RA-Related Autoantibodies in Healthy FDR of RA Patients

描述（由申请人提供）：类风湿性关节炎（RA）是一种影响关节和关节外部位的自身免疫性疾病，导致关节破坏、显著发病率和死亡率增加。对另一种自身免疫性疾病1型糖尿病（DM）的分析表明，大多数最终受该特定疾病影响的个体表现出疾病进展的3个阶段：1）主要通过HLA相关性携带遗传风险，2）存在临床沉默的自身抗体至少数年，以及3）临床明显的高血糖症。我们认为，RA也表现出这些阶段的疾病，并以类似的方式作为1型糖尿病，分析流行病学协会内的遗传风险，自身抗体阳性，但临床上无症状的人口未受影响的个人将提供重要的见解，这种疾病的发病机制。先前对受RA影响的个体的分析已经建立了某些HLA DR4和DR1等位基因内携带的“共享表位”与RA的遗传风险和严重程度的显著关系。在受影响的个体中存在RA与高度特异性RA相关自身抗体（称为抗环瓜氨酸肽（CCP）抗体）之间也存在新建立的关系。一些研究还表明，抗CCP和其他RA相关自身抗体可能在临床疾病发作前几年就存在。然而，除了我们最近开发的初步数据外，我们对高危HLA等位基因与RA相关抗体在任何遗传风险但尚未受RA影响的人群中的存在的相关性知之甚少。此外，暴露如吸烟，咖啡，雌激素，怀孕，感染和环境毒素如二氧化硅和RA相关自身抗体的存在之间的关联也知之甚少。从以前的人群研究中，我们知道，受RA影响的个体的一级亲属（FDR）表现出患疾病的风险大幅增加，可能是由于遗传和环境因素。我们建议确定和研究人群的FDR的个人与RA，以解决以下具体目标：具体目标#1：在未受影响的FDR的个人与RA，确定之间的关联的高风险HLA等位基因的携带和RA相关的自身抗体的存在。具体目标#2：在未受影响的FDR人群中，确定流行病学暴露与RA相关自身抗体存在之间的关系。我们认为，确定这些因素之间的关系是很重要的，以增加对RA的免疫发病机制的理解，以及潜在的发展战略，选择临床上未受影响的个人谁将是预防模式或非常早期的治疗干预的候选人。

DESCRIPTION (provided by applicant): Rheumatoid Arthritis (RA) is an autoimmune disease that affects joints and extra-articular sites, leading to joint destruction, significant morbidity and increased mortality. Analysis of another autoimmune disease, Type 1 Diabetes Mellitus (DM), has shown that the majority of individuals ultimately affected with that particular disease exhibit 3 phases of disease progression: 1) Carriage of genetic risk primarily through HLA associations, 2) Presence of clinically silent autoantibodies for at least several years, and 3) Clinically apparent hyperglycemia. We propose that RA also exhibits these phases of disease and that, in a similar manner as Type 1 DM, analysis of epidemiologic associations within the genetically at-risk, autoantibody positive but clinically asymptomatic population of unaffected individuals will provide important insights into the pathogenesis of this disease. Previous analyses of individuals affected with RA has established a significant relationship of the "shared epitope" that is carried within certain HLA DR4 and DR1 alleles to both the genetic risk and severity of RA. There is also a newly-established relationship between the presence of RA in affected individuals and highly specific RA-related autoantibodies designated anti-cyclic citrullinated peptide (CCP) antibodies. Several studies have also demonstrated that anti-CCP and other RA-related autoantibodies may be present several years prior to the onset of clinical disease. However, with the exception of preliminary data we have recently developed, little is known about the association of high-risk HLA alleles and the presence of RA-related antibodies in any population that is genetically at-risk but not yet affected by RA. In addition, associations between exposures such as smoking, coffee, estrogens, pregnancy, infections, and environmental toxins such as silica and the presence of RA-related autoantibodies are also poorly understood. From previous population studies we know that first degree relatives (FDRs) of individuals affected with RA exhibit a substantially increased risk of developing disease, likely due to both genetic and environmental factors. We propose to identify and study a population of FDRs of individuals with RA in order to address the following specific aims: Specific Aim #1: In unaffected FDRs of individuals with RA, determine the association between the carriage of high risk HLA alleles and the presence of RA-related autoantibodies. Specific Aim #2: In this population of unaffected FDRs, determine the association between epidemiologic exposures and the presence of RA-related autoantibodies. We believe that defining the relationship between these factors is important to increasing the understanding of the immunopathogenesis of RA as well as potentially developing strategies for the selection of clinically unaffected individuals who would be candidates for prevention modalities or very early therapeutic interventions.