T cells originating in the gut can cause psoriasis
T cells in psoriatic skin often originate in the gut. We know this because they express ⍺Eβ7 integrin, a marker of mucosal activation and origin (Pauls et al 2001; Kilshaw 1999). This means some psoriasis cases must be caused by T cells which recognize the same proteins in both the gut and skin.
Antibodies against fungi are elevated in Crohn’s and psoriasis
Crohn’s disease is a common comorbidity of psoriasis. The antibody signature against fungi observed in Crohn’s and psoriasis means some T cells must be recognizing fungal proteins in the gut and skin (Main et al 1998; Dotan et al 2006; Squiquera et al 1994; Liang et al 2003). There are many different kinds of fungi present in the gut, so figuring out which species are involved in Crohn’s is hard. In contrast, there is only one fungus on psoriatic skin, Malassezia (Findley et al 2013; Tett et al 2017).
Phagocytes confound fungal species, while T cells can tell fungal species apart
Unlike phagocytes which recognize fungi mainly through sugars (mannan, beta-glucan, chitin) present on all fungal species, T cells can target individual fungal species because they detect proteins rather than sugars. While sugars don’t evolve much, proteins evolve rapidly, which means distantly related fungal species such Candida and Malassezia have no identical proteins. So a T cell which activates by detecting a specific fungus will only attack closely related fungal species. For example, T cells targeting Malassezia don’t attack Candida because proteins on these distantly related fungal species are too different (Kanda et al 2002).
This T cell specificity means there must be Malassezia in the gut, otherwise T cells originating there would not be able to recognize fungi on the skin! For example, T cells in the gut which activated by recognizing Candida proteins cannot cause inflammation on the skin because there are no Candida cells there.
This argument seems plausible, but is there direct evidence to confirm it? Yes!
Studies of Malassezia in the gut
Malassezia are present in the gut. This was reported by many recent studies (Hallen-Adams et al 2015; Suhr et al 2016; Liguori et al 2016). Earlier studies were based on cell culture, and Malassezia do not grow well in culture, so they were missed. These recent studies were based on consensus PCR which can detect Malassezia without needing to grow them first.
Studies of Malassezia in inflammatory bowel disease
Case-control studies find strong associations between inflammatory bowel disease and Malassezia in gut biopsies and stool (Kellermayer et al 2012; Richard 2018). When this evidence is combined with antibodies against fungi found in most Crohn’s patients (Main et al 1998; Dotan et al 2006), it provides very strong evidence that T cells targeting Malassezia in the gut are causing Crohn’s disease. This is well explained in the animated Crohn’s video.
Studies of vedolizumab in Crohn’s disease
Vedolizumab is an injectable drug used to treat inflammatory bowel disease (Crohn’s in particular). This drug forces T cells in the gut to spread to other organs. These T cells were causing gut inflammation, so once they’re forced to leave the gut, inflammatory bowel disease symptoms improve. Interestingly, many Crohn’s patients develop psoriasis as an unintended side effect of vedolizumab (Tadbiri et al 2018; Wendling et al 2018; Sody et al 2017). This means T cells in the gut of Crohn’s patients, when they reach the skin, can cause psoriasis. These T cells must be recognizing the same proteins in both sites; these proteins are probably from a fungus present in both the skin and gut. The only fungus in psoriatic skin lesions is Malassezia. As outlined in the previous paragraphs, Malassezia are present in the gut and are suspected of causing inflammatory bowel disease.
Studies of Malassezia in psoriasis
In psoriasis, T cells specifically target Malassezia proteins (Kanda et al 2002), as predicted above. Antibodies against Malassezia are elevated in psoriasis (Squiquera et al 1994; Liang et al 2003). Killed Malassezia applied to the skin triggers psoriasis in genetically susceptible individuals (Lober et al 1982).
Summary
Many cases of psoriasis are the result of T cells originating in the gut. Vedolizumab side effect studies prove this beyond doubt. These T cells recognize Malassezia proteins. When T cells detect Malassezia on the skin, they produce psoriatic inflammation.
Animated psoriasis video: https://youtu.be/I7FSKlwIxMA
