Spondyloarthritis, Acute Anterior Uveitis, and Fungi: Updating the Catterall–King Hypothesis

Abstract

Spondyloarthritis is a common type of arthritis which affects mostly adults. It consists of idiopathic chronic inflammation of the spine, joints, eyes, skin, gut, and prostate. Inflammation is often asymptomatic, especially in the gut and prostate. The HLA-B*27 allele group, which presents intracellular peptides to CD8+ T cells, is by far the strongest risk factor for spondyloarthritis. The precise mechanisms and antigens remain unknown. In 1959, Catterall and King advanced a novel hypothesis explaining the etiology of spondyloarthritis: an as-yet-unrecognized sexually acquired microbe would be causing all spondyloarthritis types, including acute anterior uveitis. Recent studies suggest an unrecognized sexually acquired fungal infection may be involved in prostate cancer and perhaps multiple sclerosis. This warrants reanalyzing the Catterall–King hypothesis based on the current literature. In the last decade, many links between spondyloarthritis and fungal infections have been found. Antibodies against the fungal cell wall component mannan are elevated in spondyloarthritis. Functional polymorphisms in genes regulating the innate immune response against fungi have been associated with spondyloarthritis (CARD9 and IL23R). Psoriasis and inflammatory bowel disease, two common comorbidities of spondyloarthritis, are both strongly associated with fungi. Evidence reviewed here lends credence to the Catterall–King hypothesis and implicates a common fungal etiology in prostate cancer, benign prostatic hyperplasia, multiple sclerosis, psoriasis, inflammatory bowel disease, and spondyloarthritis. However, the evidence available at this time is insufficient to definitely confirm this hypothesis. Future studies investigating the microbiome in relation to these conditions should screen specimens for fungi in addition to bacteria. Future clinical studies of spondyloarthritis should consider antifungals which are effective in psoriasis and multiple sclerosis, such as dimethyl fumarate and nystatin.

Implicating Dysbiosis of the Gut Fungal Microbiome in Uveitis, an Inflammatory Disease of the Eye

“…This is the first direct evidence implicating gut fungal microbiome dysbiosis in UVT, and it supports a few earlier investigations that provided clues of the involvement of the fungal microbiome in ocular diseases like UVT. 17,18 The relevance of the observed dysbiosis in UVT patients would be all the more meaningful if functional attributes were associated with the genera that decreased or were enriched in UVT patients. Enrichment of five of the nine fungal genera in UVT patients was on expected lines since the enriched organisms like Aspergillus gracilis, Candida glabrata, Malassezia globosa, and M. restricta were opportunistic pathogens.…”

“…[14][15][16] Few studies have demonstrated an increased immune sensitivity to fungal antigens in UVT implying that these fungal antigens may be an important risk factor of idiopathic UVT, especially for those associated with spondyloarthritis and multiple sclerosis. 17 In addition, Zárate-Bladés et al, 18 who had characterized only the bacterial populations, failed to identify the antigenic mimic that triggers UVT in the mice model of spontaneous UVT thus implying that other microbial communities including fungi may help to identify the trigger for UVT. Recently we showed association of gut fungal microbiome with bacterial keratitis.…”

Malassezia and Parkinson's Disease

“…Due to improved microbe detection techniques, many groups now report finding Malassezia within the body of both healthy adults and immunocompetent patients with various ailments (14–16, 23–25, 33, 52–61). Malassezia 's potential role in diseases of internal organs is just coming to light (19, 54, 62–64). It is important to note that Malassezia 's presence is not synonymous with disease: in the vast majority of individuals, Malassezia colonize the body without causing symptoms.…”

“…If Malassezia are involved in diseases of internal organs, AIDS would be expected to precipitate such diseases in genetically susceptible individuals—similarly to how it precipitates SD by allowing Malassezia to over proliferate on the skin. Interestingly, recent studies (reviewed in the next two sections) implicate Malassezia in arthritis (62) and demyelination (19), two common AIDS symptoms where no secondary infections were thought to be present.…”

Altered Bacteria-Fungi Inter-Kingdom Network in Gut of Ankylosing Spondylitis Patients

“…Up to 70% of AS patients have subclinical gut inflammation and 5-10% of these patients have more severe intestinal inflammation that progresses to clinically defined IBD (7). As intestinal dysbiosis has been increasingly linked to IBD in recent years (8-10), it is reasonable to speculate a close link between gut microbiota and AS development (3,11). Previous works have shown that the patients and transgenic rat model of AS had increased immunoglobulins G (IgG) or pro-inflammatory cytokines in response to bacterial products such as outer membrane protein and lipopolysaccharide (LPS) (12,13).…”