New developments in our understanding of ankylosing spondylitis pathogenesis Original paper

What was studied?

This article provides an in-depth examination of the pathogenesis of ankylosing spondylitis (AS), focusing on recent developments in understanding the role of immune responses, particularly Type 17 immunity, in its development. It delves into the multifactorial aspects of AS pathogenesis, including genetic factors, immune cell involvement, and gut microbiome alterations. A significant part of the research highlights the involvement of the IL-23/IL-17 axis in driving inflammation and joint damage, particularly in the context of autoimmune responses. The review also presents the contribution of immunometabolism and local metabolic environments in the joints as important factors in disease progression. In addition, it explores therapeutic advancements targeting Type 17 immune responses, such as monoclonal antibodies and small molecules, and how these have provided insights into managing AS more effectively.

Who was studied?

The studies referenced in the article primarily focus on patients with ankylosing spondylitis (AS) and spondyloarthritis (SpA), as well as animal models. These include individuals diagnosed with AS, with some studies specifically comparing male and female patients due to observed gender differences in disease prevalence and progression. Genetic studies involving twins and first-degree relatives of AS patients suggest a strong hereditary component, with a significant association with the HLA-B27 gene. Additionally, the review references animal models, particularly HLA-B27 transgenic rats and mouse models of AS, which provide insights into the role of gut microbiota, immune system interactions, and metabolic changes in AS pathogenesis. The human studies also focus on biomarkers like IL-17 and IL-23, and immune cells, particularly T-helper cells, which are elevated in AS patients and play a crucial role in disease mechanisms.

Most important findings

The review identifies several key findings regarding the pathogenesis of AS. First, it reaffirms the importance of the IL-23/IL-17 immune axis, which has been implicated in the inflammation seen in AS. IL-23, a cytokine produced by myeloid cells, stimulates the differentiation of T-helper (TH17) cells, which in turn secrete pro-inflammatory cytokines such as IL-17, IL-22, and IL-17F. These cytokines are critical for the inflammation observed in the entheses (the sites where tendons or ligaments insert into the bone), a hallmark of AS. The article also discusses the importance of genetic factors, particularly the HLA-B27 allele, in increasing the susceptibility to AS. Moreover, the review highlights the growing evidence linking the gut microbiome to AS, with studies showing that patients with AS often exhibit dysbiosis, or microbial imbalance, in their gut. Changes in gut microbiota may influence immune responses, exacerbating inflammation and contributing to disease progression.

Another important finding from the article is the emerging role of the local metabolic environment in the joints in driving AS. The review discusses how metabolic factors, such as high salt diets and low pH, can influence T-cell responses, particularly TH17 cells, and how these factors might contribute to joint inflammation. Animal studies have demonstrated that a high-salt diet can exacerbate autoimmune responses, including those in the joints of AS models, further linking diet and metabolism to disease pathogenesis.

Key implications

The implications of these findings are significant for both understanding AS and developing more targeted therapies. The identification of the IL-23/IL-17 axis as central to AS pathogenesis supports the use of monoclonal antibodies targeting IL-17, such as secukinumab, in treating the disease. These therapies have shown promise in clinical trials, offering better control of disease activity and symptoms. Additionally, the potential role of gut microbiota in AS suggests that modifying the microbiome through dietary interventions, probiotics, or antibiotics might offer a novel approach to managing the disease. The connection between the local metabolic environment and immune responses opens new avenues for therapeutic strategies, such as targeting metabolic pathways in the joint and gut. Overall, the review suggests that AS treatment should be personalized, taking into account the genetic, immune, and metabolic factors involved in each patient’s disease.