My research focus is Spondyloarthropathy (SpA), a group of autoimmune diseases that includes reactive arthritis (ReA), ankylosing spondylitis, psoriatic arthritis (PsA), and arthritis associated with inflammatory bowel disease. This group of conditions is characterised by inflammation of the spine (spondylitis), large joints and entheses (connective tissue between tendon or ligament and bone), skin (psoriasis), and ileitis or colitis. Interestingly, studies have identified common genetic links between individuals who develop different manifestations of SpA, which are linked to cellular stress, enhanced inflammatory responses, and reduced control of bacterial infections. My research aims to uncover the initial events that lead to abnormal immune responses manifesting as disease in genetically susceptible individuals.
This project focused on the ability of bacterial infections to exploit elevated cellular stress in susceptible hosts, which lead to chronic inflammation and disease development. Using a preclinical model of ReA, I highlighted a key role for macrophages, a type of white blood cell, to take up and disperse Chlamydia from the genital tract to other tissues after infection. Inflammatory arthritis and skin disease were dramatically suppressed when macrophages were depleted, which was associated with reduced inflammation and cellular stress. Furthermore, I have shown a relationship between cellular stress and the severity of SpA. In mice resistant to cellular stress, clinical signs of PsA were markedly reduced, which was associated with reduced markers of inflammation.
Standard SpA treatments begins with non-steroidal anti-inflammatory drugs and conventional Disease-modifying anti-rheumatic drugs (DMARDS) which are effective in suppressing disease activity and slowing progression in Rheumatoid Arthritis, but are less successful in patients with SpA, especially those with spinal disease. Biological DMARDS such as Tumour Necrosis Factor inhibitors are limited by adverse events and failure to respond while rarely achieving drug-free remission. These approaches target and alleviate inflammation but ignore the underlying mechanisms of disease, including cellular stress, abnormal gut microbiome, and compromised control of bacterial pathogens.
The overarching question my grant set out to answer was whether limiting cellular stress will improve host defence against bacterial infections and reduce the severity of psoriatic arthritis and reactive arthritis in preclinical models. More specifically, I aim to discover whether enhanced cellular stress in individuals affect mucosal barrier integrity in the gut (in psoriatic arthritis) or genital tract (in reactive arthritis), which impairs normal host defence against bacterial infections. Elevated cellular stress in the hosts’ immune system may negatively affect the ability to clear bacterial infections, resulting in the activation or persistence of inflammatory pathways that drive disease development/progression.
Answering these questions will fill current knowledge gaps in the factors that drive SpA development in susceptible individuals in addition to the conditions, which lead to clinical relapse upon treatment cessation. Addressing these questions will highlight the mechanisms that drive inflammation, providing a therapeutic strategy to alleviate cellular stress and improve mucosal integrity to prevent disease development and/or reduce disease severity.
In ReA, one of the key unanswered questions is how arthritis manifests from infections in the genital tract. My findings have demonstrated that after Chlamydia infection, macrophages recruited into the genital tract take up and disperse Chlamydia to other tissues. Additionally, in mice susceptible to SpA, macrophages display reduced ability to clear bacterial infections and therefore elevating overall bacterial burden. The link between macrophages and clinical manifestation of disease is highlighted further with a dramatic reduction in joint disease when macrophages were depleted before Chlamydia infection. This observation was associated with increased cellular stress and production of mediators of inflammation in the genital tract and joints. Furthermore, immune cells isolated from cellular stress resistant mice after Chlamydia infection produced lower levels of proinflammatory factors than controls. Together, these findings identify the pivotal role played by macrophages in ReA and highlight cellular stress as a potential therapeutic target.
In PsA, I demonstrated that mice resistant to cellular stress develop less severe psoriatic arthritis. I have focused on two potential factors that may have contributed to decreased disease severity 1) improved gut barrier integrity and 2) enhanced immune control of bacterial infections.
There is strong association between gut inflammation (also known as leaky gut syndrome) and SpA. The intestinal barrier plays a key role in interacting with beneficial bacteria and keeping potentially harmful bacteria at bay. Physical disruption or impairment of the integrity of the gut barrier due to elevated cellular stress may result in bacterial infections and over-activation of proinflammatory responses by the host immune system. To test this, control mice and mice lacking a key gene mediating cellular stress (CHOP) were orally administered the molecule FITC-dextran. One and four hours after treatment, lower levels of FITC-dextran were detected in the blood of cellular stress resistant mice compared to controls This result indicated that reduced cellular stress improved gut barrier integrity and reduced leakage of FITC-dextran from the gut into the blood stream.
Impaired immune control of bacterial infections is another explanation of how SpA develops in susceptible individuals. One of the major immune cells responsible for bacterial clearance is the macrophage, which eat and rapidly kill bacteria by producing antimicrobial factors. However, some forms of bacteria such as Salmonella can exploit elevated cellular stress in macrophages and enter a dormant and persistent state. This results in the macrophages producing excessive pro-inflammatory factors, such as TNF leading to disease manifestation. My results have shown that the immune systems of mice resistant to cellular stress produce more bacteria-clearing inflammatory factors and less SpA-associated mediators. Whether this translates to an improvement in the capacity of macrophages to kill bacteria requires further investigation. Nonetheless, these results demonstrate the relationship between cellular stress, gut integrity, and immune control of bacterial pathogens.
The findings of my research are still preliminary but may benefit people with musculoskeletal disease in the future. Exploring how cellular stress and impaired control of bacterial infections contribute to inflammatory processes that lead to disease development will benefit future research into novel treatments for SpA and other autoimmune diseases such as Rheumatoid Arthritis.
If my hypotheses are correct, the next step is to deliver antibiotics or inhibitors of cellular stress to macrophages or to the mucosal barrier to facilitate bacterial clearance and/or improve barrier integrity. This would be expected to prevent disease development in people at risk and to suppress clinical signs of psoriatic arthritis and reactive arthritis in people with disease.