Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins

Hensvold, Aase; Magnusson, Patrik K. E.; Joshua, Vijay; Hansson, Monika; Israelsson, Lena; Ferreira, Ricardo; Jakobsson, Per‐Johan; Holmdahl, Rikard; Hammarström, Lennart; Malmström, Vivianne; Askling, Johan; Klareskog, Lars; Catrina, Anca I.

doi:10.1136/annrheumdis-2013-203947

Cited by 143 publications

(120 citation statements)

References 46 publications

(33 reference statements)

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…The sera autoantibodies are polyclonal and reactive to Ig (RF) [6], ACPAs [13] or carbamylated fetal calf serum (anticarb antibodies) [14]. There is a strong environmental component, rather than MHC genetics, driving the production of the RA autoantibodies, as shown in twin studies [15], indicating a role for the innate immune system. It is possible that the innate immune system, and in particular at the earliest time points, autoantibodies maybe less associated with MHC class II, and possibly reflect an activation of a natural repertoire of autoreactive B cells by innate immune responses.…”

Section: Stage 1 -Autoimmune Priming In Healthy Individualsmentioning

confidence: 99%

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

2014

Self Cite

View full text Add to dashboard Cite

Extensive genome-wide association studies have recently shed some light on the causes of chronic autoimmune diseases and have confirmed a central role of the adaptive immune system. Moreover, better diagnostics using disease-associated autoantibodies have been developed, and treatment has improved through the development of biologicals with precise molecular targets. Here, we use rheumatoid arthritis (RA) as a prototype for chronic autoimmune disease to propose that the pathogenesis of autoimmune diseases could be divided into three discrete stages. First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint-specific inflammatory reaction occurs. This inflammatory reaction might be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling. In this review, we discuss the stages involved in RA pathogenesis and the experimental approaches, mainly involving animal models that can be used to investigate each disease stage. Although we focus on RA, it is possible that a similar stepwise development of disease also occurs in other chronic autoimmune settings such as multiple sclerosis (MS), type 1 diabetes, and systemic lupus erythematosus.Keywords: Animal models r Autoimmunity r Rheumatology Revisiting past efforts of RA researchEven though much detail has been recently revealed on the genetics and epidemiology of autoimmune diseases, several concepts on autoimmunity have been around for a long time. Early rheumatology studies were already deeply engaged in analyzing rheumatoid factors (RFs), that is, autoantibodies to Ig, and the Correspondence: Dr. Rikard Holmdahl e-mail: Rikard.Holmdahl@ki.se strong genetic association of RA with the HLA-DR alloantigens. However, many of the underlying causes of RA and the different stages in the disease process are still unclear even with the most recent information and therefore many of the old conceptual questions remain.The main result of recent genome-wide association studies (GWAS) is the confirmation of the strong association between "classical" (RF-positive) RA and the "shared epitope" MHC class II alleles [1][2][3]. The shared epitope is a specific peptide-binding pocket, originally defined as a structure in the polymorphic DRB1 chain shared by many alleles with basic amino acids at positionwww.eji-journal.eu 1594 Rikard Holmdahl et al. Eur. J. Immunol. 2014. 44: 1593-1599 70 and 74 [2], to which one now also may add positions 11 and 13 that are also strongly associated with RA [3]. In addition, the identity of around hundred genetic loci, with minor contribution to RA susceptibility, strengthen the dogma that RA is caused by aberrant autoreactive T cells [4,5]. Even though the influence of MHC and CD4 + T cells are more validated than ever, we still search for th...

show abstract

Section: Stage 1 -Autoimmune Priming In Healthy Individualsmentioning

confidence: 99%

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The presence of anti-citrullinated protein antibodies (ACPA) is also highly specific to RA (over 90%) and linked with a more progressive, destructive arthritis (Klareskog et al, 2008;Silveira et al, 2007;Snir et al, 2010). ACPA have been described up to 10 years before disease onset and are additionally correlated with RA risk factors such as smoking and periodontal disease (Hensvold et al, 2015;Mahdi et al, 2009;Wegner et al, 2010). RF is generally thought to be absent from rodent models, but aggressive erosive disease is linked to the presence of anticitrullinated cyclic peptide antibodies (anti-CCP) which may be generated within RA pannus ELS.…”

mentioning

confidence: 99%

Animal models of rheumatoid arthritis: How informative are they?

McNamee

Williams

Seed

2015

European Journal of Pharmacology

View full text Add to dashboard Cite

Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo.3

show abstract

“…2). В отличие от больных РА, у здоровых людей, у которых в дальнейшем не наблюдалось развитие РА, выявляется низкий уровень АЦБ с ограниченной реактивностью к небольшому чис-лу цитруллинированных белков [47,48]. Поскольку пос-ле дебюта РА «сероконверсия» АЦБ наблюдается редко [49], это свидетельствует о том, что гиперпродукция ан-тител является «причинным» фактором, а не следствием болезни и рассматривается как важное доказательство существования «преклинической» системной «аутоим-мунной» фазы РА.…”

Section: роль ау тоантителunclassified

“…Примеча-тельно, что взаимодействие SE и КРТ возрастает при цит-руллинировании КРТ и инициирует передачу «внутрикле-точного сигнала», меняющего фенотип ДК, приводя к по-ляризации иммунного ответа по Th17-типу, снижению об-разования и ослаблению активности Т-регуляторных кле-ток [154,167]. Примечательно, что носительство SE в большей степени ассоциируется с высокими титрами по-лиреактивных АЦБ у пациентов с РА, чем АЦБ-позитив-ных пациентов без РА [48,168]. Это позволяет сделать вы-вод о том, что SE играет более важную роль в развитии РА у АЦБ-позитивных пациентов, чем в индукции синтеза самих АЦБ [169], в более широком смысле -РА как ауто-иммунного заболевания, чем «системного аутоиммуните-та» как фазы, предшествующей развитию РА.…”

Section: генетические фак торыunclassified

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

Насонов¹

2017

rsp

View full text Add to dashboard Cite

Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins

Abstract: Environment, lifestyle and stochastic factors may be more important than genetics in determining which individuals develop ACPAs. Genetic factors (particularly SE) may have a relatively larger role in determining which ACPA-positive individuals will ultimately develop arthritis.

Cited by 143 publications

References 46 publications

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

Animal models of rheumatoid arthritis: How informative are they?

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

Contact Info

Product

Resources

About