Brugia malayi is a filarial nematode, one of the long-lived parasites which cause the major tropical diseases of elephantiasis and river blindness. The other human-infective filarial parasites include B. timori, Wuchereria bancrofti, Loa loa, Onchocerca volvulus and Mansonella perstans. Of these, only B. malayi is readily infective in laboratory animals, and W. bancrofti is the most prevalent with an estimated 100 million cases worldwide.
Improved drug treatments, and donation programmes of ivermectin and albendazole, offer signficant respite and are being promoted through the Global Programme for Elimination of Lymphatic Filariasis(GPELF). However, large scale chemotherapy may require frequent treatment , and it is not known if drug resistance will emerge, or adverse effects deter participation. Thus, as with other pathogens, an immunological route is also being pursued.
A remarkable finding in filariasis is that infection is accompanied by some of the most profound immunological changes seen in any human parasite. Prominent among these are a block in parasite-specific T cell proliferation, and a pronounced bias towards Th2 responses. IgE and IgG4 antibody levels can reach extraordinary levels in patients, indicative of a dysfunctional immune regulation during infection. We have demonstrated that lesions in proliferation and skewing to Th2 differentiation can readily be demonstrated in animal models.
Filarial-specific T cell proliferation is ablated in infected patients, as observed consistently in many different laboratories. Moreover, there is selective loss of IFN-g and IL-5 cytokine responses, while IL-4 remains intact. IL-10 and TGF-b may play a role in this suppression, although this has not been confirmed. Similar immunological deficits have been observed in other chronic infections such as tuberculosis, leprosy and schistosomiasis. Two opposing hypotheses can be constructed: that depression of T-cell reactivity is a physiological response to chronic infection, or that T-cell hyporesponsiveness is induced by pathogens as a prerequisite for long-term establishment in the host.
Infective larvae and adult worms of Brugia drive strongly polarised Th2-type responses in mice, but whether these responses are protective is controversial. The survival of parasites in patients with high type-2 responsiveness invalidates a simplistic "Th2 protects against helminths" hypothesis for filariasis in humans, while the emergence of regulatory T cell populations provides a new perspective on the dynamics of human disease.