The goal of the ICER (International Centers for Excellence in Research) program is to develop a sustained research program in areas of high infectious disease burden through partnerships with scientists and physicians in developing countries in three countries, Mali, Uganda, and India. The stated goal of the ICER program was to partner with in-country scientists to address major endemic diseases and foster research in areas such as malaria, HIV, filarial infections and tuberculosis. The hope was to build sustainable research programs by providing a long-term commitment, thus allowing difficult research challenges to be addressed, and, importantly, to train local scientists so that they are prepared to tackle emerging and re-emerging infectious diseases into the future. By the expression patterns of arginase 1 (Arg 1)/NO synthase 2 (Nos2), alternative activation markers, and cytokines in monocytes from filaria infected (INF) and uninfected (UN) individuals ex vivo and in response to filarial antigen, we have shown that monocytes from INF exhibit significantly diminished expression of Nos2 and significantly enhanced expression of Arg 1. These changes were associated with significantly increased expression of resistin, mannose receptor C type 1 (MRC 1), macrophage galactose type C lectin (MGL), and chemokine ligand 18 (CCL18). In response to BmA, purified monocytes from infected individuals also expressed significantly lower levels of IL 12 and IL 18 but, in contrast, exhibited significantly higher levels of expression of TGFβ, IL 10, and SOCS 1. Inhibition of arginase resulted in significantly diminished expression of resistin, MRC 1, MGL, and CCL18 as well as significantly enhanced expression of Nos2, IL 12, and IL 18 suggesting that arginase is involved in the establishment of the alternatively activated phenotype and immunoregulatory function of monocytes. Thus, patent human filarial infection is associated with the expansion of monocytes characterized by an arginase dependent 'alternatively'activated immunoregulatory phenotype. As lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele and elephantiasis we have elucidated the role of CD4+ T cell subsets in the development of lymphatic pathology by examining, of cytokines in individuals with filarial lymphedema and compared them to responses from asymptomatic, infected individuals. Parasite antigen but not control antigen induced significantly higher production of the prototypical Th1-type cytokines IFNg and TNFa in patients with lymphedema compared to asymptomatic individuals. Interestingly, the expression of the Th17 family of cytokines IL-17A, IL-17F, IL-21 and IL-23 was also significantly upregulated by BmA stimulation in lymphedema patients. On the other hand, expression of natural regulatory T cell markers - Foxp3 and GITR - was significantly impaired in lymphedema patients. While we did not find any significant differences in the expression of TLRs following parasite Ag stimulation, BmA induced significant upregulation of Nod1 and Nod2 in patients with lymphedema. Our findings implicate increased Th1/Th17 responses, decreased Tregs as well as NLR in the pathogenesis of filarial lymphedema. Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of a tissue invasive helminth may modulate the predominant Th1 (IFN γmediated) response needed to control Mycobacterium tuberculosis (Mtb) infection. By analyzing the cellular responses to mycobacterial antigens (in patients with latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with Mtb significantly diminishes Mtb specific Th1 (IL 12/IFN γ) and Th17 (IL 23/IL 17) responses that was related to increased expression of CTLA 4 and PD 1. Blockade of CTLA 4 restored production of both IFN γand IL 17, while PD 1 blockade restored IFN γproduction only. Thus, coincident filarial infection exerted a profound inhibitory effect on protective mycobacterial-specific Th1 and Th17 responses in latent tuberculosis and suggests a mechanism by which concomitant filarial (and other systemic helminth) infections predispose to the development of active tuberculosis in humans. The factors governing latency in tuberculosis are not well understood, but appear to include pathogen and host factors. To study the role of Th1, Th2 and Th17 responses in latent tuberculosis, we examined the immune responses of those tuberculin skin test positive (PPD+;latent TB) or skin test negative (PPD- healthy contacts) individuals to PPD, Mtb culture filtrate antigen (Mtb CFA) or anti-CD3. While PPD- and Mtb CFA-specific Th1 and Th2 cytokines were not significantly different between the two groups, Th17 cytokines IL-17 and IL23 were significantly decreased in PPD+ individuals. This cytokine modulation is associated with significantly increased expression of CTLA-4 as well as Foxp3 in response to PPD and Mtb CFA. While CTLA-4 blockade had no significant effect on IL-17 and IL-23 production of PPD+ individuals, depletion of Tregs significantly increased the production of both cytokines. Thus, latent Tb is characterized by an increased activity of Tregs and a coincident downregulation of Th17 cells.
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