M. Bhushan

Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization.

Langerhans cells (LC) are members of the wider family of dendritic cells. LC reside in the epidermis where they serve as sentinels of the immune system, their responsibilities being to sample the external environment for changes and challenges and to deliver information (antigen) to responsive T lymphocytes within skin draining lymph nodes. The ability of LC to migrate from the epidermis to regional lymph nodes is therefore of pivotal importance to the induction of cutaneous immune responses. The journey that LC have to make from the skin has a number of requirements. Initially it is necessary that LC disassociate themselves from surrounding keratinocytes and are liberated from other influences that encourage their retention in the epidermis. Subsequently, migrating LC must successfully traverse the basement membrane of the dermal–epidermal junction and make their way, via afferent lymphatics, to draining lymph nodes. Effective entry into lymph nodes is necessary, as is correct positioning of cells within the paracortex. There is increasing evidence that both cytokines and chemokines, and their interaction with appropriate receptors expressed by LC, orchestrate the mobilization and movement of these cells. We here consider the parts played by these molecules, and how collectively they induce and direct LC migration.

Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis

Neovascularization appears to play an early and important part in the evolution of psoriatic plaques. We studied the distribution and production of two known angiogenesis factors, endothelial cell stimulating angiogenesis factor (ESAF) and vascular endothelial growth factor (VEGF), in the skin of patients with chronic plaque psoriasis and normal control subjects. Our results showed that tissue levels of ESAF and VEGF were significantly elevated in involved as compared with normal control skin (P = 0·006 and P < 0·0001, respectively). Tissue levels of ESAF and VEGF were also raised in involved skin as compared with uninvolved skin in patients with psoriasis (P = 0·001 and P < 0·0001, respectively). Tissue levels of ESAF and VEGF in plaques of psoriasis correlated closely with the clinical severity of psoriasis (r = 0·6 and r = 0·9, respectively). Serum levels of ESAF and VEGF were significantly raised in patients with psoriasis as compared with control subjects (P = 0·001 and P = 0·02, respectively). In vitro culture studies revealed that ESAF is produced by both keratinocytes and fibroblasts in approximately equal quantities in normal skin, whereas VEGF is secreted predominately by keratinocytes. A similar pattern is seen in both involved and uninvolved skin of patients with psoriasis. However, there is increased secretion of both factors in keratinocytes and fibroblasts from involved and uninvolved skin as compared with normal control skin (P < 0·001). The increased levels and secretion in plaques of psoriasis of two molecules, ESAF and VEGF, known to promote new blood vessel formation, suggest a pathogenetic role for them in this disease.

The Salford Psoriasis Index: an holistic measure of psoriasis severity

We have developed, tested and validated a new scoring system for psoriasis: the Salford Psoriasis Index (SPI). The SPI incorporates the current clinical extent of psoriasis based on the Psoriasis Area and Severity Index (PASI), a score indicating psychosocial disability, and past severity based on treatment history. The resultant three‐figure SPI (signs, psychosocial disability, interventions) is a similar paradigm to the TNM (tumour, nodes, metastasis) classification used for cancer staging. The first figure transforms the PASI into a number from 0 to 10 reflecting extent of psoriasis. The second assesses the psychosocial impact of psoriasis on each patient using a 0–10 visual analogue scale. The third figure reflects historical severity of disease as judged by the need for systemic treatment, admission to hospital and number of episodes of erythroderma.

IL-1β-induced Langerhans' cell migration and TNF-α production in human skin: Regulation by lactoferrin

In mice, the roles of cytokines in the initiation of epidermal Langerhans’ cell (LC) migration are well documented; however, the mechanism of this response in humans is less well defined. The purpose of the present investigation was to examine the contribution of interleukin (IL)‐1β to human epidermal LC migration and to define further the mechanisms of this response. We demonstrate here that homologous recombinant IL‐1β administered intradermally to healthy human volunteers provides a stimulus for LC migration, with significant (P < 0·01) reductions in LC densities being observed at both 2 h and 4 h following treatment. At the later time‐point of 4 h, injection of IL‐1β was also accompanied by activation of those LC remaining in the epidermis. Analysis of fluid aspirated from suction blisters formed at injection sites revealed significant (P < 0·01) tumour necrosis factor (TNF)‐α production (2·99 ± 1·18 pg TNF‐α/mg protein; mean ± s.d. of n = 10) in response to IL‐1β treatment compared with saline control injections (0·90 ± 1·05 pg TNF‐α/mg protein). Prior topical application of human recombinant lactoferrin (LF), an iron‐binding protein found in exocrine secretions and skin, inhibited IL‐1β‐mediated LC migration and also compromised the production of TNF‐α protein as measured in suction blister fluids derived from each of the treatment sites. Taken together, these data demonstrate that IL‐1β is associated with both the stimulation of human epidermal LC migration and local TNF‐α production. Topical treatment with LF compromises both these responses. These data suggest that topical LF may potentially represent a novel therapeutic in the treatment of skin inflammation where TNF‐α is an important mediator.

Tumour necrosis factor‐α‐induced migration of human Langerhans cells: the influence of ageing

Summary Background  Langerhans cells (LCs) play essential roles in the initiation and regulation of cutaneous immune responses mediated through their successful migration from the epidermis to draining lymph nodes while carrying antigen. Tumour necrosis factor (TNF)‐α, a keratinocyte‐derived cytokine, has recently been shown to play an important role in the mobilization of LCs from human epidermis. Although it is known that with age the immune system changes, the influence of increasing age on the function of human LCs has not been defined clearly.

Anti-e-selectin is ineffective in the treatment of psoriasis: A randomized trial

Summary Background Skin‐homing, memory T lymphocytes play an important role in the pathogenesis of psoriasis by interacting with the vascular addressin, E‐selectin and trafficking into lesional skin. Thus an attractive option for targeted therapy of the disease would be blockade of skin‐homing T cells with an antibody directed at E‐selectin.

Incidence of childhood linear scleroderma and systemic sclerosis in the UK and Ireland.

Childhood scleroderma encompasses a rare, poorly understood spectrum of conditions. Our aim was to ascertain the incidence of childhood scleroderma in its different forms in the UK and Ireland, and to describe the age, sex, and ethnicity of the cases.

Recent advances in cutaneous angiogenesis

An understanding of the molecular basis of angiogenesis is key to the appreciation of many of the advances made in the field of neovascularization over the past two decades. The sequence of events involved in angiogenesis includes: (i) increased vascular permeability and leakage; (ii) degradation of basement membrane; (iii) endothelial cell proliferation and migration through the surrounding extracellular matrix; and (iv) maturation and stabilization of the newly formed vessel bed. This review provides an update on the molecular basis of such pathways in the skin, with particular emphasis on the endothelial cell‐specific vascular endothelial growth factor and angiopoietins as modulators of angiogenesis that can be targeted in therapy of cutaneous disease.

Oral liarozole in the treatment of palmoplantar pustular psoriasis: A randomized, double-blind, placebo-controlled study

Background Palmoplantar pustular psoriasis (PPP) is a chronic, relapsing condition often recalcitrant to therapy. Synthetic retinoids have been found to be efficacious in the treatment of PPP, but their use is limited by side‐effects. Liarozole is an imidazole‐like compound that inhibits the retinoic acid (RA) 4‐hydroxylase‐mediated breakdown of all‐trans RA, causing elevation of plasma and cutaneous levels of RA. Thus liarozole acts as a retinoid‐mimetic drug. Liarozole has already been found to be effective in the treatment of retinoid‐responsive conditions such as chronic plaque psoriasis and ichthyoses.

Nailfold video capillaroscopy in psoriasis

Changes in the microvasculature are considered to play an important part in the pathogenesis of psoriasis and its associated arthritis. The novel method of nailfold video capillaroscopy is an extension of the technique of widefield nailfold microscopy which has been of diagnostic and predictive use in the in vivo study of the microcirculation in systemic sclerosis and other connective tissue disorders. However, similar studies in patients with psoriasis and psoriatic arthritis and/or nail changes have produced conflicting results. We tested the hypothesis that any abnormalities in nailfold capillaries of either a quantitative or qualitative nature might be observed more readily in subjects with pathology adjacent to the nailfold, i.e. distal interphalangeal (DIP) joint changes and/or nail dystrophy, when using this technique. Forty‐four patients with psoriasis were recruited (21 males, 23 females). Twelve patients had psoriasis alone, 13 had psoriasis and nail changes, six had DIP joint involvement with changes of psoriasis elsewhere, and 13 had psoriasis, DIP arthritis and nail changes. Capillary density and standard capillary dimensions were studied and compared with those of 44 age‐ and sex‐matched control subjects. There was a significant (P < 0·05) decrease in capillary loop density in patients with either psoriasis plus nail disease (14·5 ± 5·7 capillaries per 3 mm field) or psoriasis plus nail and DIP joint disease (14·3 ± 5·0) when compared with controls (19·2 ± 3·8). In patients with psoriatic arthritis affecting the DIP joints, there was a statistically significant (P < 0·05) decrease in arterial and venous capillary limb diameters, and this was also seen in those with arthritis associated with nail changes. However, there was no difference in capillary dimensions between patients with psoriasis and/or nail changes when compared with normal controls. Morphological abnormalities previously described in the literature were not noted in any of our four patient groups. Our findings of diminution in both nailfold capillary bed density and dimensions of the arterial and venous capillary limbs suggest that vascular injury, previously noted in ultrastructural studies, may play a part in the pathogenesis of psoriatic arthritis. However, in contrast to previous studies, we found no specific pattern of a morphological nature of nailfold capillaries in patients with psoriasis with or without nail changes, when compared with normal controls.