Circulating T Cells of Patients with Active Psoriasis Respond to Streptococcal M‐Peptides Sharing Sequences with Human Epidermal Keratins

Abstract

Psoriasis is a T-cell mediated inflammatory skin disease which has been associated with group A, bhaemolytic streptococcal infections. Four 20 a.a. long M6-peptides sharing 5-6 a.a. sequences with human epidermal keratins were identified. To investigate the role of potentially cross-reactive T cells in the pathogenesis of psoriasis, interferon-g (IFN-g) and interleukin-4 (IL-4) responses of circulating T cells to these peptides were analysed by ELISPOT and RT-PCR in 14 psoriatic patients, 12 healthy individuals and six patients with atopic dermatitis (AD). Untreated psoriatic patients' responses were significantly higher to these peptides than healthy and AD controls, while responses to a control M6-peptide, not sharing sequences with keratin, were negligible in all groups. No difference was found in response to streptokinase/streptodornase (SK/SD). M6-protein and peptides exclusively elicited IFN-g production, with little IL-4 production, even in AD patients. Interferon-g responses to all the M6-peptides were abolished after successful treatment of psoriatic patients, but responses to SK/SD were unaffected. The results indicate that active psoriasis is associated with Th1-like cells responding to streptococcal M6-peptides sharing sequences with human epidermal keratin. This is consistent with the hypothesis that psoriasis may be induced and exacerbated in susceptible individuals by M-protein specific Th1-like cells that cross-react with human epidermal keratin.

The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

“…Keratinocyte-derived proteins [18][19][20][21][22]42 , among which keratins, were previously identified as autoantigens, especially in a subset of patients with psoriasis linked to group-A b-hemolytic streptococcal throat infections. Our study now identifies the AMP LL37 as a new autoantigen in psoriasis that is recognized by circulating T cells in 46% of psoriasis patients and up to 75% of patients with moderate-to-severe psoriasis.…”

“…We also tested reactivity to keratins, as these proteins were identified as autoantigens in a subset of psoriasis patients [18][19][20][21][22] . In keeping with the literature [18][19][20][21][22] , we detected reactivity to Keratins that was statistically significant for Keratin17 ( Supplementary Fig. 3, lefts panels).…”

New insights of T cells in the pathogenesis of psoriasis

“…The concept of molecular mimicry explains how anti-streptococcal T cells can be activated in the skin to target-specific tissue antigen(s) and subsequently causing disease. 20,21 Indeed, peripheral blood T cells from psoriatic patients but not healthy controls have been shown to respond to several synthetic peptides corresponding to these shared homologous sequence motifs for the production of IFN-c. 22,23 Further study demonstrated that CD8 1 T cells in the peripheral blood from psoriasis patients carrying the HLA-Cw6 allele, which has been reported to have a strong association with psoriasis, had a significant IFN-c response to the peptide selected from the shared sequence by keratin 17 and M6 protein and the predicted HLA-Cw6 binding. 24 Additionally, the majority (.90%) of these responding cells express the skin homing cutaneous lymphocyteassociated antigen determinant.…”

The Immunologic and Genetic Basis of Psoriasis

“…Another approach has been to try to identify specific antigens (both exogenous and endogenous) in patients with psoriasis that could activate the immune system with creation of pathogenic T cells. Both infectious and noninfectious T-cell activating factors have been suggested as candidate triggering factors, including retrovirus (human immunodeficiency virus 1 35 ), bacteria-derived superantigens, 36 gous keratin-derived peptides, 38 neuropeptides such as substance P, 39 and human papillomavirus. 40 Thus far we have focused on acquired-type of immune response (Figures 2 and 3 …”