Immunopathogenesis of lymphatic filarial disease

Abstract

Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ~40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, tropical pulmonary eosinophilia, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites, the host inflammatory response to the parasites and their secreted antigens, the host inflammatory response to the endosymbiont Wolbachia, and those seen as a consequence of secondary bacterial or fungal infections. Inflammatory damage induced by filarial parasites appears to be multifactorial, with endogenous parasite products, Wolbachia, and host immunity all playing important roles. This review will initially examine the prototypical immune responses engendered by the parasite and delineate the regulatory mechanisms elicited to prevent immune-mediated pathology. This will be followed by a discussion of the proposed mechanisms underlying pathogenesis, with the central theme being that pathogenesis is a two-step process-the first initiated by the parasite and host innate immune system and the second propagated mainly by the host's adaptive immune system and by other factors (including secondary infections).

Figure 1

Regulation of the immune responses in filarial infections. The complex outcome of the interaction between the filarial parasite and the host immune system determines the immunological outcomes including protection against pathology. The host – parasite interaction involves a variety of cell types, cytokines and other molecules that interact to influence the development of pathology.

Figure 2

Pathogenesis of lymphatic filarial disease. Live filarial parasites and/or their products have a direct effect on lymphatic endothelial cells as well as on the cells of the innate and adaptive immune system. The interplay between inflammatory/ immune mediators, slow attrition of the parasites, Wolbachia and other factors contribute to pathogenesis and development of filarial disease. Secondary microbial infections further aggravate the pathology. The clinical manifestations of filarial disease include lymphedema, hydrocele and elephantiasis.