H. Valdimarsson

Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens?

Psoriasis is a T-cell-mediated disease that can be triggered by infection with group A beta-haemolytic streptococci. It is proposed that psoriatic skin lesions are initiated by exotoxin-activated T cells, and persist because of specific T cells that react both with streptococcal M protein and a skin determinant, possibly a variant of keratin. As discussed here by Helgi Valdimarsson and colleagues, cytokines released by the superantigen (SAg)-stimulated T cells could induce or enhance the expression of the crossreactive autoantigen, leading to the rescue and activation of autoreactive T cells. In this way, the SAg-determined T-cell receptor V beta phenotype would be maintained by T cells in psoriatic lesions.

Immunopathogenic mechanisms in psoriasis.

Psoriasis is a common autoimmune skin disease characterized by T cell‐mediated hyperproliferation of keratinocytes. The disease has a strong but complex genetic background with a concordance of approximately 60% in monozygotic twins, and recent linkage and high resolution association studies indicate that HLA‐Cw*0602 is itself a major susceptibility allele for psoriasis. Patients carrying this allele have been shown to have different clinical features and earlier age of disease onset, and patients homozygous for this allele have about 2·5 times higher disease risk than heterozygotes. Published data indicate that CD8+ T cells may play a major effector role in psoriasis. Epidermal infiltration of predominantly oligoclonal CD8+ T cells, and probably also of CD4+ T cells in the dermis, is a striking feature of chronic psoriasis lesions, indicating that these cells are responding to specific antigens. We argue that CD4+ T cells are essential for initiating and maintaining the pathogenic process of psoriasis but that cross‐primed CD8+ T cells are the main effector cells responding to antigens in the HLA‐Cw*0602 binding pocket of keratinocytes. It is further proposed that CD8+ T cells are involved in the control of the Th1 polarization, which is observed in psoriasis lesions, through a complex interplay between CD4+, CD8+ T cells and cross‐presenting dendritic cells. It is also suggested that spontaneous remissions or fluctuations in disease activity may be determined by a balance within the lesions between effector and suppressor CD4+ and CD8+ T cells.

Epidermal T lymphocytes and HLA-DR expression in psoriasis.

Double staining immunofluorescent techniques and monoclonal antibodies were used to study the numbers, distribution, HLA‐DR expression and relationship of T‐cell subpopulations and dendritic cells in psoriatic skin. In the dermis there was a definite increase in both T helper and T suppressor cells in uninvolved skin of psoriatic patients, and the appearance of clinical lesions was not associated with any detectable change in the numbers of these cells in the dermis. In contrast, cruption of skin lesions was associated with an increase in the numbers of epidermal HLA‐DR+ dendritic cells and also with epidermal influx and activation of T helper cells, while resolution of lesions coincided with increased epidermal entry and activation of T suppressor cells. Both the T helper and T suppressor cells were preferentially found adjacent to epidermal dendritic cells.

T-cell subpopulations in the blood and skin of patients with psoriasis

Monoclonal antibodies were used to determine, simultaneously, the proportions of T‐cell populations in the peripheral blood and in the skin lesions of fifty‐one patients with psoriasis. The results were analysed in relation to the extent, age and clinical type of the skin lesions. In the group of patients with extensive lesions, a significant reduction in the number of total T (TT) and T helper/inducer‐cells, (TH), but not in T suppressor/cytotoxic cells (Ts) was observed in the peripheral blood. Furthermore, the skin TH/TS ratio was greater in late guttate and in chronic plaque lesions than the corresponding ratio in the blood. These findings suggest that there is an active selective recruitment of TH cells into established psoriatic lesions. In contrast, the TH/TS ratio in early guttate lesions was the same as in the blood, and significantly lower than in the plaque lesions. An additional finding was a decrease of TS, and a corresponding increase of null cells in the blood of patients with chronic plaque psoriasis. These observations provide further evidence for the participation of T cells in the pathogenesis of psoriasis.

Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study

Background  Guttate psoriasis has a well‐known association with streptococcal throat infections but the effects of these infections in patients with chronic psoriasis remains to be evaluated in a prospective study.

A Susceptibility Gene for Psoriatic Arthritis Maps to Chromosome 16q: Evidence for Imprinting

Several genetic loci have been reported for psoriasis, but none has been specifically linked to psoriatic arthritis (PsA), a condition that affects >10% of patients with psoriasis. A genetic component for PsA is suggested by segregation within families and high concordance among identical twins. We performed a linkage scan to map genes contributing to PsA. We identified 178 patients with PsA out of 906 patients who were included in our genetic study of psoriasis. Using a comprehensive genealogy database, we were able to connect 100 of these into 39 families. We genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis using the Allegro program. On the basis of the initial results, we genotyped more markers for the most prominent loci. A linkage with a LOD score of 2.17 was observed on chromosome 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03 was observed when conditioned for maternal transmission. A suggestive locus on chromosome 16q has previously been implicated in psoriasis. Our data indicate that a gene at this locus may be involved in paternal transmission of PsA.

Obesity in psoriasis: Leptin and resistin as mediators of cutaneous inflammation

Background  Obesity is a significant risk factor for psoriasis and body mass index (BMI) correlates with disease severity.

The effects of cyclosporin A on T lymphocyte and dendritic cell sub-populations in psoriasis

Sequential skin biopsies from six patients with severe psoriasis were studied during treatment with cyclosporin. Four of the patients cleared completely and the remaining two showed a marked improvement. A subset of dendritic cells, HLA‐DR+ but lacking the T6 antigen characteristically expressed by Langerhans cells (DR+ 6‐), was observed in lesional epidermis. They disappeared during treatment, before clinical improvement was apparent and at a rate which correlated with clearance of psoriasis. These cells were not found in normal or uninvolved psoriatic epidermis and their number in lesional skin appeared to be related to the clinical severity of the disease. Total numbers of CD4 and CD8, and HLA‐DR+ CD8 T cells were substantially reduced in both epidermis and dermis prior to clinical improvement. In contrast, there was generally no decrease in the number of HLA‐DR + CD4 T cells in the epidermis during resolution, whereas these cells were reduced by an average of 68% in the dermis. The beneficial effects of cyclosporin in psoriasis further support the hypothesis that T cells play a central role in the pathogenesis of psoriasis. The cellular changes observed in the skin during cyclosporin treatment may help to elucidate the effects of this drug on immunoregulatory mechanisms in man.

Restricted T-cell receptor Vβ gene usage in the skin of patients with guttate and chronic plaque psoriasis

A strong association between acute guttate psoriasis and group A, β‐haemolytic streptococcal infections is well established. Furthermore, streptococcal M proteins and toxins have been shown to act as superantigens, stimulating subpopulations of T lymphocytes expressing particular Vβ families.

Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin‐homing CD8+ T cells

The association of psoriasis with Streptococcus pyogenes throat infections suggests a potential antigenic target for the T cells that are known to infiltrate psoriatic skin. Streptococcal M protein share an extensive sequence homology with the human epidermal keratins. Keratin 17 (K17), while being mostly absent from uninvolved skin, is up‐regulated in psoriatic lesions. Consequentially, M‐protein‐primed T cells may recognize up‐regulated keratin epitopes via molecular mimicry. Using in vitro lymphocyte culture and cytokine flow cytometry we demonstrate that HLA‐Cw*0602+ psoriasis patients had significant CD8+ T cell interferon (IFN)‐γ responses to peptides from the K17 and M6 protein selected on the basis of sequence homology and predicted HLA‐Cw*0602 binding. These responses were about 10 times more frequent in the skin‐homing cutaneous lymphocyte‐associated antigen‐expressing (CLA+) subset of CD8+ T cells. CD4+ T cells showed only borderline responses. CLA+ CD8+ T cells from Cw6+ non‐psoriatic individuals responded to some M6 peptides but rarely to K17 peptides. Cw6– psoriasis patients showed a response that was intermediate between Cw6+ patients and controls. These findings indicate that psoriatic individuals have CD8+ T cells that recognize keratin self‐antigens and that epitopes shared by streptococcal M proteins and human keratins may be targets for the CD8+ T cells that infiltrate psoriatic skin lesions.