The end of autoimmunity
It's hard to overstate the importance of Limon and colleagues’ article published this week in Cell Host & Microbe. Not only did they discover that immune recognition of Malassezia is the main mechanism in Crohn’s disease, they also explain why CARD9 polymorphisms and anti-Saccharomyces cerevisiae antibodies (ASCAs) are both strongly associated with Crohn’s. This is really important because CARD9 and ASCAs are risk factors in other “autoimmune” diseases.
CARD9 is essential to mount an immune response against fungi. We know this because carriers of homozygous loss-of-function CARD9 mutations are at extremely high risk of fungal infections (Glocker et al 2009).
Our white blood cells detect fungi using two receptors called Dectin-1 and Dectin-2, which bind to conserved fungal cell wall components beta-glucan and mannan. CARD9 carries the message “a fungus is bound to one of these receptors”, enabling the immune system to defend our bodies against fungi. When CARD9 is missing or non-functional, the immune system can no longer detect fungi, allowing certain species such as Candida to overgrow. This often proves fatal. Fortunately loss-of-function mutations in CARD9 are very rare.
In addition to Crohn’s disease, CARD9 risk alleles increase the risk of ulcerative colitis and spondyloarthritis. This means ulcerative colitis and spondyloarthritis (eg. ankylosing spondylitis, acute anterior uveitis, oligoarthritis and prostatitis) are likely caused by our immune system attacking Malassezia in each affected organ (Laurence et al 2018).
ASCAs are a misnomer: they are not specific to Saccharomyces cerevisiae at all! They are actually antibodies against mannan and beta-glucan (Dotan et al 2006).
The reason Saccharomyces cerevisiae is used to perform this test is that our immune system rarely produces antibodies against Saccharomyces cerevisiae proteins. This means elevated ASCAs indicate an immune response against a fungus (any fungus!) is taking place. ASCAs are produced when the immune system is fighting Candida, Trichophyton, Malassezia, or any other fungus.
ASCAs are most strongly associated with Crohn’s disease, and are present in 50%-75% of patients—as opposed to <10% of healthy controls (Dotan et al 2006). Being ASCA positive increases a person’s risk of having Crohn’s disease approximately ten-fold.
ASCAs are not essential to mount an immune response against fungi, and only serve as a low sensitivity biomarker of CD4+ T cell recognition of fungi. This explains why some Crohn’s patients have low ASCAs, despite mounting an immune response against Malassezia in the gut.
In addition to Crohn’s disease, ASCAs are strongly associated with the following “autoimmune” diseases: all forms of spondyloarthritis listed above, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis and type 1 diabetes (see Alunno et al 2018 for the complete list).
You might have noticed that ASCAs are not associated with ulcerative colitis, despite Malassezia’s likely involvement in this disease. Why? Ulcerative colitis is mainly caused by CD8+ T cells which are not involved in antibody production at all. ASCAs are a poor biomarker of CD8+ T cells which are fighting Malassezia.
Autoimmunity is the biggest misnomer of all. It actually means: “My patient has chronic inflammation and I can’t find a causative microbe, so his body must be attacking itself.” A more plausible explanation is: “My patient has chronic inflammation and I can’t find a causative microbe because I lack the technology to detect it.”
High-throughput DNA sequencing has finally allowed us to determine that Malassezia colonizes most of our internal organs (reviewed in Laurence et al 2018); these organs were previously considered sterile. Limon and colleagues firmly point to Malassezia as being causative in Crohn's disease, which was long considered "autoimmune". So CARD9 and ASCAs strongly suggest that most “autoimmune" diseases are actually caused by our immune system fighting Malassezia. It's time to stop using the term "autoimmune" disease.