Altered Circulating Levels of Matrix Metalloproteinases and Inhibitors Associated with Elevated Type 2 Cytokines in Lymphatic Filarial Disease

Lymphatic filariasis afflicts over 120 million people worldwide. While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology characterized by swelling of the scrotal area and lower limbs (hydrocele and lymphedema). Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. 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 inhibitors—as well as elevated levels of pro-fibrotic cytokines—characterize filarial infection-induced lymphatic pathology

Modulation of CD4+and CD8+T-Cell Function by Interleukin 19 and Interleukin 24 During Filarial Infections

Interleukin 19 (IL-19) and interleukin 24 (IL-24) are cytokines that are highly expressed in filarial infections. To study the role of IL-19 and IL-24 in regulating T-cell responses, we examined the frequency of T-helper type 1 (Th1)/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, Th22/Tc22, and Tr1 cells in 26 filariae-infected individuals stimulated with filarial antigen following IL-19 or IL-24 neutralization. IL-19 or IL-24 neutralization resulted in significantly enhanced frequencies of Th1/Tc1 and/or Th17/Tc17 cells and significantly reduced frequencies of Th2/Tc2, Tr1, and/or Th9/Tc9 cells. Thus, we demonstrate that IL-19 and IL-24 are associated with the modulation of T-cell responses in filarial infections

Parasite Antigen-Specific Regulation of Th1, Th2, and Th17 Responses in Strongyloides stercoralis Infection

Chronic helminth infections are known to be associated with modulation of antigen - specific CD4(+) T responses. However, the role of CD4(+) T cell responses in human infection with Strongyloides stercoralis (Ss) is not well-defined. To examine the role of CD4(+) T cells expressing Th1, Th2 and Th17 cytokines in strongyloidiasis, we compared the frequency of these subsets in infected individuals (INF) to frequencies (F(o)) in Ss-uninfected (UN) individuals. INF individuals exhibited a significant decrease in the spontaneous and antigen specific F(o) of both mono - and dual functional Th1 cells compared to UN. Similarly, INF individuals also exhibited significantly decreased F(o) of mono - and dual - functional Th17 cells upon antigen - stimulation compared to UN. In contrast, both the spontaneous and antigen - induced F(o) of mono- and dual - functional Th2 cells was significantly increased in INF compared to UN individuals. This differential T cell response was predominantly antigen - specific since it was abrogated upon control antigen or mitogen stimulation. The regulation of Th1, Th2 and Th17 cells was pre-dominantly dependent on IL-10, while the regulation of Th2 but not Th1 or Th17 cells was also dependent on TGFβ. In addition, treatment of Ss infection significantly increased the antigen - specific F(o) of Th1 and Th17 cells and decreased the F(o) of Th2 cells in INF individuals. Thus, Ss infection is characterized by a parasite - antigen dependent regulation of mono- and dual - functional Th1, Th2 and Th17 cells, a regulation also reversible by anti-helminthic treatment