RA-Related Autoantibodies in Healthy FDR of RA Patients

RA 患者健康 FDR 中的 RA 相关自身抗体

• 批准号: 8324330
• 负责人: JILL M NORRIS
• 金额: $ 37.73万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-18 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324330
• 关键词: Address; Affect; Alleles; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmunity; Breast Feeding; Cereals; Child; Clinical; Coffee; Colorado; DR1 gene; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Enrollment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epitopes; Estrogens; Evolution; Exhibits; First Degree Relative; Food; Genetic; Genetic Risk; Gluten; Goals; Health Sciences; Hyperglycemia; Individual; Infectious Pregnancy Complications; Injury; Insulin-Dependent Diabetes Mellitus; Joints; Manuscripts; Milk; Modality; Morbidity - disease rate; Newborn Infant; Oral Contraceptives; Organ; Outcome Measure; Pathogenesis; Patients; Peptide antibodies; Performance; Phase; Population; Population Study; Populations at Risk; Prevention; Prevention strategy; Prospective Studies; Randomized; Recruitment Activity; Research Design; Rheumatoid Arthritis; Risk; Severities; Signs and Symptoms; Silicon Dioxide; Site; Smoking; TNFRSF10A gene; Therapeutic; Therapeutic Intervention; Toxic Environmental Substances; Universities; Vaccination; Virus Diseases; base; cohort; cyclic citrullinated peptide; endocrine pancreas development; epidemiologic data; experience; high risk; inflammatory marker; insight; interest; joint destruction; mortality; pill; population based; primary outcome; proband

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.

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，会影响关节和关节外部位，导致关节破坏，明显的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，大多数受该特定疾病影响的个体最终表现出3个疾病进展的阶段：1）主要通过HLA关联运输遗传风险，主要是通过HLA关联，2）至少存在临床上静音自身抗体至少几年，并且至少存在3）临床上的超级抗体。我们建议RA还表现出这些疾病的这些阶段，并且以与1型DM相似的方式分析了遗传性高危，自身抗体阳性的流行病学关联，但临床上未受影响的个体的临床无症状人群将提供对这种疾病病原体的重要见解。先前对受RA影响的个体的分析已经建立了在某些HLA DR4和DR1等位基因内与RA的遗传风险和严重程度之间携带的“共享表位”的显着关系。在受影响个体中RA的存在与指定抗环状柠檬硫化肽（CCP）抗体的高度特异性自身抗体之间的RA存在之间也存在新建立的关系。几项研究还表明，在临床疾病发作之前几年可能存在抗CCP和其他与RA相关的自身抗体。但是，除了我们最近开发的初步数据外，对于任何具有遗传风险但尚未受到RA影响的人群中，高风险HLA等位基因的关联以及与RA相关的抗体的存在知之甚少。此外，二氧化硅，咖啡，雌激素，妊娠，感染和环境毒素等暴露之间的关联也很熟悉。从以前的人群研究中，我们知道，受RA影响的个体的一级亲戚（FDR）表现出大大增加患疾病的风险，这可能是由于遗传和环境因素所致。我们建议识别和研究RA患者的FDR人群，以解决以下特定目的：具体目的＃1：在不受RA的个体的FDR中，确定了高风险HLA等位基因的运输与RA相关的自动抗体的存在之间的关联。具体目的＃2：在未受影响的FDR人群中，确定流行病学暴露与RA相关自身抗体的存在之间的关联。我们认为，定义这些因素之间的关系对于增加对RA的免疫发病的理解以及可能成为预防候选者或非常早期治疗干预措施的临床上未受影响的个体的策略很重要。

项目成果

Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumatoid arthritis.

类风湿性关节炎中多功能 T 细胞与天然和糖基化 II 型胶原的反应性。

• DOI: 10.1002/art.34459
• 发表时间: 2012
• 期刊: Arthritis and rheumatism
• 作者: Snir,Omri;Backlund,Johan;Bostrom,Julia;Andersson,Ida;Kihlberg,Jan;Buckner,JaneH;Klareskog,Lars;Holmdahl,Rikard;Malmstrom,Vivianne
• 通讯作者: Malmstrom,Vivianne

Towards prevention of autoantibody-positive rheumatoid arthritis: from lifestyle modification to preventive treatment.

• DOI: 10.1093/rheumatology/kev347
• 发表时间: 2016-04
• 期刊: Rheumatology (Oxford, England)
• 作者: Gerlag DM;Norris JM;Tak PP
• 通讯作者: Tak PP