Genetics of ankylosing spondylitis—insights into pathogenesis

Abstract

Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B(*)27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B(*)27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B(*)27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.

The Ankylosing Spondylitis-Associated HLA-B*2705 Presents a B*0702-Restricted EBV Epitope and Sustains the Clonal Amplification of Cytotoxic T Cells in Patients

“…The antigen presentation performed by such HLA-B supertypes could be a key event (7,21). A way to validate this hypothesis could be a functional comparison between very close pair of alleles, like as the B*2705 and the B*2709, which have a single amino acid substitution (Asp116His) (22) but are differently associated with AS (19,(23)(24)(25).…”

New Possibilities of Pharmacotherapy for Immunoinflammatory Rheumatic Diseases: A Focus on Inhibitors of Interleukin-17

“…Как и при псориазе, отмечена связь между развити-ем ПсА и носительством однонуклеотидного (протектив-ного) полиморфизма генов, кодирующих ИЛ23R и ИЛ23, а также полиморфизмом гена ACT1 (TRAF3IP2), участву-ющего в сигнализации, опосредуемой ИЛ17R [34,35].…”

“…В отличие от РА и ПсА, для ко-торых характерна деструкция костной ткани, уникальной чертой АС является образование новой костной ткани [33]. Наряду со строго доказанной ролью HLA-B27 при АС, в недавних исследованиях была продемонстрирована связь между полиморфизмом гена, кодирующего ИЛ23Р, и предрасположенностью к развитию АС [34,35]. Широ-комасштабный скрининг генома позволил установить, что носительство варианта ИЛ23Р rs11209026 (arg381Gln) предотвращает развитие АС и ассоциируется со снижени-ем фосфорилирования STAT3 и синтеза ИЛ17.…”

“…Широ-комасштабный скрининг генома позволил установить, что носительство варианта ИЛ23Р rs11209026 (arg381Gln) предотвращает развитие АС и ассоциируется со снижени-ем фосфорилирования STAT3 и синтеза ИЛ17. В развитии АС (а также псориаза и ВЗК) предполагается участие и других генов, связанных с осью ИЛ23/ИЛ17, в том чис-ле ИЛ6Р, ИЛ12В, ИЛ27, CADR9 (nuclear transcription factor Y subunit B-4-like), STAT3 и TYK2, а также эпигенети-ческих «автографов» этих генов [35,36]. По данным экс-периментальных исследований, воспаление, связанное с активацией оси ИЛ17/ИЛ23, приводит к развитию арт-рита, энтезита [37][38][39] и новой костной ткани при АС.…”

Endothelial Dysfunction and Cardiovascular Risk in Patients With Ankylosing Spondylitis

“…[8] It is caused by cardiovascular disease and chronic renal failure [3]. It is established that the presence of chronic systemic inflammation is an important predictor of cardiovascular (CV) disease [5; 7; 12] due to the development of endothelial dysfunction, and further -atherosclerosis and atherothrombosis, remodelling of vascular wall and myocardium [10] and, therefore, the main cause of numerous life-threatening adverse conditions.…”