Psoriasis & Psoriatic Arthritis

§   Psoriasis and microbially-evoked autoantigens—Ex vivo experimental study using human T-cells (see especially Clin Exp Immunol 1999 Sep[1]): Amino acid sequences in skin keratin subtypes 14 and 17 have homology with peptides from the bacterium Streptococcus pyogenes, thereby providing clear evidence of molecular mimicry between an infectious agent and chronic human disease, as reviewed in a previous section. Evidence has shown that psoriatic patients have T-cells which specifically target keratin 17 thereby indicating that keratin 17 serves as an autoantigen in psoriasis; Johnston et al[2] wrote, “…psoriatic individuals have CD8(+) T cells that recognize keratin self-antigens.” As noted earlier in this chapter, increased production of keratin 17 can be induced by the pro-inflammatory cytokines gamma-interferon, which plays a key role as a mediator of psoriatic inflammation, and IL-6, which is abundant in psoriatic lesions. Factors that can increase IFN-g and/or IL-6 production are numerous and include such phenomena as infection, injury, obesity, and consumption of a pro-inflammatory diet; increased production of IFN-g and IL-6 is characteristic of nearly any immune response and is certainly not specific to psoriasis or any other rheumatic condition. As noted previously, the ALEEAN sequence present in keratin 17 is also found in keratin subtype 14, which is overexpressed in psoriatic skin; thus, for T-cells already primed to respond to ALEEAN following exposure to Streptococcus pyogenes, the dual exposure to ALEEAN in keratins 14 and 17—both of which are uniquely present in psoriatic skin—may promote localized attack by T-cells against keratinocytes, ie, immune cross-reactivity via molecular mimicry. In sum, the totality of data supports the following:

u Exposure to microbes induces IFNg and/or IL-6: IFN-g and IL-6 production is increased during overt or occult infection/colonization/dysbiosis, such as with Streptococcus pyogenes and other pathogenic microorganisms.

v Increased production of IFN-g and IL-6 increases production of keratin-17: Increased production of IFN-g and IL-6 increases production of keratin-17.

w Keratin-17 is an autoantigen in psoriatic skin: keratin-17 is a clinically-important autoantigen in psoriasis based on its location, molecular homology with proteins made by Streptococcus pyogenes which is a known trigger in psoriasis, and the identification of T-cells which are specifically responsive to keratin-17

x Therefore, microbial exposure à IFN-g and IL-6 à increased keratin-17 = increased autoantigen production induced by proinflammatory cytokines induced by microbial exposure.

y Furthermore, increased production of autoantigen keratin-17 by IFN-g and IL-6 is probably not microbe-dependent. Of note, obesity in general and visceral adipose tissue in particular are causally associated with increased production of these inflammatory cytokines. If non-microbial induction of IFN-g and IL-6 can stimulate increased production of autoantigen keratin-17, then we would expect conditions such as obesity/hyperadiposity to be associated with more severe psoriasis; indeed this appears to be the case, as recently shown in studies showing that obese young women are at increased risk for severe psoriasis[3] and that weight loss treatments can improve psoriasis.[4]

 

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[1] Gudmundsdottir AS, Sigmundsdottir H, Sigurgeirsson B, Good MF, Valdimarsson H, Jonsdottir I. Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis? Clin Exp Immunol. 1999 Sep;117(3):580-6

[2] Johnston A, Gudjonsson JE, Sigmundsdottir H, Love TJ, Valdimarsson H. Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8(+) T cells. Clin Exp Immunol. 2004 Oct;138(1):83-93 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809187/pdf/cei0138-0083.pdf

[3] "Multivariate analysis demonstrated an association between excess increase in body mass index and psoriasis in females only. Being overweight in adole­scence was the main factor behind this observation." Bryld LE, Sørensen TI, Andersen KK, Jemec GB, Baker JL. High body mass index in adolescent girls precedes psoriasis hospitalization. Acta Derm Venereol. 2010 Sep;90(5):488-93

[4] "There are two recent reports of chronic severe psoriasis improving with weight loss after Roux-en-Y gastric bypass surgery. We have observed two patients with body mass indices greater than 50 kg/m(2) who had marked improvement in their psoriasis after gastric bypass surgery." Hossler EW, Maroon MS, Mowad CM. Gastric bypass surgery improves psoriasis. J Am Acad Dermatol. 2010 Jul 21. [Epub ahead of print]