Differential Cytokine and Antibody Responses to Adult and Larval Stages ofOnchocerca volvulusConsistent with the Development of Concomitant Immunity

Abstract

The possibility of concomitant immunity and its potential mechanisms in Onchocerca volvulus infection were examined by analyzing cytokine and antibody responses to infective larval (third-stage larvae [L3] and molting L3 [mL3]), adult female worm (F-OvAg), and skin microfilaria (Smf) antigens in infected individuals in a region of hyperendemicity in Cameroon as a function of age. Peripheral blood mononuclear cell interleukin 5 (IL-5) responses to F-OvAg and Smf declined significantly with age (equivalent to years of exposure to O. volvulus). In contrast, IL-5 secretion in response to L3 and mL3 remained elevated with increasing age. Gamma interferon responses to L3, mL3, and F-OvAg were low or suppressed and unrelated to age, except for responses to Smf in older subjects. IL-10 levels were uniformly elevated, regardless of age, in response to L3, mL3, and F-OvAg but not to Smf, for which levels declined with age. A total of 49 to 60% of subjects had granulocytemacrophage colony-stimulating factor responses to all O. volvulus antigens unrelated to age. Analysis of levels of stage-specific immunoglobulin G3 (IgG3) and IgE revealed a striking, age-dependent dissociation between antibody responses to larval antigens (L3 and a recombinant L3-specific protein, O. volvulus ALT-1) which were significantly increased or maintained with age and antibody responses to F-OvAg, which decreased. Levels of IgG1 to L3 and F-OvAg were elevated regardless of age, and levels of IgG4 increased significantly with age, although not to O. volvulus ALT-1, which may have unique L3-specific epitopes. Immunofluorescence staining of whole larvae showed that total anti-L3 immunoglobulin levels also increased with the age of the serum donor. The separate and distinct cytokine and antibody responses to adult and infective larval stages of O. volvulus which are age related are consistent with the acquisition of concomitant immunity in infected individuals.The filarial parasite Onchocerca volvulus infects about 18 million people, and a further 100 million live in areas in which O. volvulus is endemic in Africa and Latin America. The resulting disease, onchocerciasis, is characterized by severe dermatitis and blindness (21). There is epidemiological evidence that acquired immunity against O. volvulus infection occurs in humans. For example, in regions of high endemicity, despite constant exposure to infected Simulium flies, 1 to 5% of the population exhibits no clinical manifestations of disease. These individuals are considered to be immune to infection and are referred to as putatively immune (PI) (15,17,46,47). Furthermore, in chronically infected (INF) individuals, the number of skin microfilariae (mf) tends to level off between the ages of 20 and 40 years, suggesting that these individuals have developed a means of limiting acquired infections (11). It has been suggested that the means of limiting acquired infections is through concomitant immunity (36), whereby newly introduced infective-stage larvae (third-stage larvae [L3]) are eliminated ...

In a bovine model of onchocerciasis, protective immunity exists naturally, is absent in drug-cured hosts, and is induced by vaccination

“…The existence of concomitant immunity against superinfection with L 3 during the patent phase is controversial. In contrast to responses to adult female and Mf antigens, lymphoproliferation in response to O. volvulus L 3 antigen has been reported to increase with host age, consistent with the development of partial protection against this stage (40). However, in a statistical model based on nodulectomy data collected from hyperendemic areas of West Africa, adults were shown to acquire far more mature parasites per year than children acquired, and this finding was attributed to the immunosuppressive influence of female worms (41).…”

Recombinant Ov-ASP-1, a Th1-Biased Protein Adjuvant Derived from the Helminth Onchocerca volvulus, Can Directly Bind and Activate Antigen-Presenting Cells

“…Like other filarial nematodes, Onchocerca volvulus worms secrete a large number of immunoregulatory molecules to subvert the immune responses and minimize severe pathology and thus enabling their ability to establish a chronic infection in humans that can last Ͼ15 years (16). The native ASP-1 protein of O. volvulus (Ov-ASP-1) is located in the secretory granules of the glandular esophagus of the infective third-stage larvae and is predicted to have multiple immunoregulatory functions (2,17). Our previous studies demonstrated that recombinant Ov-ASP-1 (rOv-ASP-1) is not only a protective Ag in vaccinated mice against O. volvulus third-stage larvae, but also a potent adjuvant for bystander proteins (2,(17)(18)(19).…”

“…The native ASP-1 protein of O. volvulus (Ov-ASP-1) is located in the secretory granules of the glandular esophagus of the infective third-stage larvae and is predicted to have multiple immunoregulatory functions (2,17). Our previous studies demonstrated that recombinant Ov-ASP-1 (rOv-ASP-1) is not only a protective Ag in vaccinated mice against O. volvulus third-stage larvae, but also a potent adjuvant for bystander proteins (2,(17)(18)(19). In OVAimmunized mice, rOv-ASP-1 exceeded the efficacy of alum or monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) adjuvants in terms of end-point total IgG or IgG1 and IgG2a Ab titers (18).…”

Gastrointestinal nematode infection is associated with variation in innate immune responsiveness

“…Furthermore, the population from which our subjects were sampled has received periodic school-based anti-helmintic (mebendazole) treatments since 1994 [8] and annual community-based treatment (albendazole + ivermectin) since 2001 [9]. This background of periodic de-worming may have had an important influence, given that different immune responses might be expected against different life-history stages of the same parasite [15]. Where adult worm infections are periodically curtailed, but larval exposure is continuous, this could favour the development of distinct immunological states to those found in chronic infections that continuously harbour adult worms for many years.…”