RA-Related Autoantibodies in Healthy FDR of RA Patients

描述（由申请人提供）：类风湿关节炎（RA）是一种自身免疫性疾病，影响关节和关节外部位，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，大多数最终患有这种特殊疾病的个体表现出3个阶段的疾病进展：1)主要通过HLA关联携带遗传风险，2)至少存在若干年的临床沉默自身抗体，3)临床明显的高血糖。我们认为类风湿性关节炎也表现出这些疾病阶段，并且与1型糖尿病类似，在遗传风险、自身抗体阳性但未受影响的临床无症状人群中分析流行病学关联将为该疾病的发病机制提供重要见解。先前对类风湿关节炎患者的分析表明，某些HLA DR4和DR1等位基因中携带的“共享表位”与类风湿关节炎的遗传风险和严重程度存在显著关系。此外，RA患者的存在与高特异性RA相关自身抗体（抗环瓜氨酸肽（CCP）抗体）之间也有新的关系。一些研究也表明，抗ccp和其他ra相关的自身抗体可能在临床发病前几年就存在。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相关抗体存在的关联知之甚少，这些抗体存在于任何遗传上有风险但尚未受RA影响的人群中。此外，吸烟、咖啡、雌激素、怀孕、感染和环境毒素（如二氧化硅）与ra相关自身抗体的存在之间的关系也知之甚少。从以前的人群研究中我们知道，患有类风湿性关节炎的个体的一级亲属（fdr）表现出显著增加的患病风险，可能是由于遗传和环境因素。我们建议确定和研究RA患者的fdr人群，以满足以下特定目的：特定目的1：在RA患者未受影响的fdr中，确定高风险HLA等位基因携带与RA相关自身抗体存在之间的关系。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对于增加对类风湿性关节炎免疫发病机制的理解非常重要，也可能为选择临床未受影响的个体制定策略，这些个体将成为预防模式或早期治疗干预的候选人。

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.