The clinical relevance and pathogenesis of microbes in ankylosing spondylitis
Journal
International journal of rheumatic diseases
Date Issued
2023-03-27
Author(s)
Abstract
We read with great interest the article by Long et al., in which the authors reported the association between Klebsiella pneumonia (K. pneumoniae) and ankylosing spondylitis (AS).1 The authors reported that the presence of K. pneumoniae in feces, immunoglobulin (Ig) A (IgA), and IgG against K. pneumoniae were significantly associated with AS when compared with healthy people. To augment those key points, findings from relevant studies were discussed below. In particular, this research emphasizes an important topic in the pathogenesis of AS. It has been found in previous studies that the molecular mimicry between human leukocyte antigen (HLA)-B27 (HLA-B27) and K. pneumoniae-derived antigens plays a key role in the pathogenesis of this autoimmunity disease.2 Evidence from multiple experimental models for immune-mediated inflammatory diseases, including multiple sclerosis and arthritis, suggests that T helper cell 17 (Th17) cells are involved in autoimmunity.3 Th17 cells develop from naive T cells under conditions where both transforming growth factor �] (TGF-�]) and pro-inflammatory cytokines such as interleukin (IL)-6 (IL-6) and IL-1�] induce the expression of the IL-23 receptor.2, 4-8 It has also been found that the peptide binding groove on HLA-B27 may play a significant role in the mimicry.2, 4, 5, 9 Therefore, upon pathogen insults, antigen-presenting cells activate phagocytosis and present the domain of the pathogen to the surface of the cell. Cytotoxic T lymphocytes10, 11 then identify the binding domain of the antigen of K. pneumoniae and attack the peptide binding groove of HLA-B27. As a result, these reactions may cause cross-reaction between the antibody (such as IgA) and HLA-B27, thus initiating the immune response.2 Furthermore, it has been shown that when triggered, HLA-B27 molecules lacking light chain b2-microglobulin are transformed into HLA-B27 heavy chain homodimers.2 The misfolding of HLA-B27 protein results in a change in its 3-dimensional structure, leading to an affinity to form a complex with the pathogen. This phenomenon can lead to inflammation or even severe spondylosis and arthropathy.2 The association between other pathogens and AS has also been explored,4, 5 which include oral or periodontal pathogens12 and other enteric pathogens.13, 14 Periodontal pathogens possess arginine protease (PAD) and research indicates that arginine is crucial for their interactions with HLA-B27.4 Thus, it has been provided that if an HLA-B27+ individual is infected with Porphyromonas gingivalis PADs,7, 12, 15-20 it can trigger a cytotoxic T-cell-mediated autoimmune response that is specific to HLA-B27, leading to inflammation in the joints.4 Likewise, it has been demonstrated that the expression of HLA-B27 is linked to changes in the gut microbiota, and the difference in the abundance of certain species in gut microbiota between AS patients and healthy individuals is significant.9 Intestinal dysbiosis can trigger activate a Th17-mediated immune response in the intestinal lamina propria, causing the rapid release of IL-17 in the gut and leading to osteoclastogenesis and inflammatory bone loss.9 Whie some mechanisms are still unclear, recent literature suggests a strong association between gut inflammation and spondylitis, with HLA-B27 alleles and the IL-17/IL-23 immune axis playing central pathogenic roles. These pathogens and K. pneumoniae may share similar mechanisms to induce AS. Lastly, while this research provides valuable insights, it is also clinically relevant to investigate the association between K. pneumoniae and the symptoms of AS. The hallmark pathology of AS is enthesitis,6 which can cause Inflammation and the formation of syndesmophytes that bridge between adjacent vertebrae in the spine, ultimately leading to bony fusion and the characteristic bamboo spine appearance on radiographs.21 As such, future studies are needed to address the relationship between K. pneumoniae and the symptoms of AS. If a link is established, screening for HLA and tests for K. pneumoniae-derived antigens may facilitate the diagnosis of AS, as similar to how such approaches are used for various other diseases.10, 21, 22 Additionally, studies have also demonstrated the association between enteric pathogens and inflammatory arthritis, including rheumatoid arthritis,15, 23-26 psoriatic arthritis,27 and spondyloarthritis.5, 21 This underscores the significance of this topic and the need to further elucidate the role of K. pneumoniaein the etiology and pathogenesis of AS.5 Given the multifactorial nature of AS, cohort studies involving larger populations28, 29 are needed to generate more evidence and improve patient care and patient education.30-32 All authors (KSM, PK, and CL) provided their ideas and critical contribution. KSM, PK, and CL contributed to the editing of the manuscript. KSSM and PEK contributed equally as first authors. KSM and CL contributed equally as corresponding authors. None declared. The authors declare no conflict of interest.
Subjects
UNIVERSAL HEALTH-CARE; DISEASE-CONTROL; MANIFESTATIONS; PREVENTION; FRAMEWORK
SDGs
Publisher
WILEY
Type
editorial