Integrating neuronal involvement into the immune and genetic paradigm of vitiligo.

In this review we show how the neuronal theory is relevant to the convergence theory for the mechanism causing vitiligo, especially the segmental type. Neuropeptides and neurotransmitters, such as neuropeptide Y and dopamine, can be central to the pathological mechanisms of melanocyte destruction. They link into a bidirectional network connecting cutaneous nerves, the neuroendocrine axis and the immune system, and through their local influence on cutaneous inflammation, to the antigen-specific regulatory T cells and the chemokine ligand type 9/chemokine receptor type 1 axis, which is thought to be the final pathway for melanocyte destruction.

Morphologic observations on the dermal nerves in vitiligo: an ultrastructural study.

BACKGROUND: Vitiligo is a common idiopathic skin disorder. The etiology is unknown, although various hypotheses have been advanced. These include the neuronal hypothesis, where neuronal factors are thought to play a role in the pathogenesis of this disease. METHODS: Skin biopsies were taken from marginal and central parts of four vitiligo patients. Biopsies were also taken from nonvitiliginous skin of each patient and from four normal control subjects. Sections were examined under the electron-microscope. Nerve fibers in the superficial dermis were examined. RESULTS: Subtle ultrastructural changes, including regeneration and degeneration, were consistently found in dermal nerves of vitiligo lesions. The most consistent feature, seen in all four vitiligo patients studied (in both lesional and marginal areas), was an increased thickness of the basement membrane of Schwann cells. This change was found in approximately three-quarters of all dermal nerves in vitiligo biopsies, but in only about one-quarter of dermal nerves in normal control skin. About half the abnormal dermal nerves in vitiligo skin showed minor axonal damage, although indicators of regeneration (increased mitochondria and rough endoplasmic reticulum) predominated. The dermal nerves in vitiligo showed no difference in fiber diameter or fiber density in comparison with controls. CONCLUSIONS: In vitiligo both axonal degeneration and nerve regeneration may occur, with the latter possibly being a reactive change to earlier axonal damage. These findings support the hypothesis that there is a neuronal component to this disease.

Neuropeptides and general neuronal marker in psoriasis--an immunohistochemical study.

Nerve fibres immunoreactive to antibodies to vasoactive intestinal polypeptide (VIP) and substance P (SP) were increased in lesional psoriatic skin when assessed semiquantitatively. Biopsies from psoriatic plaques on the arm were studied in 13 patients and compared with biopsies from non-lesional areas (in three of the same psoriatic subjects) and from normal skin in seven non-psoriatic controls. Immunohistochemical methods were used on cryocut skin sections to demonstrate the neuropeptides SP, VIP, calcitonin gene-related peptide and neuropeptide Y, and the general neuronal marker protein gene product (PGP) 9.5. The immunofluorescence was examined by semiquantitative and, for PGP 9.5, by quantitative methods. VIP reactive nerve fibres were increased at areas of eccrine sweat glands throughout the dermis, at the dermo-epidermal junction, and in the epidermis, in psoriasis lesional skin. SP reactive nerve fibres were increased at the dermo-epidermal junction, where the nerves ran parallel with and perpendicularly through the junction. PGP 9.5 reactive nerve fibres showed an increase at the dermo-epidermal junction, in the papillary dermis, and at the eccrine sweat glands in lesional psoriatic skin but not in non-lesional, or in control skin. These findings support the hypothesis that neuropeptides may be involved in the pathogenesis of psoriasis.

Neuropeptide and neuronal marker studies in vitiligo.

Neuropeptide and neuronal marker immunoreactivity was studied in skin biopsies from lesional and marginal areas in 12 patients with vitiligo, and in seven normal controls. The vitiligo was active in seven, static in two, and of unknown activity in three. Antibodies against general neuronal marker PGP 9.5 (PGP 9.5), substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY), were used. The epidermis, dermo-epidermal junction, papillary and reticular dermis, and appendages, were assessed semiquantitatively for reactivity with each antibody. Staining with PGP 9.5 in the upper dermis was assessed quantitatively by image analysis. An increase in reactivity against NPY antibody was seen in five of 10 cases (three with active vitiligo) in the marginal areas, and in three of 12 subjects (all with active vitiligo) in the lesional vitiligo areas. VIP antibody reactivity showed a minimal increase in the marginal and lesional vitiligo areas (in two cases each, both of whom had active vitiligo). SP and CGRP reactivities did not differ from normal. PGP 9.5 staining was minimally increased at the dermo-epidermal junction and lower Malpighian layer in biopsies from marginal areas in three of 10 subjects (all with active vitiligo). Quantitative analysis of PGP 9.5 reactivity in the upper dermis showed no difference between vitiligo and normal biopsies. These findings support the concept of neuronal or neuropeptide involvement in vitiligo, and in particular suggest that NPY may have a role in the pathogenesis of the disease.

The relationship between stress and the onset and exacerbation of psoriasis and other skin conditions.

The role of stressful life events in the progress of various skin conditions was studied retrospectively in patients who presented with either psoriasis (where there is some agreement about the importance of stress), urticaria, acne, alopecia and non-atopic eczema (where there is some uncertainty regarding the role of stress), or malignant melanoma, fungal infection, basal cell carcinoma and melanocytic naevi (where stress is considered less relevant). When patients in the three groups were matched for age, those with psoriasis were more likely to report that the experience of stress pre-dated the onset and exacerbations of their condition than patients with other skin diseases. For the psoriasis patients the most common types of life events were family upsets (such as bereavements), and work or school demands, but chronic difficulties were also common. There was no relationship between the severity of stress and time to onset or exacerbations. The results support the notion that stress is more likely to be associated with the onset of psoriasis than other conditions, but also that there may be considerable individual variation in the ability to cope, suggesting that psychological interventions may be helpful for particular patients.

The relationship between disease severity, disability and psychological distress in patients undergoing PUVA treatment for psoriasis.

BACKGROUND: Patients suffering from severe psoriasis report high levels of personal distress and disability as a result of their disease. OBJECTIVE: The purpose of this study was to examine the relationship between disease severity, personal distress and disability. METHODS: Twenty-two patients provided a self-rating of disease severity and completed the Psoriasis Disability Index (PDI) and the General Health Questionnaire (GHQ). A dermatologist provided a clinical assessment from the case notes. RESULTS: Although the clinical assessment was not related to patient ratings, patient-rated severity scores, GHQ and PDI were correlated with each other. GHQ could only be predicted by disease severity when it was mediated by PDI scores. CONCLUSIONS: These results indicated that psoriasis affects psychological distress through its effects on the patients' everyday lives.