Genetic variations in the NALP3 inflammasome a susceptibility factor for inflammatory diseases

Innate immunity has received impressive attention in the past decade owing to the discovery of the Toll like receptors (TLRs) and the NOD-like receptors (NLRs). While the TLRs specialize in fighting microbes at the cell surface, the NLRs complement by detecting and responding to intracellular microbes. Recently, the non-microbe sensing NLR called inflammasomes. have been identified. which senses metabolic stress as well as certain pathogenic microbes and elicits host's inflan1matory response. The NLR, NALP3 (formerly known as cryopyrin) forms a large cytoplasmic complex called the 'inflan1masome' when NALP3, activated by a stimuli, associates with the adaptor proteins ASC and CARD-8. This interaction leads to the activation of pro-inflanm1atory caspase-l which subsequently results in the formation ofInterleukin (IL)-IB and IL-18. Mutations in the gene encoding NALP3, termed NLRP3 can lead to its constitutive activation resulting in an uncontrolled production of IL-IB. These mutations have been implicated in hereditary inflammatory diseases, often grouped under cryopyrin associated periodic syndromes (CAPS). This thesis describes a patient with a long history of arthritis and antibiotic resistant feveL but without the typical symptoms of CAPS. The patient was found to be a heterozygous carrier of two common polymorphisms Q705K in NLRP3 and CIOX in the CARD-8. Experimental studies showed elevated levels of caspase-l and IL-I Bin the patient, and a total c1inical remission was achieved by IL-I B blockade. These two polymorphisms combined, were found to occur in approximately 4% of the controi population, suggesting the possibility of a genetic predisposition for inflanm1ation in these individua1s. Therefore, a cohort of rheumatoid arthritis (RA) patients, where elevated IL-I B could be one of the reasons behind chronic inflammation, was investigated. We found that carrying the combined polymorphisms resulted in increased RA susceptibility and a more severe disease course. Hypothetically, this subgroup of patients might benefit from IL-IB blockade. Additional studies are warranted to elucidate the functional effects of the two polymorphisms and to determine whether they identify a subgroup of patients that could benefit from IL-I targeted therapy. Given the structural similarity of NALP3 to other NALPs. the possibility of involvement of the alternative, homologous genes cannot be eliminated. List of original publications This thesis is based on the following two papers, which will be referred to by their Roman numerals I and II: Venna D, Lerm M, Blomgran Julinder R, EIiksson P, Söderkvist P and Särndahl E. Gene Polymorphisms in the NALP3 Inflanm1asome are Associated with InterlelJlön-1 Production and Severe Inflanm1ation. Relation to ConmlOn Inflan1matory Diseases? Arthritis Rheum 2008; 58: 888-894 II Kastbom A*, Verma D*, EIiksson P, Skogh T, Wingren G and