B.S. Baker

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.

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.

Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions.

A strong association exists between guttate psoriasis and group A, β‐haemolytic streptococcal infections. To demonstrate the presence of streptococcal‐specific T cells in psoriatic skin, T‐cell lines (TLs) were established from biopsies of lesions from five patients with guttate psoriasis, and compared with TLs from five patients with eczema, five with lichen planus, two with pityriasis rosea and three with nickel contact dermatitis. TLs from purified protein derivative (PPD)‐induced delayed hypersensitivity sites in three normal individuals were also studied. All five of the psoriatic TLs responded in a proliferation assay to heat‐killed isolates of group A streptococci, compared with only one eczema, two lichen planus and one pityriasis rosea. The response of one nickel contact dermatitis and two PPD TLs to group A streptococci was markedly less than to nickel and PPD, respectively. One of the psoriatic TLs was cloned in the presence of type 5 streptococcal M protein. The nine clones obtained were all CD3+, CD4+, CD45RO+, TCR α,β+, γ,δ−. However, they were all unreactive with antibodies to TCR V β 5, 6, 8 or 12. Eight of the nine clones reacted, to a varying extent, to one or two of three preparations of group A streptococci expressing different M proteins. The streptococcal response of four consistently reactive clones from this patient was HLA‐DR‐restricted and inhibited by anti‐HLA‐DR antibody in a dose‐dependent manner. On stimulation these four clones secreted high levels of γ‐interferon and detectable levels of IL‐2, IL‐10 and granulocyte/macrophage colony stimulating factor (GM‐CSF) depending upon the nature of the stimulus, but no IL‐4 or TNF‐α production was detected.

Long-term cyclosporin for psoriasis

Thirteen patients with severe persistent psoriasis, intolerant of, or unresponsive to, other current treatments have been treated with cyclosporin (Cys) for periods varying from 12–25 (mean 18) months. The dose ranged from 1–4 mg/kg/day (mean 2.8 mg). There was a 72% reduction in the mean PASI score at 4 weeks, and at the end of the study, an 81% reduction. Adjuvant therapy with topical steroids was used in 11 of the 13 patients after the first 3 months of Cys treatment to persistent patches on an intermittent basis with beneficial effect. Six patients developed mild to moderate hypertension, in three this was controlled by a reduction in the dose of Cys, and in the other three by hypotensive agents. The mean serum creatinine rose from 72 to 90μM/1 during the study. Hypertrichosis occurred in seven of the 13 patients. Low dosage Cys is an effective treatment for clearing psoriasis and maintaining improvement on a long‐term basis.

Renal function and biopsy findings after 5 years' treatment with low-dose cyclosporin for psoriasis.

Renal biopsies were performed in eight patients with chronic plaque psoriasis who had been treated with low‐dose cyclosporin (CyA) (range 1–6 mg/kg/day; average dose 3.3 mg/kg/day) for an average period of 5 years. In six of the eight patients biopsies showed features consistent with CyA nephrotoxicity. Tubular atrophy and arteriolar hyalinosis were present in all six, four had an increase in interstitium. and two showed an increased incidence of glomerular obsolescence. Two of the patients showed all of these features, two patients had three features, and the remaining patients had two features. Renal function was assessed by glomerular liltration rate (CFR) and serum creatinine. Both a fall in the GFR and a rise in the serum creatinine correlated with the severity of the features of CyA nephrotoxicity seen on biopsy. However, the best predictor of the biopsy findings was a failure of renal function to show significant improvement when CyA was discontinued for a month.

Cytokine expression in psoriatic skin lesions during PUVA therapy

To determine whether an improvement in skin lesions as a result of PUVA therapy may be correlated with changes in cytokine patterns, RT-PCR amplification was used to compare the levels of IL-2, IL-6, IL-8, IL-10, TNF-α and IFN-γ cytokine mRNA expression in serial biopsies from three chronic plaque psoriatic patients. In each case, 3-mm punch biopsies were taken from lesional skin before and during 2–28 days of treatment with PUVA. Total mRNA was extracted from each biopsy, cDNA synthesized, and then amplified by 35 cycles of PCR using cytokine-specific primers. The specificity of the PCR products was confirmed by the Southern blot technique. Substantial levels of specific mRNA for each of the cytokines studied was present in the lesions prior to treatment. In two of the three patients who responded well to PUVA, a reduction in all the cytokines including IL-10 was observed compared with baseline levels. In contrast, PUVA proved to be ineffective in clearing the psoriasis of the third patient whose skin lesions worsened during the course of treatment. This was accompanied by an increase in IFN-γ but not of the other cytokines investigated, above the pretreatment level. This study showed an association between PUVA-induced resolution and decreases in the levels of various cytokines highly expressed in psoriatic lesions.

Is epidermal cell proliferation in psoriatic skin grafts on nude mice driven by T-cell derived cytokines?

Plasminogen activity and DNA synthesis by epidermal cells have been reported to be doubled in psoriatic skin grafts compared with grafts of normal skin 6 weeks after transplantation to nude mice. In our study human lymphocytes disappeared from such grafts within 48 h whilst some DR‐positive human dendritic cells were retained in the grafts for up to 4 weeks. However, the grafts were infiltrated by Thy 1.2+ mouse lymphocytes within 6 days and this infiltration persisted at a moderate level throughout the observation period. It consisted of perivascular aggregates, scattered dermal and papillary T cells, and some mouse T cells were also found in the epidermal compartment. Grafts of psoriatic and non‐psoriatic control skin were infiltrated to a similar extent, suggesting a low‐grade rejection response against the human xenografts. These findings raise the possibility that psoriatic keratinocytes are responding abnormally to inflammatory cytokines released by mouse lymphocytes reacting against the skin grafts.

The role of cytokines in the generation of skin lesions in dermatitis herpetiformis

The infiltration of polymorphonuclear neutrophils (PMN) into the upper dermis which characterizes the skin lesions of dermatitis herpetiformis (DH) has never been satisfactorily explained. This study has shown that lesional skin of patients with DH has increased expression of endothelial leucocyte adhesion molecules (ELAM) in the deep dermis, combined with a markedly increased staining for interleukin 8 (IL‐8) in the basal epidermal layer. Dendritic cells which stained for granulocyte macrophage colony stimulating factor (CM‐CSF) were also observed at the dermo‐epidermal junction. and this phenomenon was more pronounced in lesional than in uninvolved DH skin. ELAM. IL‐8 and GM‐CSF are known to promote infiltration and activation of PMN, and it is suggested that these cytokines may play a key role in the generation of DH lesions.

Induction of cutaneous lymphocyte-associated antigen expression by group A streptococcal antigens in psoriasis

Abstract The cutaneous lymphocyte-associated antigen (CLA) has been proposed as a homing receptor for the selective migration of memory T cells into the skin. To investigate the effect of group A streptococci (GAS) on the migration of T cells in psoriasis, CLA expression was assessed by double-staining for CD3 and the HECA-452 epitope on peripheral blood T cells from 13 patients with psoriasis, 10 patients with other inflammatory skin diseases and 12 normal controls before and after 7 days culture with a GAS sonicate, Candida albicans (control antigen) or medium. In addition, CLA + , and CLA – , CD3 + CD45RO + subsets were isolated from individuals in each group and Vβ2 expression and proliferation to GAS studied. Mean CLA expression by freshly isolated T cells was almost identical in the three groups. After culture with GAS, T cells from the psoriatic patients and control groups showed a significant increase in mean percentage CLA+ expression compared to medium (P < 0.002, P < 0.05, respectively). This induction was inhibited by the addition of anti-IL-12 antibody. However, in psoriatic patients, but not in controls, the GAS-induced increase was significantly greater than that of C. albicans (P < 0.002) and was accompanied by a decrease in T cells positive for the peripheral lymph node homing receptor, L-selectin (P < 0.05). The percentage of Vβ2+ T cells was markedly higher in the CLA+ than in the CLA– T-cell subset in psoriatic patients (P < 0.01) and controls; both subsets proliferated to GAS, in each group. These findings suggest a differential modulation of specific tissue homing receptors on T cells by GAS in psoriasis.

T lymphocytes in lesional skin of patients with dermatitis herpetiformis

Ten patients with dermatitis herpetiformis had biopsies taken from involved skin.Monoclonal antibodies and the avidin‐biotin peroxidase staining technique were used to stain for T cells and Langerhans cells in skin sections. A significant increase in the number of CD3‐positive T cells was observed in the upper dermis of involved compared with uninvolved skin (P<0.0005). Most of the T cells in involved skin were CD45RO‐positive memory cells; CD4‐positive T cells exceeded the number of CD8‐positive T cells by a ratio of 4:1. In addition, CD1a‐positive dendritic cells were observed within the clumps of T cells in involved dermis in nine of the 10 patients, but were absent from the dermis of uninvolved skin. Double immunofluorescent staining demonstrated that approximately 20–40% of the CD3‐positive T cells were activated, and expressed the HLA‐DR antigen.