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Abstract
Even in the absence of an adaptive immune system in murine models, lymphatic dilatation and dysfunction occur in filarial infections, although severe irreversible lymphedema and elephantiasis appears to require an intact adaptive immune response in human infections. To address how filarial parasites and their antigens influence the lymphatics directly, human lymphatic endothelial cells were exposed to filarial antigens, live parasites, or infected patient serum. Live filarial parasites or filarial antigens induced both significant LEC proliferation and differentiation into tube-like structures in vitro. Moreover, serum from patently infected (microfilaria positive) patients and those with longstanding chronic lymphatic obstruction induced significantly increased LEC proliferation compared to sera from uninfected individuals. Differentiation of LEC into tube-like networks was found to be associated with significantly increased levels of matrix metalloproteases and inhibition of their TIMP inhibitors (Tissue inhibitors of matrix metalloproteases). Comparison of global gene expression induced by live parasites in LEC to parasite-unexposed LEC demonstrated that filarial parasites altered the expression of those genes involved in cellular organization and development as well as those associated with junction adherence pathways that in turn decreased trans-endothelial transport as assessed by FITC-Dextran. The data suggest that filarial parasites directly induce lymphangiogenesis and lymphatic differentiation and provide insight into the mechanisms underlying the pathology seen in lymphatic filariasis.
Highlights
Among the clinical manifestations of human infection with the filarial nematodes Wuchereria bancrofti and Brugia malayi, the most debilitating are those associated with lymphatic dysfunction and/ or obstruction
The extent of proliferation induced by Brugia malayi parasites (BmA) or BmMAg was comparable to that induced by recombinant soluble human vascular endothelial growth factor (VEGF)-A at 25 ng/ml used as a positive inducer of proliferation
It has been postulated that with sufficient infection chronicity, individuals who harbor adult Wuchereria bancrofti will develop lymphangiectasia in the vicinity of the worm nests [20]. It is not clear what induces the lymphatic dysfunction in filaria-infected individuals, previous studies have shown that filarial antigens do not induce proliferation of human umbilical vein endothelial cells (HUVEC) in vitro and, inhibited their proliferation [21]
Summary
Among the clinical manifestations of human infection with the filarial nematodes Wuchereria bancrofti and Brugia malayi, the most debilitating are those associated with lymphatic dysfunction and/ or obstruction (e.g. lymphedema, elephantiasis). Individuals infected with the lymphdwelling filariae can develop tissue scarring and fibrosis within and around the lymphatic vessels resulting in permanent and characteristic pathology manifested clinically by irreversible lymphedema or elephantiasis [2,3]. In histologic studies of lymph nodes taken from patients with bancroftian filariasis, there were intact adult filarial worms with little or no associated inflammation [18,19]. Together, these observations suggest a primary role of the parasites or parasite-encoded proteins in modulating lymphatic integrity and function. It has been speculated that, with chronic infection, it is the death of the adult worms (be it immune mediated or just intrinsic worm lifespan) and the release of parasite antigens (or Wolbachia) that induce proinflammatory responses that render a poorly functioning (and dilated) patent lymphatic completely obstructed [20]
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