Immunologic tolerance in lymphatic filariasis. Diminished parasite-specific T and B lymphocyte precursor frequency in the microfilaremic state.

Abstract

To explore the mechanisms of antigen-specific immune unresponsiveness seen in microfilaremic patients with bancroftian filariasis, T and B cell precursor frequency analysis was performed using PBMC from individuals with either asymptomatic microfilaremia (MF, n = 7) or chronic lymphatic obstruction (CP, n = 20). Highly purified CD3+ cells were partially reconstituted with adherent cells and their proliferative response to parasite antigens determined in cultures of T cells by limiting dilution analysis. A filter immunoplaque assay also assessed the frequency of both total and parasite-specific Igproducing B cells. While the lymphocyte proliferation to mitogens and to a nonparasite antigen (Streptolysin-O, ISLO]) were similar in all groups of patients, the frequency of parasite-specific CD3+ T cells was significantly lower (geometric mean IGMI, 1/3,757) in MF patients when compared to that in CP patients (GM 1/1,513; P < 0.001). Similarly, the proportion of lymphocytes producing parasite-specific IgE or IgG was significantly lower in MF patients (IgE mean, 0.2%; IgG mean, 0.33%) compared with CP patients (IgE mean, 3.2%; IgG mean, 1.76%; P < 0.05 for both comparisons). These observations imply that low numbers of parasite-specific T and B lymphocytes may be partially responsible for the severely diminished capacity of lymphocytes from patients with MF to produce parasite-specific antibody and to proliferate to parasite antigen in vitro. Such differences in parasite-specific lymphocyte responses suggest that tolerance by clonal anergy may be a critical mechanism for maintaining the microfilaremic state. (J.

Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset.

“…For example, asymptomatic microfilaremia (MF)' is thought to result from parasite-specific "immune hyporesponsiveness" by the host, thereby allowing the microfilariae to persist in the circulation (3)(4)(5). This hypothesis has been supported by observations of selectively impaired T and B cell responses to filarial antigens (Ags) among MF subjects (3-1 1), but the Agspecific anergy does not extend to all immune responses in MF individuals, as frequencies of polyclonal IgE-and IgG4-secreting lymphocytes ( 12) and serum antifilarial IgE and IgG4 levels are usually elevated (9,13). In contrast, strong filarial Agdriven T and B cell responses are observed among amicrofilaremic individuals with chronic lymphatic obstruction (CP).…”

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

“…Lymphatic filariasis covers a spectrum of disease states from asymptomatic carrier (microfilaremic) to chronic lymphatic dysfunction and elephantiasis (3,4). Notably, the asymptomatic subjects, who carry high levels of circulating transmissionstage microfilariae, display a muted immunological response (5)(6)(7)(8), failing to mount parasite-specific T cell proliferative and cytokine responses. The degree of suppression is accentuated with higher parasite loads (9), and can be reversed by anti-filarial chemotherapy (10,11).…”

CTLA-4 and CD4+CD25+ Regulatory T Cells Inhibit Protective Immunity to Filarial Parasites In Vivo

“…D own-regulation of T cell function resulting in immune suppression is a quintessential feature of chronic helminth infections (1)(2)(3)(4)(5)(6)(7). In human filariasis, immunosuppression is characterized by the impairment of both Ag-specific Th1 and Th2 immune responses (8 -10).…”

“…In human filariasis, immunosuppression is characterized by the impairment of both Ag-specific Th1 and Th2 immune responses (8 -10). Filarial parasites suppress host immunity through a variety of immunoregulatory layers involving T cells, macrophages, and dendritic cells (DC) 3 (6,(11)(12)(13)(14)(15). Of these layers, regulation within the CD4 ϩ T cell compartment plays a vital role in determining the outcome of infection (16), combining the induction of regulatory T (Treg) cell responses (10,16,17) and the development of intrinsically hyporesponsive or "conditioned" effector T (Teff) cells (10,16).…”