Regulation of immunity and inflammation during parasitic helminth infection by inflammasomes

More than 1.5 billion people, or 24% of the world's population, are infected with helminths worldwide. Infections are highly epidemic in tropical and subtropical areas, with the greatest numbers occurring in sub-Saharan Africa, the Americas, China and East Asia. Helminths are strongly immunomodulatory, which has facilitated their ability to resist attack by their host's immune system, which has made attempts to vaccinate against parasitic helminths an enormous challenge. In order to develop a vaccine, we need to understand more about the nature of the protective immune response against helminths, and how helminths have evolved to control the host immune system to enable their survival. Inflammasomes are important for immunity against invading microbial pathogens such as bacteria, viruses and protozoa by promoting the maturation and secretion of inflammatory cytokines such as IL-18 and IL-1β and resultant Type 1-mediated immunity. However, the roles for inflammasomes in Type 2 immunity to parasitic helminths are less well studied. Therefore, this dissertation has focused on studying the roles of distinct inflammasome activation pathways (NLR Family Pyrin Domain Containing (NLRP3 and NLRP1) in immunity and inflammation following infections with multiple species of gastrointestinal helminth. Firstly, we show that intestinal whipworm infection, Trichuris muris, and its excretory/secretory proteins can promote NLRP3-dependent IL-18 and IL-1β secretion in vivo and in vitro, in concert with signals from bacteria. Critically, we have identified a novel mechanism by which NLRP3-dependent IL-18 suppresses innate and adaptive immune responses to T. muris, resulting in immunopathology and more persistent infections. This suggest that worm-mediated NLRP3 inflammasome activation is one potential mechanism of how parasitic worms may enhance their survival in their host. We next assessed whether NLRP3 plays a similar or different role in regulation of immunity to a different species of parasite helminth, Nippostrongylus brasiliensis, a model of hookworm that infects both the lung and intestine. Similar to results we observed with whipworm infections, N. brasiliensis infections promoted NLRP3-dependent increases in IL-18 and IL-1β levels in the lungs and gut and ablation of NLRP3 resulted in increased anti-parasitic immunity in the lung. NLRP3-deficient mice displayed marked increases in neutrophil recruitment to the lung, a cell type that is potently toxic to parasite larvae. Thus we demonstrate that NLRP3 may restrain anti-parasitic neutrophil responses within the lung. Lastly, we investigated for the first time the role for a distinct inflammasome regulator, NLRP1, in immunity to a parasitic helminth. We found that NLRP1 does suppress immunity to both T. muris and N. brasiliensis infection in a similar way to NLRP3, however NLRP3 appears to play a greater role in regulating innate immunity to N. brasiliensis, in particular. Together these data provide novel insights into the activating and regulatory pathways of both the innate and adaptive immune systems following gastro-intestinal helminth infections. By understanding the precise mechanism of how inflammasomes regulate immunity and inflammation following helminth infection, it may help inform the development of novel vac vaccines against human infections

Study ABO / Rh Systems with IL-18 & IL-33 in Iraqi Patients with Diabetes Mellitus Type II

Type 2 diabetes mellitus (DM) is a group of metabolic disorder disease. The inflammatory markers act as a new risk factor for development of type 2 diabetes with a possible association with ABO/Rh blood groups. Human ABO genes are located on chromosome 9q34.1-q34.2. The aim of this study was to investigate the possible association between inflammatory markers, interleukin (IL) -18 and IL-33 in type 2DM and ABO blood groups. Sixty four patients with newly diagnosed type2 DM and control group consist of twenty healthy Iraqi individual. Laboratory test were include ABO blood groups using standard serological procedures and detection IL-18 and IL-33 in serum by ELISA kits. The Present data showed a significant increase in the serum level of IL-18 between type 2 DM patients and control, while there was no significant difference in the serum level of IL-33. At the same time both study blood groups O patients & control showed lowest level of serum IL-18, while blood group A with allele A showed less concentration of IL-33 in patients & control. Blood group O showed the highest percentage in patients & control, also Rh positive showed higher percentage. In conclusion, positive relation between IL-18 concentration and risk of type 2 DM, thus may be a predictor for newly diagnostic diabetic patient, while Serum levels of IL-33 might be a predictor marker of disease progression. No associations were found between ABO & Rh groups with type 2 DM