Jan A. Marcusson

CGRP-immunoreactive nerves in prurigo nodularis – an exploration of neurogenic inflammation

Background: The present study has explored the localization and distribution of calcitonin gene‐related peptide (CGRP)‐immunoreactive (IR) nerve fibers in prurigo nodularis, especially emphasizing its relationships to mast cells and eosinophils, which all are important contributors to inflammation.

Chronic fatigue syndrome and nickel allergy

50 patients with chronic fatigue syndrome (CFS) and 73 controls were patch tested with 8 metal allergens. We found an overrepresentation of allergies among the CFS patients, which was not significant. However, allergy to nickel occurred in 36% of patients in the CFS group and in 19% of subjects in the control group (p<0.05). The high frequency of nickel allergy was more noteworthy in females in the CFS group than among female controls (52% and 24%, respectively, p<0.05). Similarly, in the males the figures were 14% and 9%. We suggest that in vivo immunoactivation by ions of nickel, or metal cross‐reacting with nickel, could be an etiological factor in CFS.

Light and electron microscopic immunohistochemical observations of p75 nerve growth factor receptor-immunoreactive dermal nerves in prurigo nodularis.

Abstract Prurigo nodularis is an inflammatory skin disease characterized by neurohyperplasia. Neurotrophins and their receptors play a critical role in nerve growth, differentiation, maturation and maintenance, including cutaneous nerve fiber growth and innervation. They may also be responsible for events related to the growth and differentiation control of keratinocytes. To explore the exact distribution of the p75 low-affinity nerve growth factor receptor (p75 NGFr) in the cutaneous nerve components, p75 NGFr immunofluorescence as well as ultrastructural immunohistochemical studies were performed on prurigo nodularis lesional skin and normal human skin samples. The immunofluorescence results revealed that nerve fibers and bundles were increased in number and size in lesional upper dermis with stronger p75 NGFr immunoreactivity than in the corresponding normal tissue. At the ultrastructural level, a lot of nerve fibers clustered together in the prurigo nodularis dermal tissue. The axons were enlarged and branched, but the axons themselves seldom showed any NGFr immunoreactivity. The Schwann cell bodies were extended and irregularly shaped, and tended to separate into many branches enveloping the axons. The Schwann cell membrane showed strong p75 NGFr immunoreactivity. The perineurium cells also revealed strong p75 NGFr immunoreactivity. The Schwann cells inside the perineurium were less p75 NGFr-immunoreactive than those outside the perineurium. The membrane of certain basal keratinocytes showed NGFr immunoreactivity as well. The present results indicate that overexpression of p75 NGFr in Schwann cells and perineurium cells could contribute to the neurohyperplasia in prurigo nodularis.

Histamine‐containing mast cells and their relationship to NGFr‐immunoreactive nerves in prurigo nodularis: a reappraisal

The mast cell, which is a histamine‐containing cell, has been found to have far more functions in skin inflammation than hitherto understood. To investigate the appearance of mast cells in prurigo nodularis, histamine immunohistochemistry in combination with nerve growth factor receptor (NGFr) double‐staining as well as electron microscopic studies were performed. The results revealed that the histamine‐containing cell number was increased in the lesional dermis. The mast cell size was also increased and the shape had become more dendritic. They tended to contact the epidermis and even infiltrated into it. In the histamine and NGFr double‐staining, both an increased histamine‐containing mast cell number and an increased number of NGFr‐immuno‐reactive nerve fiber profiles were revealed in the upper dermis of the prurigo nodularis lesional skin. Mast cells were seen in close vicinity to NGFr‐positive nerves and sometimes even seemingly to contact single nerve fibers. At the ultrastructural level, it is obvious that the mast cell bodies become larger, having more abundant cytoplasm and organelles (e.g. mitochondria), but comparatively fewer characteristic granules. Mast cells were often observed to sprout long dendrites, with or without granules. The cells were also frequently seen to contact other cell types, and a mast cell infiltration into the epidermis was also found. The statistical results of mast cell numbers showed a significant increase in prurigo nodularis lesional skin compared to the normal controls. The present results further indicate that mast cells, together with cutaneous nerve fibers, are actively involved in the pathogenesis of the disease.

Indium and iridium allergy in patients exposed to dental alloys

Patients and Methods All patients in this study were referred to the Dermatology Clinic at Huddinge Hospital for suspected hypersensitivity to dental materials. Most had no oral mucosal reactions, but had systemic symptoms as previously described (1). During 1990–1995, indium and iridium salts were sporadically patch tested, but during 1995–1996, patients were consecutively patch tested (Table 3). During 1990–1995, 5 patients were positive to indium and iridium (Table 3). During 1995–1996, 205 patients were tested and 8 were positive. Patch tests with Finn Chambers (3) and reagents, prepared and obtained from Chemotechnique Diagnostics (Malmö, Sweden), were applied to the back for 2 days and read after 4 days (1,

Eosinophil cationic protein- and eosinophil-derived neurotoxin/eosinophil protein X-immunoreactive eosinophils in prurigo nodularis

Abstract It is known that eosinophils are actively involved in allergy and inflammation. The granular components of eosinophils, eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin/eosinophil protein X (EDN/EPX), play an important role in such allergic and inflammatory processes. Prurigo nodularis is a chronic inflammatory skin disease with obvious cutaneous nervous involvement. To detect ECP and EDN/ EPX expression in the eosinophils and their relation to nerve fibres in prurigo nodularis, ECP and EDN/EPX single-labelling immunofluorescence, and ECP and PGP 9.5 double-labelling immunofluorescence, were performed. In prurigo nodularis lesional skin, the ECP- and EDN/EPX-containing cells, which were mainly distributed in the upper dermis, were significantly increased in number compared to their numbers in uninvolved and normal skin. The immunoreactivity of ECP and EDN/EPX in prurigo lesional skin was stronger than in uninvolved skin or control skin. The PGP 9.5-immunoreactive nerves were also increased in number in the areas where there were increased eosinophils. The nerves were in close proximity to eosinophils, and occasionally even seemed to be in contact. The present results indicate that the cutaneous nerves and the ECP- and EDN/EPX-containing eosinophils are possibly involved in the pathogenesis of the disease. The close relationship of nerves and eosinophils indicates that the cutaneous nerves may influence eosinophil function in the chronic inflammatory states of prurigo nodularis. ECP and EDN/EPX could thus be released to the local tissue and modulate the inflammation of the prurigo nodularis lesion.

Protective effects of tanning on cutaneous DNA damage in situ.

Background: The incidence of skin cancer, the most common type of cancer in the Western world, has been shown to be associated with the degree of exposure to solar radiation. However, little is known on how human skin can be protected against UV-induced DNA damage by constitutive and induced pigmentation. Objective: To study the effect of skin pigmentation induced by a sunbed-type of treatment on the formation of UV-induced DNA damage in human skin in situ. Methods: A photoproduct assay was performed in untanned and tanned skin of healthy volunteers. Results: There is no significant difference in the induction of photoproducts between untanned and tanned skin. Conclusion: Our data demonstrate that constitutive skin pigmentation is more efficient than the induced one in protection against formation of photoproducts.

Unusual skin reaction to silicone content in breast implants.

We present a patient who had a long history of unsuccessful bilateral mammary operations with insertion and extraction of various implants, some of which were filled with silicone gel, others with saline. In addition to complications in the tissue surrounding the prosthesis, she had distant widespread skin lesions which, we believe, were due to leakage from the implant. A cutaneous test with material from various implants, such as the gel content and the shells, caused an unusually prolonged inflammatory response, which was difficult to classify as being either irritative or allergic. Macromorphologically and histologically, the provoked lesions resembled the previous cutaneous lesions. We believe that the patients complications are due to an unusual host response to silicone.

LANGERHANS CELLS IN PRURIGO NODULARIS INVESTIGATED BY HLA-DR AND S-100 IMMUNOFLUORESCENCE DOUBLE STAINING

The Langerhans cell is one of the antigen-presenting cells in the immune system. To study the presence of cutaneous Langerhans cells in prurigo nodularis, age- and sex-matched prurigo nodularis patients and healthy volunteer skin biopsies were investigated by an HLA-DR and S-100 immunohistochemical double staining method. The results showed that the HLA-DR- and S-100-immunoreactive (IR) Langerhans cells were altered in prurigo nodularis epidermis and dermis. The number of epidermal Langerhans cells in the prurigo nodularis patients was decreased in five and increased in two cases. In the dermis, the HLA-DR- and S-100-IR cells were apparently more numerous than in the controls. In the involved skin there were also more S-100-IR coarse nerve fibres in the dermis as compared to controls. The results indicate that dermal Langerhans cells (HLA-DR and S-100 double-labeled) as well as other dermal HLA-DR- and S-100-IR dendritic cells, but most likely not epidermal Langerhans cells, may be critically involved in the development or persistence of prurigo nodularis.

The lymphocyte response to nickel salt in patients with orthopedic implants

In this pilot study, 14 patients with different symptoms and signs in relation to orthopedic implants were compared with 12 asymptomatic patients to determine the in vitro lymphocyte response to nickel sulfate. We conclude that nickel allergy may explain some, but not most, of the local and generalized symptoms associated with orthopedic implants.