Alopecia areata in a rhesus monkey (Macaca mulatta).

BACKGROUND: A 14-year-old female rhesus monkey (Macaca mulatta) of Chinese origin has been suffering from alopecia universalis since childhood. METHODS: Recently, the health status of the animal was recorded comprehensively by detailed clinical examination including hematology and serology supplemented by histological and immunohistochemical investigations of skin biopsies and molecular biological techniques to clarify the causes of the persistent hair loss. RESULTS AND CONCLUSIONS: The hairless gene (hr) nonsense mutation was ruled out by polymerase chain reaction and by sequencing of the corresponding gene. Histological examinations revealed a prominent chronic lymphocytic perifolliculitis and folliculitis affecting anagen stage hair follicles as well as miniaturized hair follicles. Immunohistochemistry using the antibodies CD3, CD20 and CD4 confirmed the diagnosis of a T-cell-mediated autoimmune disease resembling alopecia areata universalis in humans.

Interferon-gamma-deficient mice are resistant to the development of alopecia areata.

BACKGROUND: Alopecia areata (AA) is a T-cell mediated putative autoimmune disease of hair follicles, which can be transferred by CD4(+) T cells. However, whether T-helper (Th) 1 or Th2 cytokines are predominant has not yet been defined. OBJECTIVES: To elucidate the importance of Th1 cells in the pathogenesis of AA we investigated the functional role of interferon (IFN)-gamma in the experimental induction of AA. METHODS: AA was experimentally induced by grafting full-thickness skin from AA-affected C3H/HeJ mice on to C3H/HeJ mice with a targeted deletion of the Th1 cytokine IFN-gamma gene (IFNgamma(-/-)) and on to wild-type mice (IFNgamma(+/+)). RESULTS: While 90% of wild-type mice developed AA, none of the IFNgamma(-/-) mice exhibited hair loss. Immunohistochemistry of skin sections revealed a dense perifollicular and intrafollicular infiltrate of CD4(+) and CD8(+) T cells in controls, while in IFNgamma(-/-) mice skin-infiltrating CD8(+) T cells were absent and the number of CD4(+) cells was significantly reduced. Aberrant expression of major histocompatibility complex class I and II molecules in the putative immune-privileged infrainfundibular site of the hair follicle was found to be weaker in AA-resistant IFNgamma(-/-) mice than in control mice with AA. Flow cytometry revealed that leucocytes of IFNgamma(-/-) mice did not respond to the transfer of AA-affected skin. As distinct from IFNgamma(+/+) mice, neither T-cell activation markers nor Th1 cytokines were upregulated in draining lymph node cells or skin-infiltrating leucocytes of AA-resistant IFNgamma(-/-) mice. However, there was no evidence for a shift towards a Th2 cytokine profile, nor for upregulation of regulatory T cells in IFNgamma(-/-) mice. CONCLUSIONS: IFNgamma(-/-) mice fail to activate Th1 cells in response to the transplanted (auto)antigens, which suggests an essential requirement for IFN-gamma-mediated Th1 activation in the induction of AA.

Alterations in the epidermal-dermal melanin axis and factor XIIIa melanophages in senile lentigo and ageing skin.

BACKGROUND: Senile lentigo (SL) is a pigmentation disorder that occurs predominantly on the dorsa of the hands, the forearms and the face; its incidence increases with age. Histological hallmarks of SL lesions are hyperpigmentation of the epidermis and elongation of the epidermal rete ridges. Various factors such as alpha-melanocyte-stimulating hormone, endothelin-1 or stem cell factor are involved in the onset and maintenance of the increased pigmentation. Alterations of the dermal compartment have not yet been analysed in detail in SL. OBJECTIVES: To study the occurrence and distribution of melanin in the dermis from SL and aged skin, biopsies from 12 subjects were morphologically analysed by light and electron microscopy in comparison with unaffected skin. METHODS: Punch biopsies of SL and adjacent skin from 12 male or female volunteers aged 52-81 years were prepared for light and electron microscopy and samples were analysed by morphological, morphometric, histochemical and immunohistochemical methods. RESULTS: The epidermis from SL revealed morphological features such as hyperpigmentation of basal keratinocytes and the formation of elongated rete ridges. S100+ melanocytes in the stratum basale were not markedly increased, indicating that the hyperpigmentation is predominantly due to changes in melanin synthesis, distribution or turnover. Quantification of epidermal cells expressing the proliferation marker Ki67 did not show an increase of this parameter in SL, indicating that at least in the established lesion cell proliferation is not enhanced. We further focused on the dermal compartment and observed granulated cells which were more abundant in SL. Electron microscopic and histochemical analysis revealed that the granulation of these cells is based on melanosomes, mostly present in large melanosomal complexes. Immunohistochemistry using antibodies to CD68 and factor XIIIa (FXIIIa) showed these melanophages to be predominantly FXIIIa+ dermal dendrocytes, which were about six times more abundant than CD68+ macrophages. CONCLUSIONS: In SL an increased number of melanophages was found compared with unaffected skin from the same subject. These melanophages were identified as FXIIIa+ dermal dendrocytes. Possible functional consequences of the massive melanin uptake by dermal dendrocytes are discussed.

Treatment of alopecia areata in the DEBR model using Cyclosporin A lipid vesicles.

Alopecia areata (AA) is a chronic cutaneous disease with a suspected autoimmune origin. We evaluated the efficacy of 0.5% Cyclosporin A (CyA) in a topically applied liposomal formulation as a potential treatment for AA using the Dundee Experimental Bald Rat (DEBR) model. The vehicle consisted of liposomes (75% phosphatidylcholine, 5% lysophosphatidylcholine, 5% sterol, natural oils) of 10% wt. in ethanol with and without 2% wt. terpenes (d-limonene: citral: cineole, 10:45:45) as a penetration enhancer (PE). Fifteen DEBR were allocated to 3 groups of 5. Groups I, II and III received CyA vesicles with PE, CyA vesicles without PE, and CyA in ethanol respectively. All rats were treated twice a day for 6 weeks within a 4 cm2 area on one bald flank with CyA while the contralateral flank received an equivalent control formulation. Rats in group I exhibited visible hair regrowth on the drug treated site after one week of drug application. Group II rats had visible hair regrowth by the end of the second week. The hair growth was progressive and reached a maximum density at the site of application after six weeks in both groups. Histological examination revealed a reduced inflammatory infiltrate and improved hair follicle morphology within the drug treated area as compared to the contralateral vehicle treated skin. Group III rats showed neither visible signs of hair growth nor reduction of hair follicle inflammation. The results of this proof of concept preliminary study suggest that CyA vesicle formulations with and without PE have promising potential as a topical treatment for AA in humans.

Chronic delayed-type hypersensitivity reaction as a means to treat alopecia areata.

The acute phase of alopecia areata (AA) is characterized by an increase in CD44v3+ and CD44v10+ skin-infiltrating leucocytes (SkIL). Induction of a contact eczema, one of the therapeutic options in AA, can be mitigated strongly by a blockade of CD44v10. The observation that induction of a delayed type hypersensitivity (DTH) reaction abrogates an autoimmune reaction, where both responses apparently use similar effector mechanisms, is surprising and prompted us to search for the underlying mechanisms. AA-affected C3H/HeJ mice were treated with the contact sensitizer SADBE (squaric acid dibutylester) and leucocyte subpopulations and their activation state was evaluated in SkIL and draining lymph nodes. AA-affected mice exhibited an increased number of SkIL with a predominance of T lymphocytes. After treatment with the contact sensitizer SADBE recovery of SkIL was reduced and monocytes predominated. However, a significantly increased number of leucocytes was recovered from draining lymph nodes. Draining lymph node cells from untreated and treated AA mice exhibited all signs of recent activation with high-level expression of co-stimulatory and accessory molecules and an increased percentage of CD44v3+ and CD44v10+ leucocytes. In contrast, SkIL of SADBE-treated AA mice contained relatively few activated T cells and reduced numbers of CD44v3+ and CD44v10+ cells. Thus, the activation state and the distribution of leucocyte subsets in SADBE-treated AA mice are consistent with a blockade of leucocyte extravasation. Accordingly, the therapeutic effect of long-term SADBE treatment may rely on impaired leucocyte traffic.

[Alopecia areata. Clinical aspects, pathogenesis and rational therapy of a T-cell-induced autoimmune disease]. / Alopecia areata. Klinik, Pathogenese und rationale Therapie einer T-Zell-vermittelten Autoimmunerkrankung.

Alopecia areata is a T-cell mediated autoimmune disease directed against an unknown auto antigen of the hair follicle. There is a genetic predisposition to develop alopecia areata, whereas environmental triggers have so far not been identified. The diagnosis can be established by characteristic clinical features of alopecia areata including its severe forms alopecia areata totalis and universalis. Nail changes may help confirm the diagnosis. On rare occasions a histopathological examination may be necessary, whereas other laboratory investigations are unnecessary. Because of the high rate of spontaneous remission, the efficacy of a rational treatment of alopecia areata has to be proven in controlled studies and it should be associated with only minor side effects. According to the rules of evidence-based medicine, treatment with a contact sensitizer is at present the most effective treatment of alopecia areata showing only mild side effects. However, it is time-consuming and in some cases ineffective, making it desirable to develop new, more specific forms of treatment.

Dietary soy oil content and soy-derived phytoestrogen genistein increase resistance to alopecia areata onset in C3H/HeJ mice.

Alopecia areata (AA) is a complex, multi-factorial disease where genes and the environment may affect susceptibility and severity. Diet is an environmental factor with the potential to influence disease susceptibility. We considered dietary soy (soya) oil content and the soy-derived phytoestrogen genistein as potential modifying agents for C3H/HeJ mouse AA. Normal haired C3H/HeJ mice were grafted with skin from spontaneous AA affected mice, a method previously shown to induce AA. Grafted mice were given one of three diets containing 1%, 5% or 20% soy oil and observed for AA development. In a separate study, mice on a 1% soy oil diet were injected with 1 mg of genistein three times per week for 10 weeks or received the vehicle as a control. Of mice on 1%, 5%, and 20% soy oil diets, 43 of 50 mice (86%), 11 of 28 mice (39%), and 2 of 11 mice (18%) developed AA, respectively. Four of 10 mice injected with genistein and 9 of 10 controls developed AA. Mice with AA had hair follicle inflammation consistent with observations for spontaneous mouse AA, but no significant association was observed between the extent of hair loss and diet or genistein injection. Mice that failed to develop AA typically experience white hair regrowth from their skin grafts associated with a moderate macrophage and dendritic cell infiltration. Soy oil and derivatives have previously been reported to modify inflammatory conditions. Hypothetically, soy oil compounds may act on C3H/HeJ mice through modulating estrogen-dependent mechanisms and/or inflammatory activity to modify AA susceptibility.

SKIBO diseases: a concept to avoid bloody diagnostic procedures in ambiguous skeletal lesions.

In cases with an "atypical" radiologic pattern-osteolytic as well as osteosclerotic or mixed - the radiologist should pay attention to the patient's skin. There he will often find specific changes that are the key to a correct interpretation of the radiologic abnormalities. In such cases the synopsis is of more value in differential diagnosis than more or less unspecific histologic findings. Entities with a non-arbitrary conjunction of changes of the skin and bones we call SKIBO diseases. Some of them have a high potential for mimicking malignant bone lesions, often with the consequence of unnecessary biopsies. In this article we present the typical dermatologic and radiologic signs and symptoms of neurofibromatosis, sarcoidosis and pustulotic arteroosteitis (PAO) with special focus on such skeletal lesions that may mimic malignancy.

Treatment of alopecia areata in C3H/HeJ mice with the topical immunosuppressant FK506 (Tacrolimus).

Alopecia areata-like hair loss has been observed in C3H/HeJ mice and can be defined as a tissue-restricted T cell mediated disease of the hair follicle. Because FK506 has been described as suppressing T cell mediated autoimmune diseases, we addressed the question whether topical treatment of C3H/HeJ mice with FK506 has a beneficial effect on alopecia areata (AA). For this purpose six C3H/HeJ mice with AA were treated topically with 0.1% FK506 ointment, four mice received the vehicle only. Four of six FK506-treated mice showed complete hair regrowth, whereas 1/4 vehicle-treated mice regrew hair. Mice treated successfully with FK506 had reduced perifollicular infiltrates of CD4+ and CD8+ cells and a decreased expression of MHC class I and II and ICAM-1 on hair follicle epithelium, compared to control mice. We conclude that topical treatment with FK506 is able to induce hair regrowth in AA of C3H/HeJ mice, most likely by suppressing the T cell mediated immune response.

Trichoteiromania.

We describe a 61-year-old patient who compulsively rubbed her hair and her scalp because of a psychiatric disorder. Permanent rubbing resulted in fracturing of the hair shafts, leaving 2 cm long hairs and areas with stubs of 1mm length, giving the impression of bald spots. The distal ends of affected hair shafts were split, giving the impression of white tips. Light microscopy of the hair shafts showed split, brush-like ends of otherwise normal hair. We suggest the name trichoteiromania, which means "compulsive rubbing of hair", as a new term to describe hair loss in such cases.

Hermansky-Pudlak syndrome.

A 55-year-old man had oculocutaneous albinism and a history of frequent bruising following minimal trauma. The simultaneous occurrence of these features was first described by Hermansky and Pudlak in 1959. The Hermansky-Pudlak syndrome follows an autosomal recessive trait and is most frequently found in Puerto Rico and in the Swiss alps. It consists of the triad phenotype of hypopigmentation, prolonged bleeding time due to platelet storage pool deficiency and accumulation of ceroid pigment in lysosomal organelles. Other serious features are pulmonary fibrosis and granulomatous colitis. The disorder is caused by mutations in the HPS1 gene on chromosome 10q23. The HPS1 gene product is involved in the trafficking of melanosomes, platelet dense bodies, and lysosomes.

Current and potential agents for the treatment of alopecia areata.

Alopecia areata is considered to be a T-cell mediated autoimmune disease of the hair follicle. Current immunosuppressive approaches and immunomodulatory treatment with contact sensitizers such as diphenylcyclopropenone and squaric acid dibutylester are dealt with in this review article. The efficacy of the various modes of treatment is evaluated by a review of literature and their mode of action is discussed. In accordance with the mechanism of autoimmune pathogenesis of AA, improved future treatments may be immunosuppressive or immunomodulatory, or they should otherwise protect the hair follicle from the injurious effects of the inflammation. Such possible future therapeutic approaches include the use of liposomes as an improved vehicle, application of immunosuppressive cytokines like TGF-beta and IL-10, inhibition of apoptosis mediated by the Fas-FasL system, inhibition of the lymphocyte homing receptor CD44v10, induction of tolerance as well as principles of gene therapy.

Pitfalls of irritant patch testing using different test chamber sizes.

BACKGROUND: Test chambers for irritant patch testing are usually larger than those used in allergic patch testing. In general, larger areas show stronger skin reactions than smaller areas. OBJECTIVE: This study investigated whether this difference is of practical relevance, when a model irritant is applied in small and large Finn chambers and evaluated by measurement of transepidermal water loss (TEWL). METHODS: Patch testing was performed with 2 concentrations of sodium lauryl sulfate (SLS) (0.25% and 0.5%) on forearms of healthy volunteers. Large (inner diameter, 12 mm) and small (inner diameter, 8 mm) chambers were used. RESULTS: A variance analysis (3 factors, 2-tailed) showed that the test outcome, as assessed by TEWL, was strongly dependent on SLS test concentration and test chamber size. The larger chambers gave approximately 30% to 50% higher values than the smaller. CONCLUSIONS: This may be explained by the fact that with the small chambers, the adjacent small area of nontreated skin was also assessed by the evaporimeter, biasing the results. A formula estimating TEWL value of the large chamber from values of the small chambers has been proposed.