transforming-growth-factor-beta and Elephantiasis--Filarial

Two different Th2 subsets have been defined recently on the basis of IL-5 expression - an IL-5(+)Th2 subset and an IL-5(-)Th2 subset in the setting of allergy. However, the role of these newly described CD4(+) T cells subpopulations has not been explored in other contexts.. To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5(+)IL-4(+)IL-13(+) CD4(+) T cells and IL-5(-)IL-4 IL-13(+) CD4(+) T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP).. INF individuals exhibited a significant increase in the spontaneously expressed and antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5(+)Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4(+)IL-5(-)Th2 subpopulation and the levels of parasite antigen - specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets.. Our findings suggest that both IL-5(+) and IL-5(-)Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes.

Topics: Adult; Aged; Animals; Antigens, Helminth; Elephantiasis, Filarial; Female; Humans; Interleukin-10; Interleukin-5; Male; Middle Aged; T-Lymphocyte Subsets; Th2 Cells; Transforming Growth Factor beta; Young Adult

Lymphatic filarial disease is known to be associated with elevated Th1 responses and normal or diminished Th2 responses to parasite-specific antigens. The roles of Th17 cells and the recently described Th22 cells have not been examined in detail in either filarial infection itself or in filarial disease (e.g., lymphedema and elephantiasis). To explore the roles of Th17 and Th22 cells and their subsets, we examined the frequencies of these cells in individuals with filarial lymphedema (chronic pathology [CP]), in clinically asymptomatic infected (INF) individuals, and in uninfected (UN) individuals ex vivo and in response to parasite and nonparasite antigens. Those with disease (CP) had significantly expanded frequencies of Th17 and Th22 cells, compared with either INF or UN individuals, at baseline (ex vivo) and in response to parasite antigens. This antigen-driven expansion of Th17 and Th22 cells was dependent on interleukin 1 (IL-1), IL-23, and, to lesser extent, transforming growth factor β (TGF-β), as blockade of any of these cytokines resulted in significantly diminished frequencies of Th17 and Th22 cells. Our findings, therefore, suggest that filarial parasite-driven expansion of Th17 and Th22 cells is associated with the pathogenesis of filarial infections and disease.

Topics: Animals; Brugia malayi; Elephantiasis, Filarial; Humans; Interleukin-1; Interleukin-23; T-Lymphocyte Subsets; Th17 Cells; Transforming Growth Factor beta; Wuchereria bancrofti

Lymphatic filariasis is known to be associated with diminished CD4⁺ Th1 and elevated CD4⁺ Th2 responses to parasite-specific antigens. The roles of cytokine-expressing CD8⁺ T cells in immune responses to filarial infections are not well defined. To study the roles of CD8⁺ T cells expressing type 1, type 2, and type 17 cytokines in filarial infections, we examined the frequencies of these cells in clinically asymptomatic, patently infected (INF) individuals, directly ex vivo and in response to parasite or nonparasite antigens; these frequencies were compared with the results for individuals with filarial lymphedema (i.e., clinical pathology [CP]) and those without active infection or pathology (i.e., endemic normal [EN]). INF individuals exhibited significant decreases in the frequencies of CD8⁺ T cells expressing tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin-22 (IL-22) at baseline and/or in response to filarial antigens, compared with CP and EN individuals. In contrast, the same individuals exhibited significant increases in the frequencies of CD8⁺ T cells expressing IL-4, IL-5, IL-9, IL-13, and IL-21, compared with CP and/or EN individuals. Curative treatment resulted in significantly increased frequencies of CD8⁺ T cells expressing IL-2 and significantly decreased frequencies of CD8⁺ T cells expressing type 2 cytokines. Finally, the regulation of these responses appears to be independent of IL-10 and transforming growth factor β (TGF-β), since blockade of IL-10 or TGF-β signaling did not significantly alter the frequencies of type 1 or type 2 cytokine-expressing CD8⁺ T cells. Our findings suggest that alterations in the frequencies of cytokine-expressing CD8⁺ T cells are characteristic features of lymphatic filarial infections.

Topics: Adult; Aged; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Elephantiasis, Filarial; Humans; Interleukin-10; Middle Aged; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Th9 cells are a subset of CD4(+) T cells, shown to be important in allergy, autoimmunity, and antitumor responses; however, their role in human infectious diseases has not been explored in detail. We identified a population of IL-9 and IL-10 coexpressing cells (lacking IL-4 expression) in normal individuals. These cells respond to antigenic and mitogenic stimulation, but are distinct from IL-9(+) Th2 cells. We also demonstrate that these Th9 cells exhibit Ag-specific expansion in a chronic helminth infection (lymphatic filariasis). Comparison of Th9 responses reveals that individuals with pathology associated with filarial infection exhibit significantly expanded frequencies of filarial Ag-induced Th9 cells, but not of IL9(+)Th2 cells in comparison with filarial-infected individuals without associated disease. Moreover, the per cell production of IL-9 is significantly higher in Th9 cells compared with IL9(+)Th2 cells, indicating that the Th9 cells are the predominant CD4(+) T cell subset producing IL-9 in the context of human infection. This expansion was reflected in elevated Ag-stimulated IL-9 cytokine levels in whole blood culture supernatants. Finally, the frequencies of Th9 cells correlated positively with the severity of lymphedema (and presumed inflammation) in filarial-diseased individuals. This expansion of Th9 cells was dependent on IL-4, TGF-β, and IL-1 in vitro. We have therefore identified an important human CD4(+) T cell subpopulation coexpressing IL-9 and IL-10, but not IL-4, the expansion of which is associated with disease in chronic lymphatic filariasis and could potentially have an important role in the pathogenesis of other inflammatory disorders.

Topics: CD4-Positive T-Lymphocytes; Elephantiasis, Filarial; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-1; Interleukin-10; Interleukin-4; Interleukin-9; T-Lymphocyte Subsets; Transforming Growth Factor beta

Wolbachia, an endosymbiont present in filarial nematodes, have been implicated in a variety of roles, including the worm development and survival. Elucidation of the role of Wolbachia in filarial nematode biology and pathogenesis has become the focus of many studies and its contribution to parasite survival or immune response is still unclear. Recombinant Wolbachia HSP60 decreases T cell activation and lymphoproliferation in filarial infected people compared to endemic controls as observed by the assessment of T cell activation markers and cytokine responses in the peripheral blood mononuclear cells. Reduced T cell activation may be linked to T regulatory cell activity since it is associated with increased expression of CTLA4 and CD25 on CD4(+) T cells in filarial infected group upon stimulation with recombinant Wolbachia HSP60. In addition, elevated interleukin-10 and TGF-β cytokines corroborate the reduced CD4(+) T cell activation and interferon-γ observed upon recombinant Wolbachia HSP60 stimulation in filarial patients. Hence, these findings indicate that Wolbachia HSP60 may also contribute to the immune modulation seen in filarial patients.

Topics: Adolescent; Adult; Animals; Bacterial Proteins; Brugia malayi; Cells, Cultured; Chaperonin 60; Child; CTLA-4 Antigen; Elephantiasis, Filarial; Female; Humans; Immunomodulation; Interferon-gamma; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Lymphocyte Activation; Male; Recombinant Proteins; Symbiosis; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Wolbachia

Patent lymphatic filariasis is characterized by a profound down-regulation of immune responses with both parasite Ag-specific tolerance and bystander suppression. Although this down-regulation is confined to the Th1 arm of the immune system in response to parasite Ag, we hypothesized a more generalized suppression in response to live parasites. Indeed, when we examined the cytokine profile of a cohort of filaria-infected (n = 10) and uninfected (n = 10) individuals in response to live infective-stage larvae or microfilariae of Brugia malayi, we found significant impairment of both Th1 and Th2 cytokines characterized by diminished production of IFN-gamma, TNF-alpha, IL-4, IL-5, and IL-10 in infected patients. The molecular basis of this impaired Th1/Th2 response was examined, and we identified three major networks of immunoregulation and tolerance. First, impaired induction of T-bet and GATA-3 mRNA underlies the Th1/Th2 deficiency in infected individuals. Second, regulatory networks, as evidenced by significantly increased expression of Foxp3 (natural regulatory T cell marker) and regulatory effectors such as TGF-beta, CTLA-4, PD-1, ICOS, and indoleamine 2,3-dioxygenase play an important role in immunosuppression. Third, the compromise of effector T cell function is mediated by the enhanced induction of anergy-inducing factors cbl-b, c-cbl (cbl is abbreviation for Casitas B lymphoma), Itch, and Nedd4. Indeed, blocking CTLA-4 or neutralizing TGF-beta restored the ability to mount Th1/Th2 responses to live parasites and reversed the induction of anergy-inducing factors. Hence, we conclude that a profound impairment of live parasite-specific Th1 and Th2 immune responses occurs in lymphatic filariasis that is governed at the transcriptional level by a complex interplay of inhibitory mediators.

Topics: Animals; Antibodies, Blocking; Antigens, CD; Antigens, Differentiation; Brugia malayi; Cells, Cultured; CTLA-4 Antigen; Cytokines; Down-Regulation; Elephantiasis, Filarial; Forkhead Transcription Factors; GATA3 Transcription Factor; Host-Parasite Interactions; Humans; Immune Tolerance; Signal Transduction; Suppressor of Cytokine Signaling Proteins; T-Box Domain Proteins; Th1 Cells; Th2 Cells; Transcription Factors; Transforming Growth Factor beta; Ubiquitin-Protein Ligases

The immunological mechanisms involved in maintenance of an asymptomatic microfilaremic state (MF) in patients with lymphatic filariasis remain undefined. MF patients have impaired filarial antigen (Ag)-specific lymphocyte proliferation and decreased frequencies (Fo) of Ag-specific T cells, and yet elevated serum IgE and antifilarial IgG4. To investigate the mechanism of Ag-specific anergy in MF patients in contrast to amicrofilaremic individuals with chronic lymphatic obstruction (CP), the Fo of Ag-specific lymphocytes from peripheral blood mononuclear cells secreting either IL-4 or IFN-gamma were assessed by filter spot enzyme-linked immunosorbent assay, and IL-10 and transforming growth factor-beta (TGF-beta) mRNA transcript levels were assessed by a semiquantitative reverse transcriptase polymerase chain reaction technique. The Fo of filaria-specific IL-4-secreting lymphocytes were equivalent in both MF (geometric mean [GM] = 1:11,700) and CP (GM = 1:29,300 P = 0.08), whereas the Fo of IFN-gamma-secreting lymphocytes were lower in MF (GM = 1:39,300) than in CP (GM = 1:4,200, P < 0.01). When the ratio of IL-4/IFN-gamma (T helper type 2 [Th2]/Th1)-secreting cells was examined, MF subjects showed a predominant Th2 response (8:1) compared with a Th1 response in CP individuals (1:4). mRNA transcript levels of IL-10 were also significantly elevated in MF compared with CP individuals (P < 0.01). Further, IL-10 and TGF-beta were shown to have a role in modulating the Ag-specific anergy among MF subjects, in that neutralizing anti-IL-10 or anti-TGF-beta significantly enhanced lymphocyte proliferation response (by 220-1,300%) to filarial Ags in MF individuals. These findings demonstrate that MF subjects respond to parasite antigen by producing a set of suppressive cytokines that may facilitate persistence of the parasite within humans while producing little clinical disease.

Topics: Adult; Animals; Antibodies, Helminth; Brugia malayi; Cytokines; Elephantiasis, Filarial; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin E; Immunoglobulin G; Interferon-gamma; Interleukin-10; Interleukin-4; Middle Aged; RNA, Messenger; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Transcription, Genetic; Transforming Growth Factor beta