Project(s) for intake 2021:
Causes of chronic autoimmunity in Spondyloarthropathy
Reactive Arthritis (ReA), Ankylosing Spondylitis (AS) and other spondyloarthropathies (SpAs) are the second most frequent cause of chronic inflammatory rheumatisms worldwide affecting about 1% of the general population and, thus, represent a significant socio-economic burden. Although the etiology of SpAs is poorly understood, environmental and genetic components are critical risk factors. Infectious agents, such as Brucella and Chlamydia, play a crucial role in the determination of these multifactorial disorders. There is also a strong genetic predisposition linked to the major histocompatibility complex (MHC) Class I complex HLA-B27 gene: HLA-B27 is present in up to 90% of AS and 45% of ReA patients, but only in about 3% of the general population. HLA-B27 binds and presents certain unique peptides derived from bacterial, viral or self-antigens to CD8+ cytotoxic T (CTL) cells. This led to the suggestion that SpA pathogenesis is driven, at least in part, by the development of autoimmunity or autoinflammation. However, the underlying pathogenic mechanisms still have to be fully delineated.
Growing evidence indicates that HLA-B27-associated gut dysbiosis is an important contributor to SpA development. Gut dysbiosis may promote the abnormal microbial translocation across the intestinal epithelial barrier and the leakage of bacterial products into the systemic circulation. This, in turn, may contribute to autoimmunity or autoinflammation by influencing innate as well as adaptive immunity, locally in the gut as well as systemically. However, a mechanistic understanding of the link between the microbiome, HLA-B27, and SpAs has yet to fully emerge. The project will examine the association between gut dysbiosis, host genetic factors and autoimmunity/autoinflammation in Kazakh patient and control cohorts in collaboration with Dr. Almagul Kushugulova (NLA, NUSOM).
Aim 1: To map the composition of the gut microbiome of Kazakh SpA patients and investigate a potential linkage to HLA-B27.
Patients with SpA have an altered microbiota compared to normal individuals. Gut dysbiosis appears to be an early feature of SpA, preceding the onset of clinical disease in the gut or joints and is also associated with HLA-B27 status. Thus, characterization of gut dysbiosis in SpA may reveal biomarkers for early disease detection in patients at risk.
Aim 2. To identify immunologically relevant microbial markers in Kazakh SpA patients that may drive mucosal and systemic inflammation.
The objective of this aim is to identify immune-relevant microbiota associated with SpA. The central hypothesis is that IgA-coated microbiota in SpA are enriched with adherent-invasive E. coli and these isolates act as drivers of mucosal and systemic inflammation. To test this hypothesis, we will use an enrichment strategy to isolate, sequence, and compare highly IgA-coated bacteria from SpA patients and healthy controls.
Supported by: CRP “Infectious triggers of chronic autoimmunity in spondyloarthropathy (CITAS)”; Pure ID 23850096, 01/01/21-31/12/23, 450,000 USD.