Rheumatoid arthritis (RA) is one kind of chronic inflammation disease. It affects not only joint, but often has the infringement outside the joint, such as internal organs. Besides the environmental factor, the heredity factor is involved in the pathogenesis of RA too. HLA-DR4 was found to play a role in RA pathogenesis in Taiwan. Because the DR4 positive patients actually are only one-half, other than HLA-DR gene may also be involved in RA pathogenesis. NF£eB plays an important role in immune inflammation. Activity of I£eB can affect NF£eB. I£eB£\ is a critical member in the I£eB protein family. Moreover, I£eBL is functionally similar to I£eB£\. Therefore we extrapolated polymorphisms of I£eBL gene and I£eB£\ gene of the RA patients and normal subjects. In this research, studies of these two genes from 79 RA patients and 81 normal subjects were divides into two parts. The first part used polymerase chain reaction, direct sequencing, special sequence polymerase chain reaction as well as limit fragment length polymorphism to study relations between I£eBL gene and HLA-DR4 and RA occurrence. The second part used polymerase chain reaction and limit fragment length polymorphism, to analyze relation between I£eB£\ gene and the RA occurrence. We found that there is significant increase of -421 -/A base deletion polymorphism in I£eBL gene from DR4 positive RA patients and -262 T/C polymorphism in I£eBL gene from DR4 negative RA patients. A significant reduction of -519 C/T polymorphism in I£eB£\ gene from DR4 negative RA patients was found too. In conclusion, polymorphisms of -421 -/A base deletion as well as -262 T/C in I£eBL gene may be involved in the pathogenesis of RA by alteration of I£eBL activity and thereafter binding of I£eBL to NF£eB.

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Thesis (Ph. D.)--University of Missouri-Columbia, 2001. / Typescript. Vita. Includes bibliographical references (leaves 83-86). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2001. / Typescript. Vita. Includes bibliographical references (leaves 83-86). Also available on the Internet.

Thesis--University of Michigan. / Microfilm copy of typewritten ms. Positive. Collation of the original: vi, 168 l. mounted illus. (part col.) tables. Bibliography: leaves 160-168.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 71-79). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 71-79). Also available on the Internet.

published_or_final_version / Dentistry / Master / Master of Dental Surgery

published_or_final_version / Orthopaedics and Traumatology / Master / Master of Medical Sciences

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent destruction of synovial joints. Although its causes remain largely unknown, a substantial genetic contribution is known to exist. During the last decades the benefits of early aggressive treatment have become evident, and more potent therapeutic options have become available. These advances have increased the demands for rapid accurate diagnosis and prognostic markers of disease course and therapy response. The ‘rheumatoid factor’ (RF) has long been used as a diagnostic and prognostic marker of RA. In this thesis, the utility of measuring antibodies to cyclic citrullinated peptides (CCP) was investigated. In a population-based arthritis incidence study, 69 very early arthritis patients (symptom duration < 3 months) were identified. The anti-CCP test, performed at baseline and related to diagnosis at the 2-year follow-up, had a diagnostic specificity for RA of 96% and a sensitivity of 44%, both of which were superior to RF. In a prospective cohort of 242 incident cases of RA (symptom duration < 1 year), 64% of the patients tested positive for anti-CCP at baseline (equal to RF). Despite receiving more active anti-rheumatic therapy, the anti-CCP-positive patients had a more aggressive disease course during 3 years as compared to those testing negative. The 158VV genotype of Fcγ Receptor type IIIA (FcγRIIIA), which binds IgG with higher affinity than 158FF, was associated with an increased susceptibility to RA in men, but not in women. Previous studies report conflicting results, and none stratified according to gender. The 158V/F polymorphism of FcγRIIIA was not found to influence outcome of anti-tumour necrosis factor therapy in 282 RA patients, contradicting hints from previous studies. Genetic variation in proteins of the inflammasome, an interleukin-1 (IL-1) regulating intracellular protein complex, is associated with rare autoinflammatory conditions and possibly with Crohn’s disease. In this first study on genetic variation of the inflammasome in RA, we describe a compound polymorphism of the genes CIAS1 and TUCAN that associates both with susceptibility to RA and to the severity of the disease. Hypothetically, these genes may identify a subgroup of RA patients that would benefit from anti-IL-1 therapy. This thesis work emphasizes the benefits of testing for anti-CCP in the diagnosis and outcome prediction in early arthritis. FcγRIIIA genotype is likely to affect RA susceptibility and further work should apply a gender perspective. Inflammasome genetics may influence the risk of developing RA. Additional studies are warranted to settle whether it also identifies a subgroup of RA patients benefiting from IL-1 targeted therapy.