It affects only a minority of the 120 million people infected with the causative organisms of lymphatic filariasis (LF), Wuchereria bancrofti and Brugia malayi/timori, but is clustered in families, indicating a genetic basis for development of this pathology. The majority of infected individuals develop filarial-specific immunosuppression that starts even before birth in cases where mothers are infected and is characterized by regulatory T-cell responses and high levels of IgG4, thus tolerating high parasite loads and microfilaraemia. In contrast, individuals with this pathology show stronger immune reactions biased towards Th1, Th2 and probably also Th17. Importantly, as for the aberrant lymph vessel development, innate immune responses that are triggered by the filarial antigen ultimately result in the activation of vascular endothelial growth factors (VEGF), thus promoting lymph vessel hyperplasia as a first step to lymphoedema development. Wolbachia endosymbionts are major inducers of these responses in vitro, and their depletion by doxycycline in LF patients reduces plasma VEGF and soluble VEGF-receptor-3 levels to those seen in endemic normals preceding pathology improvement. The search for the immunogenetic basis for LE could lead to the identification of risk factors and thus, to prevention; and has so far led to the identification of single-nucleotide polymorphisms (SNP) with potential functional relevance to VEGF, cytokine and toll-like receptor (TLR) genes. Hydrocele, a pathology with some similarity to LE in which both lymph vessel dilation and lymph extravasation are shared sequelae, has been found to be strongly associated with a VEGF-A SNP known for upregulation of this (lymph-)angiogenesis factor.
Pfarr
K M
KM
Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.
Debrah
A Y
AY
Specht
S
S
Hoerauf
A
A
D000818:Animals; D004605:Elephantiasis, Filarial / Q000150:complications* / Q000469:parasitology; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D042601:Lymphatic Vessels / Q000378:metabolism / Q000503:physiopathology; D008209:Lymphedema / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism; D020577:Wolbachia / Q000276:immunology
D042461:Vascular Endothelial Growth Factor A