Specific T cell unresponsiveness in human filariasis: diversity in underlying mechanisms

Abstract

In an attempt to overcome T cell unresponsiveness to filarial antigens, 65 individuals belonging to the three clinical groups of elephantiasis patients, microfilaraemics, and asymptomatic amicrofilaraemics who exhibited unresponsiveness to Brugia malayi adult worm antigen (BmA) were studied. Peripheral blood mononuclear cells were cocultured with antigen and one of the following reagents that have been reported to be effective in reconstituting T cell proliferation: interleukin-2 (IL-2), interleukin-7 (IL-7), anti-interleukin-4, anti-interleukin-10, anti-CD2, anti-CD27, anti-CD28, indomethacin, phorbol myristate acetate (PMA), or calcium ionophore (A23187). We were able to overcome antigen-specific unresponsiveness in only a minority of the individuals studied. Co-culture with IL-2, IL-7, indomethacin and PMA were the only conditions which resulted in enhanced proliferation to BmA in these individuals. In general, unresponsiveness in elephantiasis patients was easier to reverse than in other clinical groups: in 50% of elephantiasis patients, in 12.5% of microfilaraemics and in 20% of asymptomatic amicrofilaraemics. The results indicate that more than one distinct immunological mechanism may account for the antigen-specific unresponsiveness in individuals exposed to and infected with brugian filariasis.

A Filarial Nematode-Secreted Phosphorylcholine-Containing Glycoprotein Uncouples the B Cell Antigen Receptor from Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase by Promoting the Surface Ig-Mediated Recruitment of Src Homology 2 Domain-Containing Tyrosine Phosphatase-1 and Pac-1 Mitogen-Activated Kinase-Phosphatase

“…Moreover, the similarities we have observed when comparing the effects of ES-62/PC on B and T cells to date (4, 6 -10) enable us to predict with some confidence that ES-62 may desensitize T cells by a similar mechanism. There have, in fact, been more studies described in the literature on defects in proliferative responses of the latter cell type (35,43) than on B cells from filariasis patients, but as with B cells, elucidating mechanisms has proved frustratingly difficult (44). We hope that the data presented here are a significant step to resolving this situation.…”

Transmission Intensity Affects Both Antigen-Specific and Nonspecific T-Cell Proliferative Responses inLoa loaInfection

“…Despite this fundamental difference in the parasitological status of infected individuals, there are similarities between the immune response elicited by the lymphatic filariae and by L. loa. For example, immunoglobulin G4 (IgG4) levels are elevated during active infection with both lymphatic filarial worms and L. loa, while amicrofilaremic individuals have elevated levels of other parasite-specific IgG subclasses (1, 2, 15).Studies that have been carried out in other filarial infections with the aim of defining the mechanisms underlying proliferative suppression (17,25) have shown that no one single factor consistently restores proliferation in vitro. Some studies have shown an antiproliferative effect for IL-10 (17), while a more recent study with Onchocerca volvulus-infected individuals proposed that the proliferative defect is a consequence of the development of Th3 cells secreting the antiproliferative cytokines IL-10 and transforming growth factor ␤ (9).…”

“…Studies that have been carried out in other filarial infections with the aim of defining the mechanisms underlying proliferative suppression (17,25) have shown that no one single factor consistently restores proliferation in vitro. Some studies have shown an antiproliferative effect for IL-10 (17), while a more recent study with Onchocerca volvulus-infected individuals proposed that the proliferative defect is a consequence of the development of Th3 cells secreting the antiproliferative cytokines IL-10 and transforming growth factor ␤ (9).…”

Filarial Antigens Impair the Function of Human Dendritic Cells during Differentiation

“…The regulatory controls on the T-cell responses in these patently infected individuals affect type 1 responses preferentially, with interleukin 10 (IL-10) and transforming growth factor beta being the cytokines most often implicated in mediating this type 1 downregulation (15,38). Indeed, IL-10 production is not only elevated in asymptomatic (or subclinical) MF individuals but is also preferentially induced by the MF stage of the parasite (22,23).…”