Immunoregulation in onchocerciasis: predominance of Th1-type responsiveness to low molecular weight antigens of Onchocerca volvulus in exposed individuals without microfilaridermia and clinical disease

Abstract

SUMMARYChronic and generalized onchocerciasis is associated with suppression of the parasite-specific cellular responsiveness, while exposed individuals without parasitological and clinical evidence of infection (endemic normals) display prominent cellular reactivity to Onchocerca volvulus antigens (OvAg). In order to identify those parasite antigens which may account for this differential cellular responsiveness, total adult worm-derived OvAg were fractionated by means of preparative SDS-PAGE and blot-elution into 22 antigen fractions of continuously decreasing molecular weight. Peripheral blood mononuclear cells (PBMC) from microfilariae (mf)-positive onchocerciasis patients (n 18) proliferated weakly in response to all OvAg fractions. In contrast, in vitro reactivity of PBMC from endemic normals (n 9) was depressed in response to OvAg of mol. wt 200-30 kD only, while antigens of mol. wt <30 kD induced vigorous proliferation in these individuals compared with the microfilaridermic patients (P < 0 . 05). Highest proliferative reactivity of cells from endemic normals was observed in response to OvAg of mol. wt 15-11 kD. Furthermore, these low mol. wt antigen fractions induced substantial production of IL-2 and interferon-gamma (IFN-°) in PBMC from endemic normals, but not in those from onchocerciasis patients. Cells from individuals of both groups secreted similar amounts of IL-5 in response to all OvAg fractions, with highest production again being induced by low mol. wt OvAg. In contrast, PBMC from onchocerciasis patients clearly produced more IL-10 than did cells from endemic normals. This augmented IL-10 production by PBMC from mf-positive individuals was not only observed after stimulation with OvAg fractions, but was measured in unstimulated control cultures as well. IFN-°-specific mRNA in antigen-stimulated PBMC from endemic normals appeared to be more prominent than in cells from onchocerciasis patients. However, mRNA transcripts of IL-10 and IL-13 were clearly present in patients, but were absent or inconsistently observed in endemic normals. Our results suggest that vigorous Th1-type cellular responsiveness encountered in endemic normals is restricted to low mol. wt antigens of O. volvulus, while such reactivity will not be present in mf-positive individuals. Furthermore, spontaneous production of high levels of IL-10 in onchocerciasis patients is likely to suppress Th1-type immunity, and thus may favour manifestation of chronic onchocerciasis. These traits of cellular immunity may contribute to the differential outcome of O. volvulus infection, the manifestation of clinical disease, and may also regulate the build up of acquired immunity in humans.

Cytokine profiles in Wegener's granulomatosis: Predominance of type 1 (Th1) in the granulomatous inflammation

“…In contrast, in lepromatous patients 748 CSERNOK ET AL who manifest disseminated infection, the T cells respond weakly to M leprae, and the lesions express the Th2 cytokines typical of humoral responses, which include autoreactivity as ANCA production, as has been found in lepromatous leprosy, but not in tuberculoid leprosy (29). In addition, in onchocerciasis the majority of patients demonstrate a vigorous Th1 cellular response, whereas in hyperreactive onchocerciasis (Sowda) autoantibodies to defensin (ANCA) occur (30)(31)(32)(33). WG and MPA are mainly differentiated by the occurrence of granulomatous inflammation, which is present in the former and absent in the latter (1).…”

Presence of Phosphorylcholine on a Filarial Nematode Protein Influences Immunoglobulin G Subclass Response to the Molecule by an Interleukin-10-Dependent Mechanism

“…Although this has not been observed in all studies (6), it raises the possibility that PC on ES could be a contributor to the IL-10 production. Elevated spontaneous and parasite antigeninduced IL-10 production has also been detected in onchocerciasis patients relative to healthy subjects in areas of endemicity (17), although the PC-ES status of these individuals was not investigated. Elevated spontaneous levels of IL-10, by downregulating Th1 responses, could contribute to the Th2 phenotype often observed in the specific immune response of microfilaria-positive lymphatic filariasis and onchocerciasis patients (19,20).…”

Onchocerca volvulus–Exposed Persons Fail to Produce Interferon‐γ in Response toO. volvulusAntigen but Mount Proliferative Responses with Interleukin‐5 and IL‐13 Production that Decrease with Increasing Microfilarial Density

“…The notion was supported by experimental data showing production of the characteristic Th1 marker interferon (IFN)-g [3, 7, 10]. The findings, however, were not always consistent [7,[10][11][12], and it was concluded that the classical Th1/Th2 dichotomy might not be applicable to O. volvulus and other filarial infections [11,13]. In this study, we assessed cell proliferation and cytokine production in response to O. volvulus antigen in whole-blood cultures from several hundred O. volvulusexposed persons.…”