Barbara S. Baker

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.

Normal keratinocytes express Toll‐like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis

Summary Backgroundu2003Toll‐like receptors (TLRs) are part of the innate immune system involved in the response to microbial pathogens. TLR2 recognizes various ligands expressed by Gram‐positive bacteria, while TLR3, TLR4 and TLR5 are specific for double‐stranded RNA, Gram‐negative lipopolysaccharides and bacterial flagellin, respectively.

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.

Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin

Microorganisms have been implicated in the pathogenesis of psoriasis. Previous studies of psoriasis and normal skin have used swabs from the surface rather than skin biopsies. In this study, biopsies were taken from 10 patients with psoriasis and 12 control subjects from unmatched sites. Samples were analysed with massive parallel pyrosequencing on the 454 platform targeting the 16S rRNA gene and the variable regions V3–V4. The samples grouped into 19 phyla, 265 taxon and 652 operational units (OTUs) at 97% identity. A cut-off abundance level was set at 1%. The three most common phyla in both normal and psoriasis skin were Firmicutes (39% psoriasis, 43% normal skin), Proteobacteria (38% psoriasis, 27% normal skin) and Actinobacteria (5% psoriasis, 16% normal skin, pxa0=xa00.034). In trunk skin, Proteobacteria were present at significantly higher levels in psoriasis compared to controls (52 vs. 32%, pxa0=xa00.0113). The commonest genera were Streptococci in both psoriasis (32%) and normal skin (26%). Staphylococci were less common in psoriasis (5%) than in controls (16%), as were Propionibacteria (psoriasis 0.0001669%, controls 0.0254%). Both Staphylococci and Propionibacteria were significantly lower in psoriasis versus control limb skin (pxa0=xa00.051, 0.046, respectively). This study has shown some differences in microbiota between psoriasis and normal skin. Whether these are of primary aetiological significance, or secondary to the altered skin of psoriasis remains to be determined.

Psoriasis and streptococci: the natural selection of psoriasis revisited.

We have previously postulated that surviving invasive streptococcal infections may have been a factor in psoriasis becoming a common skin disease in some parts of the world. Many of the candidate genes linked to psoriasis are associated with the acquired or innate immune system, which are also important in host defence to invasive streptococcal infections. High rates of positive streptococcal throat swabs among patients with chronic plaque psoriasis suggest that they are efficient at internalizing/carrying β‐haemolytic streptococci. Internalization of streptococci in the throat is dependent upon the transforming growth factor (TGF)‐β/fibronectin/α5β1 integrin pathway. The immune cell Th17 and its related cytokine network are important in mucosal defence, being very effective against extracellular microbes but having little effect on intracellular organisms. The TGF‐β/fibronectin/α5β1 integrin pathway and the Th17 cell network also appear to be operative in psoriasis, animal models of both TGF‐β and α5β1 cutaneous overexpression being associated with characteristic psoriasis lesions. We postulate that some of the genotypic/phenotypic changes in different immunological pathways in psoriasis, including the acquired T‐cell response, the innate immune response, the TGF‐β/fibronectin/α5β1 integrin pathway and the Th17 cell system, confer protection against mortality during epidemics of invasive streptococcal infections, heightened efficiency in internalizing and allowing carriage of streptococci as well as predisposition to the development of psoriasis.

An Altered Response by Psoriatic Keratinocytes to Gamma Interferon

To determine whether psoriatic keratinocytes differ from normal keratinocytes in their response to gamma interferon, epidermal cell suspensions from normal and from lesional and uninvolved psoriatic skin were cultured in the presence of gamma interferon and the induction of HLA‐DR expression and inhibition of cell growth were measured The addition of 102 units of gamma interferon/ml during 7‐day culture period significantly increased mean HLA‐DR+ cell numbers in 21 epidermal suspensions of normal from 3.9 to 24.1% (P<0.0001), uninvolved psoriatic from 8.4 to 33.1% (P<0.01), and to a lesser extent lesional psoriatic biopsies from 12.6 to 18.3% (P<0.01). However, the increase in HLA‐DR+ cell numbers in these latter cultures was significantly less than that observed in either normal or uninvolved psoriatic epidermal cell cultures (P<0.0001). Furthermore, [3H]thymidine incorporation was substantially decreased by gamma interferon in 16 out of 22 (73%) cultures of normal epidermal cells; this decrease was statistically significant (P<0.0l). In contrast, only 4 out of 11 (36%) lesional and 9 out of 21 (43%) uninvolved psoriatic epidermal cultures showed comparable inhibition of proliferation. These findings suggest that psoriatic keratinocytes have an altered response to gamma interferon: this could explain the infrequency of keratinocyte HLA‐DR expression in psoriatic plaques in vivo and may also contribute to the increased epidermal proliferation that characterizes this disease.

Altered cell‐mediated immunity to group A haemolytic streptococcal antigens in chronic plaque psoriasis

The proliferative lymphocyte response to sonicated group A, β‐haemolytic streptococci (Strep‐A) was measured by thymidine incorporation in 78 patients with psoriasis (guttate, chronic plaque or both). Lymphocytes from 72 of these patients were also cultured with streptokinase/streptodornase (SK/SD), and 20 of the patients with chronic plaque psoriasis were further tested with PPD, Candida albicans and sonicated Streptococcus mutans, a bacterial type not associated clinically with psoriasis. The median stimulation index (SI) of the psoriasis group to the Strep‐A preparation was significantly higher than that of a group of 27 non‐psoriatic individuals (P < 0·05). Within this group, only the patients with chronic plaque psoriasis (n = 42) showed a significantly increased proliferative response compared to the non‐psoriatic controls (median SI = 123·8 and 31·9, respectively, P < 0·01). Although the lymphocyte response of the chronic plaque group to SK/SD was also markedly higher than that of the control group, this difference did not reach statistical significance. In addition, these patients did not show significantly increased responses to any of the other antigens tested, including S. mutans.

Four years of experience with cyclosporin A for psoriasis

Forty‐four patients with severe psoriasis have been treated with cyclosporin A (CyA) for 2–50 months (mean 17 months). During the study, 31 (70%) of these patients achieved a > 70% reduction in PASI score, 39 (88%) achieved a > 60% reduction and 42 (95%) a > 50% reduction. The mean initial dose of CyA was 3 mg/kg/day and the mean dose was 3–3 mg/kg/day throughout the study. Twenty‐five (57%) patients were maintained on 3 mg and six (14%) required > 5 mg/kg/day for limited periods to obtain significant improvement. In three of these patients, this was achieved with 6 mg/kg/day but, of the remainder, one required 7 mg and two required 10 mg/kg/day. Of the 44 patients, 32 (73%) are still taking CyA. Patients were discontinued because of: side‐effects directly attributable to treatment (n= 4); remission of psoriasis (n= 4); death (n= 1); defaulting (n= 1); infrequent attendance (n= 1); high doses of NSAID were necessary for arthritis (n= 1). Before starting CyA, 39 patients were normotensive; 21 (54%) developed mild hypertension. In 28 patients where the GFRs were estimated before and during treatment, there was a 16% reduction (P > 0–0001) during a mean period of 8 months. Two patients developed malignancies. The incidence of hypertension and percentage decrease in GFR were strongly correlated with the dose required to control the psoriasis.

Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families.

Abstract:u2002 A susceptibility locus for psoriasis, PSORS4, has been mapped to chromosome 1q21 in the region of the epidermal differentiation complex. The region has been refined to a 115u2003kb interval around the loricrin (LOR) gene. However, no evidence of association between polymorphisms in the LOR gene and psoriasis has been found. Therefore, we have analysed association to three candidate gene clusters of the region, the S100, small proline‐rich protein (SPRR) and PGLYRP (peptidoglycan recognition protein) genes, which all contain functionally interesting psoriasis candidate genes. In previous studies, the SPRR and S100 genes have shown altered expression in psoriasis. Also polymorphisms in the PGLYRP genes have shown to be associated with psoriasis. We genotyped altogether 29 single nucleotide polymorphisms (SNPs) in 255 Finnish psoriasis families and analysed association with psoriasis using transmission disequilibrium test. A five‐SNP haplotype of PGLYRP SNPs associated significantly with psoriasis. There was also suggestive evidence of association to SPRR gene locus in Finnish families. To confirm the putative associations, selected SNPs were genotyped also in a family collection of Swedish and Irish patients. The families supported association to the two gene regions, but there was also evidence of allelic heterogeneity.

Skin T cell proliferative response to M protein and other cell wall and membrane proteins of group A streptococci in chronic plaque psoriasis

To determine and compare the T cell response to M protein and other group A streptococcal (GAS) antigens, T cell lines (TCL) were cultured from the lesional skin of 33 psoriatic patients and 17 disease controls. GAS‐reactive skin TCL were tested in proliferation assays with recombinant M6 protein, and extracts of cell wall and membrane from type M6 GAS and its corresponding M gene deletion mutant. Initially, GAS‐reactive skin TCL were obtained from 16 of 25 (64%) psoriasis, and from seven of 17 (41%) control patients. Eleven psoriatic and four control GAS‐reactive TCL proliferated to M6 cell wall extract, whereas all the TCL from both groups responded to the extract of M6 membrane proteins. This difference in response to the two extracts was significant for both groups of patients (psoriasis, Pu2003=u20030·0335, controls, Pu2003=u20030·0156). GAS‐reactive TCL from a further eight psoriasis patients showed no difference in response to cell wall extract from M6 GAS (containing the M protein minus its C‐terminus) compared to that of its corresponding M gene deletion mutant. Furthermore, GAS‐reactive TCL did not proliferate to recombinant M6 protein. However, a small, but significant reduction in proliferation by the eight psoriatic GAS‐reactive TCL to the M‐negative (lacking the M protein C‐terminus) compared to M6‐positive membrane extract was observed (Pu2003=u20030·01). These findings suggest that GAS‐reactive T cells in skin lesions of chronic plaque psoriasis proliferate to streptococcal membrane and, to a lesser extent, cell wall proteins. However, psoriatic skin T cells do not recognize cell wall M protein.