The mechanisms underlying the profound modulation of parasite antigen-specific human T cell responses in lymphatic filariasis have been addressed by demonstrating the multiple pathways involved. In terms of APC dysfunction, human monocytes from patients with patent filarial infections are studded with filarial antigen and express markers associated with alternative activation of macrophages (MΦ). To explore the role of filaria-derived parasite antigen in differentiation of human monocytes, cells were exposed to microfilariae (mf) of Brugia malayi, and their phenotypic and functional characteristics were compared with those of monocytes exposed to factors known to generate either alternatively (interleukin-4 IL-4) or classically (macrophage colony-stimulating factor MCSF) activated MΦ. IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of MΦbut not arginase 1. IL-4-cultured monocytes had a diminished ability to promote proliferation of both CD4(+) and CD8(+) T cells compared to that of unexposed monocytes. Similar to results with IL-4, exposure of monocytes to live mf induced upregulation of CCL15, CCL17, CCL18, CCL22, CD274, and CD273 and downregulation of Toll-like receptor 3 (TLR3), TLR5, and TLR7. Exposure of monocytes to mf resulted in significant inhibition of the phagocytic ability of these cells to the same degree as that seen with IL-4. Our data suggest that short exposure of human monocytes to IL-4 induces a phenotypic characteristic of alternative activation and that secreted filarial products skew monocytes similarly. The mechanisms underlying the profound modulation of parasite antigen-specific human T cell responses in lymphatic filariasis have been addressed by demonstrating the multiple pathways involved. While several mechanisms have been implicated in mediating this T cell specific downregulation, the role for alterations in the homeostasis of T effector and memory cell populations was explored using multiparameter flow cytometry. Compared to filarial-uninfected endemic normals (EN), microfilaria (mf) positive infected patients (Inf) had a reduced CD4 central memory (T(CM)) compartment. In addition, Inf patients tended to have more effector memory cells (T(EM)) and fewer effector cells (T(EFF)) than did ENs giving significantly smaller T(EFF):T(EM) ratios. These contracted T(CM) and T(EFF) populations were still evident in patients previously mf+ who had cleared their infection (CLInf). These data indicate that filarial-infected patients have contracted T(CM) compartments and a defect in effector cell development, defects that persist even following clearance of infection. The fact that these global changes in memory and effector cell compartments do not yet occur in infected children makes early treatment of LF even more crucial. Beyond the APC dysfunction, T cells from patients with patent infection have induced pathways that in concert prevent Th1-type T cell activation. We have recently shown that the filarial infection at homeostasis is associated with an expansion of IL-10 producing adaptive Tregs as well as nTregs and that these are associated with the suppression of parasite-antigen induced pro-inflammatory Th1 cells. Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to study the spillover effect of the downregulation on responses and diseases that are non-parasitic. To this end, we have both clinical trials underway and in vitro models that have demonstrated the influence of pre-existing chronic helminth infection on susceptibility to mycobacteria, on modulating the response to aeroallergens, and potentially to HIV and malaria. Specifically, we have recently demonstrated that coincident filarial infections profoundly alter the pro-inflammatory and Th1/Th17 responses to malarial antigens (in filarial/malarial coinfections) and to mycobacterial antigens (in filarial/latent tuberculosis coinfections). Lymphatic filarial disease manifested by overt, morbid clinical pathology, characterized by swelling of the scrotal area and limb edema (hydrocele, elephantiasis, lymphedema) has been shown to be related to immunologic and pro-inflammatory factors. Circulating microbial products such as LPS and markers associated with microbial translocation have been shown to play an important role in disease pathogenesis of certain infections like HIV. Similarly, proteins associated with the acute phase response and related cytokines also play an important role in pathogenesis. We have attempted to elucidate the role of the above mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in four groups of individuals: chronic pathology individuals with or without active filarial infection, asymptomatic, filarial infected individuals and uninfected, endemic normal individuals. We show that circulating levels of LPS, acute phase proteins and certain cytokines are significantly elevated in filarial disease with active infection but not in the other groups indicating that filarial infection induced increased production of these factors correlated with the development of filarial lymphatic pathology. Tissue fibrosis is also a hallmark of lymphatic filarial disease. Matrix metalloproteinases are a family of circulating and tissue proteins that influence the development of tissue fibrosis. They are regulated by another family of proteins called tissue inhibitors of metalloproteinases. The interplay between these proteins governs tissue fibrosis in a variety of conditions. In addition, certain cytokines are known to promote pro-fibrotic events. We have attempted to elucidate the role of the above-mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in four groups of individuals: chronic pathology individuals with or without active filarial infection;asymptomatic, filaria-infected individuals;and uninfected, endemic normal individuals. We show that altered ratios of the metalloproteinases and their inhibitorsas well as elevated levels of pro-fibrotic cytokinescharacterize filarial infection-induced lymphatic pathology. Filarial-induced CD4+ and CD8+ responses have been characterized fully (using microarray/quantitative RT-PCR) in both the generally more-responsive expatriate patients and the less responsive indigenous (with lifelong exposure) filarial-infected patients. These data provide clues to the pathways induced by infection and those systemic alterations seen in chronic helminth infection.

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33
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2012
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$1,417,614
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Tosh, Kevin W; Mittereder, Lara; Bonne-Annee, Sandra et al. (2016) The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion. J Immunol 196:345-56
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