Dieter Metze

Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures.

Abstract:  The vanilloid receptor subtype 1 (VR1)/(TRPV1), binding capsaicin, is a non‐selective cation channel that recently has been shown in human keratinocytes in vitro and in vivo. However, a description of VR1 localization in other cutaneous compartments in particular cutaneous nerve fibers is still lacking. We therefore investigated VR1 immunoreactivity as well as mRNA and protein expression in a series (n = 26) of normal (n = 7), diseased (n = 13) [prurigo nodularis (PN) (n = 10), generalized pruritus (n = 1), and mastocytosis (n = 2)], and capsaicin‐treated human skin (n = 6). VR1 immunoreactivity could be observed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands. Upon reverse transcriptase‐polymerase chain reaction and Western blot analysis, VR1 was detected in mast cells and keratinocytes from human skin. In pruritic skin of PN, VR1 expression was highly increased in epidermal keratinocytes and nerve fibers, which was normalized after capsaicin application. During capsaicin therapy, a reduction of neuropeptides (substance P, calcitonin gene‐related peptide) was observed. After cessation of capsaicin therapy, neuropeptides re‐accumulated in skin nerves. In conclusion, VR1 is widely distributed in the skin, suggesting a major role for this receptor, e.g. in nociception and neurogenic inflammation.

Primary cutaneous marginal zone B-cell lymphoma : A recently described entity of low-grade malignant cutaneous B-cell lymphoma

Recently a new classification of primary cutaneous B-cell lymphomas (PCBCLs) has been proposed by the European Organization for Research and Treatment of Cancer (EORTC)--Cutaneous Lymphoma Project Group. The marginal zone B-cell lymphomas (MZLs) were not included as a distinct entity because of insufficient experience and controversial opinions. We have studied 32 patients (M:F ratio 1.5:1; age range 25-93 years; mean age 49.6 years; median age 50 years) to determine the diagnostic criteria of primary cutaneous MZL and the relationship with other low-grade malignant PCBCLs. For comparison, three patients with immunocytoma were included in the study. Clinically, patients presented with solitary or clustered reddish or red-brown papules, nodules, and plaques, sometimes surrounded by an erythematous halo. Histopathologic sections showed nodular or diffuse infiltrates involving the dermis and subcutaneous fat. Cytomorphologically small to medium-sized cells with indented nuclei and abundant pale cytoplasm (marginal zone cells, centrocyte-like cells) predominated. In addition, scattered blasts, lymphoplasmacytoid cells, and plasma cells were observed below the epidermis and at the periphery of the infiltrates. Reactive germinal centers were present in 75% of the cases. The three cases of immunocytoma showed a more monomorphous pattern with predominance of lymphoplasmacytoid cells. The marginal zone cells showed a CD20+, CD79a+, CD5- and Bcl-2+ immunophenotype. They expressed immunoglobulin G in the majority of the cases. Staining with the monocytoid B cell-related antibody KiM1p gave positive results in all specimens with a typical intracytoplasmic granular pattern. A monoclonal distribution of immunoglobulin light chains was observed in marginal zone cells in 75% of the cases. Germinal centers, when present, were either polyclonal or negative for both kappa and lambda light chains. Monoclonal rearrangement of the JH gene was detected via polymerase chain reaction (PCR) in 18 of 26 investigated specimens. Analysis in 12 patients of the bcl-2/immunoglobulin heavy chain gene rearrangement using PCR yielded negative results. Lesions were treated by surgical excision followed in some patients by local radiotherapy. Systemic antibiotic therapy was administered to three patients, with good response in two. The prognosis is excellent. After a mean follow-up of 47.9 months (range 6-252; median 24) all patients are alive without signs of systemic lymphoma. Primary cutaneous MZL represents a distinct clinicopathologic subtype of low-grade malignant PCBCL.

Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients.

A new group of subcutaneous, natural killer (NK), NK/T-cell, and other cytotoxic T-cell lymphomas of the skin has been recently described, and some have been included as distinct clinicopathologic entities in the classification of hematologic malignancies recently proposed by the World Health Organization. In the European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas, they would be classified either as CD30- large T-cell lymphoma, small/medium pleomorphic T-cell lymphoma, or subcutaneous T-cell lymphoma. Precise clinicopathologic and prognostic features of all of them have not yet been well characterized. We studied retrospectively 81 biopsies from 50 patients with subcutaneous, blastic natural killer (NK), NK/T-cell, or other non–mycosis fungoides cytotoxic T-cell lymphomas of the skin. Clinical, morphologic, phenotypical, and genetic features and data on Epstein-Barr virus association allowed us to classify our cases according to the following 7 categories: a) subcutaneous “panniculitis-like” T-cell lymphoma (SPTCL): 10 cases (estimated 5-year survival: 80%); b) blastic NK-cell lymphoma: 12 cases (estimated 5-year survival: 0%); c) nasal-type extranodal NK/T-cell lymphoma: 5 patients (estimated 5-year survival: 0%); d) epidermotropic CD8+ T-cell lymphoma: 5 cases (estimated 5-year survival: 0%); e) cutaneous γ/δ T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); f) cutaneous α/β pleomorphic T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); and g) cutaneous medium/large pleomorphic T-cell lymphoma, not otherwise specified: 2 cases. Our study shows that these cutaneous lymphomas can be classified according to precise diagnostic categories. With the exception of SPTCL, analysis of follow-up data from our patients showed that these groups of lymphomas are characterized by an aggressive course, regardless of the diagnostic category.

Borrelia burgdorferi—associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a

We report two patients with low-grade malignant primary cutaneous B cell lymphoma in association with Borrelia burgdorferi infection. Extracutaneous manifestations were ruled out by standard staging procedures. Infection with Borrelia burgdorferi was confirmed by cultivation from lesional skin in both patients. In the first patient skin lesions cleared completely after pulse therapy with cefotaxime, whereas in the second patient antibiotic treatment failed. In this patient, however, skin lesions completely cleared after intralesional injection of interferon alfa-2a. Antibiotic treatment or intralesional injection of interferon alfa-2a should be considered as a first-line treatment of Borrelia burgdorferi-associated primary cutaneous B cell lymphoma before more aggressive conventional therapeutic modalities (e.g., radiation therapy) are applied.

Intracellular Persistence of Staphylococcus aureus Small-Colony Variants within Keratinocytes: A Cause for Antibiotic Treatment Failure in a Patient with Darier's Disease

Intracellular persistence assays were performed with small-colony variants (SCVs) derived from a patient with Dariers disease from whom different phenotypes and genotypes of Staphylococcus aureus were isolated over a 28-month period; the assays revealed that >100-fold more SCV cells persisted intracellularly relative to the normal phenotype. The presence of intracellular S. aureus SCVs may protect against host defenses and antibiotic therapy and thus may have contributed to this patients very prolonged skin infection.

Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases

BACKGROUND The perception of pruritus is modified by endogenous opiates via central opiate receptors in a histamine-independent manner. OBJECTIVE The aim of this pilot study was to evaluate the efficacy and safety of naltrexone, an orally active opiate antagonist, in the treatment of severe, otherwise intractable pruritus of different origin in an open-label clinical trial. METHODS A total of 50 patients with pruritus caused by internal diseases, hydroxyethyl starch, contact with water, cutaneous lymphoma, atopic dermatitis, xerosis cutis, macular amyloidosis, psoriasis, and other skin disorders as well as with pruritus of unknown origin were randomly selected to receive naltrexone 50 mg daily. The pruritus intensity was rated by the patients before and during therapy in a visual analogue scale. RESULTS A significant therapeutic response was achieved in 35 of the 50 patients within 1 week (confidence limits of 0.55 and 0.82 at a confidence level of 0. 95). Naltrexone was of high antipruritic effect in 9 of 17 cases of prurigo nodularis and contributed to healing of the skin lesions. Tachyphylaxis was infrequent (6/50), occurred late, and could be counterbalanced by raising the dosage in 2 patients. Adverse drug effects were restricted to the first 2 weeks of treatment and included nausea (11/50), fatigue (3/50), dizziness, heartburn, and diarrhea (1/50 each). CONCLUSION The study suggests that oral opiate antagonists might be a well-tolerated and effective therapy for pruritic symptoms in many diseases.

Loss of Corneodesmosin Leads to Severe Skin Barrier Defect, Pruritus, and Atopy: Unraveling the Peeling Skin Disease

Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.

Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo

Proteinase‐activated receptor‐2 belongs to a new subfamily of G‐protein‐coupled receptors. Its precise role during inflammation and the underlying mechanisms is still unclear. Our study establishes that PAR‐2 plays a direct proinflammatory role during cutaneous inflammation in mice and humans in vivo. In a model of experimentally induced allergic (ACD) and toxic (ICD) contact dermatitis (CD) we show that ear swelling responses, plasma extravasation, and leucocyte adherence were significantly attenuated in PAR‐2 null mutant (PAR‐2−7−) mice compared with wild‐type (PAR‐2+/+) mice, especially at early stages. The proinflammatory effects by PAR‐2 activation were significantly diminished using nitric oxide‐synthase inhibitors, while NF‐kappaB and neuropeptides appear to play a minor role in these mechanisms. PAR‐2‐mediated up‐regulation of E‐selectin and cell adhesion molecule ICAM‐1;enhanced plasma extravasation was observed in humans and mice and of interleukin‐6 in mice in vivo. Thus, PAR‐2 may be a beneficial therapeutic target for the treatment of inflammatory skin diseases.— Seeliger, S., Derian, C. K., Vergnolle, N., Bunnett, N. W., Nawroth, R., Schmelz, M., von der Weid, P.‐Y., Buddenkotte, J., Sunderko¨tter, C., Metze, D., Andrade‐ Gordon, P., Harms, E., Vestweber, D., Luger, T. A., Steinhoff, M. Proinflammatory role of proteinase‐activated receptor‐2 in humans and mice during cutaneous inflammation in vivo. FASEB J. 17, 1871–1885 (2003)

Immune response modifiers – mode of action

Abstract:  The innate immune system governs the interconnecting pathways of microbial recognition, inflammation, microbial clearance, and cell death. A family of evolutionarily conserved receptors, known as the Toll‐like receptors (TLRs), is crucial in early host defense against invading pathogens. Upon TLR stimulation, nuclear factor‐κB activation and the interferon (IFN)‐regulatory factor 3 pathway initiate production of pro‐inflammatory cytokines, such as interleukin‐1 and tumor necrosis factor‐α, and production of type I IFNs (IFN‐α and IFN‐β), respectively. The innate immunity thereby offers diverse targets for highly selective therapeutics, such as small molecular synthetic compounds that modify innate immune responses. The notion that activation of the innate immune system is a prerequisite for the induction of acquired immunity raised interest in these immune response modifiers as potential therapeutics for viral infections and various tumors. A scenario of dermal events following skin cancer treatment with imiquimod presumably comprises (i) an initial low amount of pro‐inflammatory cytokine secretion by macrophages and dermal dendritic cells (DCs), thereby (ii) attracting an increasing number type I IFN‐producing plasmacytoid DCs (pDCs) from the blood; (iii) Langerhans cells migrate into draining lymph nodes, leading to an increased presentation of tumor antigen in the draining lymph node, and (iv) consequently an increased generation of tumor‐specific T cells and finally (v) an accumulation of tumoricidal effector cells in the treated skin area. The induction of predominately T helper (Th)1‐type cytokine profiles by TLR agonists such as imiquimod might have further benefits by shifting the dominant Th2‐type response in atopic diseases such as asthma and atopic dermatitis to a more potent Th1 response.

Cutaneous manifestations of blastic plasmacytoid dendritic cell neoplasm-morphologic and phenotypic variability in a series of 33 patients.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a neoplasm derived from precursors of plasmacytoid dendritic cells. Cutaneous involvement represents often the first manifestation of the disease. We studied 45 skin biopsies from 33 patients (M:F=7.25:1; median age: 71 y; age range: 30 to 89) with BPDCN to delineate histopathologic and immunophenotypic features of this disease. Patients presented with generalized (n=18), localized (n=6), or solitary (n=9) macules, plaques, and/or tumors. Staging investigations at presentation were negative in 20 patients. Unusual histologic features included a perivascular/periadnexal pattern (6 biopsies from 4 patients) and the presence of pleomorphism of neoplastic cells with blastoid cells admixed with elongated, twisted, or hyperchromatic cells (observed in 24 specimens). Negativity of 1 among the 4 markers CD4, CD56, CD123, and TCL-1 was seen in 11 biopsies, and of 2 markers in 4 biopsies. Staining for CD68 revealed positivity of the majority of cells in 1 and of scattered cells in 24/37 stained cases. Terminal deoxynucleotidyl transferase was observed in 22/37 stained cases. Staining for Bcl-6, MUM-1 and FOX-P1 revealed positivity of a variable proportion of neoplastic cells in 16/30, 19/29, and 21/23 cases, respectively. Our study shows that cutaneous lesions of BPDCN display a greater variability of morphologic and phenotypic features than recognized earlier. Discrete perivascular infiltrates, pleomorphic morphology of neoplastic cells, and unusual phenotypic profiles may be the source of diagnostic pitfalls. These atypical variants should be recognized to make an early diagnosis and to manage properly patients with this aggressive hematological disorder.