Psoriasis & Psoriatic Arthritis

 

Psoriasis and molecular mimicry—Ex vivo experimental study using human T-cells: (Clin Exp Immunol 1999 Sep[1]): The authors of this paper introduce their topic by noting that psoriasis is an inflammatory disease mediated largely by T-cells in the skin and that psoriasis has a strong association with infections by group-A beta-hemolytic streptococci bacteria, also known as Streptococcus pyogenes. The authors cite their previous work which showed that patients with active psoriasis have Th1-like cells that respond to a 20 amino acid (AA) sequence shared between a protein made by streptococcal bacteria (M protein) that has the same AA sequence as the human protein found in the skin named keratin, specifically kerakin 17. ("Keratin" is a group of fibrous structural proteins forming the key structural material of the outer layer of human skin; keratin is also the key structural component of hair and nails. Keratin 17 is not expressed in normal skin except for hair follicles, sweat/sebaceous glands, and basal cells in the scalp; however, keratin 17 is expressed in suprabasal keratinocytes in lesional psoriatic skin, thus making its presence in skin a unique feature of psoriasis lesions. 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. Langerhans cells are the dentritic cells of the epidermis; as such, they function as antigen-presenting cells (APC). Given that keratin within skin cells exists as an intracellular structural (cytoskeletal) protein, its ability to be exposed to the immune system is required for it to function as an autoantigen, a target of self-induced immunologic attack. The authors of this paper note that “cytoplasmic processes of Langerhans cells can extend into the cytoplasm of adjacent keratinocytes with frequent absence of intervening plasma membranes at the apices of these processes"; thus these epidermal APCs can uptake and present antigen via MHC class 1 and class 2 molecules to CD8 and CD4 T-cells, respectively.) These same Th1-like cells are deleted following treatment with ultraviolet B (UVB) radiation that induces clinical remission; the fact that the disappeaerance of these cells correlates with clinical improvement following treatment implies that these cells may have a direct causative role in the skin inflammation of psoriasis. In the ex vivo experiment, the authors took T-cells from the blood of 17 psoriatic patients and 17 healthy controls and then challenged these T-cells with keratin peptides and M-peptides to monitor for increased production of gamma-interferon [IFNg]), which implies specificity for the corresponding amino acid sequences. Results of the investigation showed that the most frequent and strongest responses were observed to a peptide from keratin 17 that shares a specific AA sequence with M-protein. Specifically, the overlapping AA sequence is A-L-E-E-A-N. In fact, T-cell responses to the ALEEAN sequence were stronger than to the corresponding M-peptide containing the ALEEAN sequence; this implies that sensitized T-cells preferentially attack keratin rather than the bacterial peptide. 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.  UVB treatment abolished T-cell responses to keratin and M protein, while responses to other bacterial antigens (streptokinase [SK] and streptodornase [SD]) were not affected. The authors conclude, “These findings are consistent with the notion that AA sequences which keratin has in common with M-protein may be a major target for autoreactive T cells in psoriasis.” Per Table 2 of their article, 13 of 17 psoriatic patients demonstrated a T-cell response to peptide 146-K17 (from human keratins subtypes 14 and 17) contrasted to only 4 of 17 healthy controls; interestingly, three patients and eight controls showed no responses to either keratin or M protein. This lack of perfect concordance indicates that molecular mimickry and the resulting immune cross-reaction does not account for the entirety of the pathogenesis of psoriasis, or that u the research methods employed in the study were imperfect resulting in a few false negatives and/or false positives, or v seasonal variation in streptococcal infections caused varying intensities of immune responsiveness, w seasonal vitamin D fluctuations caused varying intensities of immune responsiveness, x that a variable unaccounted for (eg, sun exposure, medication use, etc) influenced these results, or that y other nonstreptococal infections/microbes—as very well documented by Noah and collecgues[2]—and dysbiotic microbial relationships may have been causative in some cases of psoriasis. Readers and clinicians should note that the ALEEAN sequence is not the only sequence shared between human keratin and staphylococcal M-protein; other homologous sequences include LRR-LD, AKLEA, and AKLEAE.

 

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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] Rosenberg EW, Noah PW, Skinner RB Jr. Microorganisms and psoriasis. J Natl Med Assoc. 1994 Apr;86(4):305-10