Biomedical subjects
Publications and source records attributed to K Rappersberger.
The skin of a patient with diffuse melanosis as a result of malignant melanoma was examined by light microscopy, immunohistochemistry, and electron microscopy. Our findings indicate that the slate-blue discoloration in this patient was due to pigment deposition in dermal macrophages and endothelial cells. Multiple attempts to identify disseminated metastatic melanoma cells were unsuccessful.
The epidermis of clinically normal-appearing human skin harbors a phenotypically heterogeneous population of T lymphocytes (TCs), the majority of which are CD2+/CD3+/CD5+ "memory" cells, but in an unactivated state, and express the TCR-alpha/beta. In contrast to murine skin, only a very minor subpopulation of CD3+ cells in the human epidermis bears the TCR-gamma/delta. Epidermal TCs primarily are distributed along the rete ridges in the basal keratinocyte layer and are often in close apposition to Langerhans cells (LCs). These TCs were propagated from epidermal cell suspensions after stimulation with TC activating agents (Con A, rIL-1, rIL-2), then evaluated for phenotypic features and TCR diversity. Similar to the in situ situation, most were CD4-/CD8+/TCR-alpha/beta+. In addition, two cultures contained TCR-gamma/delta+ cells; one of these determined to be an adherent CD4-/CD8+ population. Epidermal TCs were significantly (p less than 0.0001) more abundant in the sole than in the other body regions examined (i.e., 40 vs. 7 CD3+ cells/linear centimeter of epidermis) and seemed to have a particular affinity for the acrosyringial epithelium of eccrine sweat ducts. Moreover, the sole usually contained a greater number of CD8+ relative to CD4+ TCs, whereas the epidermal CD4/CD8 ratio in the trunk and extremities was quite variable, although the trend also was towards a slightly larger percentage of CD8+ cells. Collectively, our data suggest that the volar epidermis has a unique microenvironment which is responsible for both the higher density of TCs, preferentially CD8+, and lower number of LCs. This study has not only provided evidence for significant regional variability in the human epidermal TC population of normal skin, but also strengthens the concept for skin-associated lymphoid tissues (SALT), whereby memory TCs recirculate back to the epidermis and interact with resident antigen-presenting cells (i.e., LC).
Eleven dysplastic melanocytic naevi with various degrees of dysplasia, as judged by light microscopy, were studied by transmission electron microscopy, and their intra-epidermal melanocytes compared with those of five superficial spreading melanomas and seven common benign naevocellular naevi. Intra-epidermal melanocytes in dysplastic naevi exhibited signs of cellular atypia, which were most pronounced in the dysplastic naevi with histological high-grade dysplasia. A correlation between the degree of dysplasia at the light microscopic level and the degree of cytological atypia at the ultrastructural level was noted, and melanocytes in dysplastic naevi with a high degree of dysplasia had ultrastructural features similar to the melanocytes in superficial spreading melanomas. Our observations support the concept that dysplastic naevi fill the biological gap between benign naevocellular naevi and malignant melanomas and suggest that at least some of the dysplastic naevi must be regarded as potential precursor lesions of malignant melanoma, particularly those exhibiting a high degree of histological dysplasia.
The skin-specific immune surveillance system protects against invading microorganisms and transformed cells expressing tumor-specific neoantigens. This system includes antigen-presenting Langerhans cells, dermal and epidermal T lymphocytes, cytokine-producing keratinocytes, and draining peripheral lymph nodes. In patients infected with human immunodeficiency virus-1 (HIV-1), this surveillance system appears to be compromised, as evidenced by a reduction in the epidermal Langerhans cell population. Because human epidermal Langerhans cell express surface-bound CD4 antigens, HLA-DR antigens, and Fc-IgG receptors, all of which are involved in HIV-1 binding to, or entry into, the target cell, the reduction in Langerhans cells in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) may be a direct consequence of HIV-1 infection and subsequent injury to Langerhans cells. Detailed ultrastructural studies have confirmed moderate to severe morphologic damage in some Langerhans cells of such patients and the presence of HIV-1-like particles on Langerhans cell surface membranes and in the extracellular spaces. The biologic consequences of Langerhans cell infection by HIV-1 could be either impaired antigen presentation function of viable Langerhans cells or possible transmission of the retrovirus to the T-cell compartment in skin or lymph nodes, with subsequent depletion of CD4+ T cells via widespread syncytia formation between HIV-1-infected and noninfected cells. The facts that herpes simplex virus, specific cytokines, and ultraviolet B radiation can activate signals for HIV-1 expression and that epidermal cells can elaborate large amounts of cytokines, particularly with enhanced ultraviolet B exposure, may have important clinical implications for HIV-1-infected patients.
In 1984, Greek physicians reported on the clustering of cases of Kaposi's sarcoma (KS) on the Peloponnesus peninsula. To gain more insight into its pathogenesis, we studied the seroepidemiologic and clinicopathologic characteristics of 12 Greek KS patients (eight male/four female) five of whom were residents of an endemic area on the Peloponnesus. These patients were in good general health with ages ranging from 48 to 80 years, had no clinical signs of immunodeficiency, and combined the features of both classic and epidemic KS in that they displayed not only involvement of acral areas but also widespread mucocutaneous lesions. Routine laboratory data were within normal limits; no patient had HTLV-1 and HIV-1/2 antibodies, but all patients had antibodies to several herpesviruses. The histopathology was characteristic of KS with the peculiar feature of a dense infiltrate composed predominantly of CD4+ T lymphocytes. Immunoenzymatic/morphologic studies of the KS cells were consistent with their origin from lymphatic endothelium. Outstanding ultrastructural findings were tubuloreticular structures and cylindrical confronting cisternae, structures that are indicative of an ongoing viral infection. Indeed, extensive electronmicroscopic studies resulted in the detection of retrovirus-like particles in close association to KS cells in five of 12 patients. This in situ observation opens the possibility that this retro-virus contributes to KS development.
We have studied the localization of vimentin in normal human skin at the ultrastructural level using a monoclonal mouse anti-vimentin antibody and a postembedding immunogold-staining technique on thin sections of Lowicryl K4M embedded biopsies. Selective immunogold labeling of intermediate-sized filaments (IF) of epidermal Langerhans cells and melanocytes and of dermal fibroblasts was demonstrated. The IF of fibroblasts were more intensely stained than those of the epidermal dendritic cells; cell processes and dendrites of all three cell populations exhibited a greater number of IF and more pronounced immunogold-labeling than the perinuclear cytoplasm, relating IF of the vimentin type to dendrite formation and/or function. The method described is an appropriate tool for immunoelectron microscopic studies of IF of the vimentin type in situ.
We describe three women with systemic lupus erythematosus and vesiculobullous skin lesions. One patient had a generalized bullous dermatosis and circulating anti-basement membrane zone IgG autoantibodies. Two patients had vesiculobullous lesions limited to the face. All patients had subepidermal blisters and an infiltrate of neutrophils and linear IgG, IgM, IgA, and C3 deposits along the basement membrane zone. These deposits were located in the sublamina densa. Ultrastructural investigation revealed a dermatolytic bullous disease in the patient with the generalized bullous eruption and anti-basement membrane zone autoantibodies and junctional blistering in those patients who had localized blistering.
Hyalinosis cutis et mucosae (HCM) is a rare autosomal recessive disease of unknown aetiology and pathogenesis. In the skin and mucous membranes there is characteristically a deposition of hyaline-like material in the papillary dermis, around the small blood vessels and around skin appendages. Besides the manifold skin lesions, the mucous membranes affected are found in the nasal and oral cavities, pharynx and larynx. The latter causes the most characteristic symptom, namely, hoarseness, from birth. The lesions of the vessel walls are the most significant histopathological alterations. Ultrastructurally, massive deposits of amorphous, hyaline-like material in the dermis, reduction in number and size of the collagen fibrils and, finally, thickening of the basal laminae could be observed. The findings suggest an abnormal production of noncollagenous proteins as well as the alteration of the lysosomal systems of fibroblasts, endothelial cells and pericytes in the pathogenesis of hyalinosis.
Amiodarone (AD) induces photosensitivity in 75% of the patients treated with this drug. Phototoxic reactions can be experimentally elicited with UVA but not with UVB. The UVA-MED is significantly reduced after 12 months of treatment. The development of photosensitivity depends on the total dose of AD; 40 g is the minimal cumulative dose requirement. Under the regimens commonly used, photosensitivity can be expected after 4 months of continuous AD treatment and appears to be unrelated to the skin type. Photosensitivity gradually decreases and returns to normal between 4 and 12 months after the withdrawal of AD. AD-related hyperpigmentation develops after an average of 20 months of continuous AD treatment and a minimal total dose of 160 g AD in about 8% of the patients (mainly of skin type I). Electron microscopic examination of the sun-exposed skin of patients without AD discoloration shows pigment deposits similar to those already described in patients with AD hyperpigmentation in exposed and non-exposed skin. Light and electronmicroscopic examination of sun-exposed skin of both clinically photosensitive and non-photosensitive patients reveals perivascular inflammation even in the absence of a clinical rash. Reduplications of vascular basal laminae occur in sun-exposed skin of both patients with and without UVA photosensitivity but are absent from non-exposed skin. In one patient, followed for 33 months after drug withdrawal, massive AD-induced hyperpigmentation was found to be reversible.
Necrobiotic xanthogranuloma is a rare generalized dermatosis occurring exclusively in association with paraproteinemia. Clinically it is characterized by large, ulcerating, nodular and plaque-like tumors of the dermis and subcutis. Histologically the lesions are composed of a nonspecific, lymphocytic and plasmacellular infiltrate and highly characteristic granulomas with giant cells of the Touton and foreign body type. Ultrastructurally, tubular cystic organelles with a central lamella and a few ribosomes at their outer membranes are found. By means of histochemical studies we excluded the skin infiltrates as the site of the paraprotein release. The pathogenesis of the disease remains unclear; it is suggested that the paraprotein has functional features of a lipoprotein, which may bind to lipoprotein receptors of the histiocytes, thereby inducing xanthoma formation.
Hemangiomas are the most frequent tumors found in newborns, but mostly regress by the age of 7. Spontaneous progression and such complications as hemorrhage, disseminated intravascular coagulation (Kasabach-Merritt syndrome), threatened cardiovascular decompensation, and threatened interference with vital functions are rare and must be treated. Embolization therapy is a new therapeutic approach: vascular malformations and hemangiomas with pronounced arteriovenous shunts are treated by selective arterial embolization of the most peripheral branches of the supplying blood vessels. In contrast, lesions with a steady, slow blood perfusion can be treated by direct embolization of the cavernous system; further thrombosis and organization of the thrombus may lead to a permanent and complete occlusion of the hemangioma. If permanent occlusion cannot be achieved, temporary or partial thrombosis may allow curative plastic or reconstructive surgery, which would otherwise be impossible.
This clinicopathologic study reports seven patients who primarily presented with ulcerative and destructive lesions of the upper aerodigestive tract and face, clinically consistent with so-called lethal midline granuloma (LMG). Histologically, the infiltrates were composed of atypical lymphoid cells that displayed angiocentricity and angiodestruction. In five patients, involvement of distant sites such as skin, lungs, lymph nodes, and bone marrow occurred, and in two cases, the disease remained localized. Immunomorphologic analysis, using monoclonal antibodies to frozen and paraffin sections, provided evidence for the diagnosis of peripheral T cell lymphoma (PTL) in all cases. The midline tumors were classified as diffuse mixed or diffuse large cell lymphoma occurred at distant sites. According to modern PTL classification systems, the lesions could be classified as pleomorphic T cell lymphomas. Those five patients who presented with or progressed to large cell lymphoma died within 18 months (mean, 7 months), whereas the two patients with localized disease are alive after 10 and 36 months, respectively. The size of the atypical lymphoid cells may be of prognostic significance since the large cell compartment seems to represent the major growth fraction in these PTLs.
A large Arab family, originating from Jerusalem, including 38 affected members (19 male and 19 female) with epidermolysis bullosa herpetiformis Dowling-Meara over four consecutive generations is described. Fourteen of 38 affected members of the family were examined clinically; their ages ranged from 2 to 35. The main clinical features were bullae, generalized, solitary, and in groups, with predilection to the skin of the palms and soles. Mild to moderate patchy hyperkeratosis of the palms and soles was found in 5 affected members of the family; their ages ranged from 2 to 7; 9 other affected adults were free. Blisters in oral mucous membranes were noted and found in summer and in periods of fever; hair, teeth, and nails were normal. Age of onset of the disease was from birth to 2 weeks. Expressivity appeared equally variable within and between sibships. Improvement was noted by progression of age from 5 to 23 years, and by some in summer and by others in winter. In contrast to previous reports, aggravation of the disease was noted during fever periods. Ultrastructural studies from a fresh blister disclosed intraepidermal blister via cytolysis of basal cell cytoplasm. The pedigree shows the transmission of an autosomal dominant gene. Affection of both consanguineous parents and their six offspring with epidermolysis bullosa herpetiformis Dowling-Meara is the most striking feature of the family--probably 25% of their offspring were homozygote.
Proliferating cells in histiocytosis X (histiocytosis X cells) share many structural and immunophenotypic features with Langerhans cells, leading to the assumption that histiocytosis X represents a proliferative disorder of Langerhans cells. Because, depending on their state of activation and/or differentiation, Langerhans cells exhibit a varying immunophenotype, we investigated whether histiocytosis X cells display a similar phenotypic heterogeneity and, if so, whether the heterogenous biological behavior of histiocytosis X is reflected by differences in the immunophenotype of the proliferating cells. In 21 patients suffering from different clinical manifestations of histiocytosis X, proliferating cells uniformly expressed class I and II alloantigens, T200, CD1, CD4, and S100 protein. In 12 of 21 cases, histiocytosis X cells additionally exhibited immunocytochemically detectable amounts of C3b and C3bi receptors and certain monocyte/macrophage antigens (CDw14, Ki-M1, Ki-M6). This immunophenotypic heterogeneity of histiocytosis X cells could not be correlated with clinical course, prognosis, and final outcome of the disease in a given patient. The capacity of histiocytosis X cells to immunophenotypically mimic various states of Langerhans cell activation and/or differentiation, however, underscores the concept of histiocytosis X as a proliferative disorder of Langerhans cell origin.
Graft-vs-host disease is generally viewed as an immunologically mediated disease. In search of additional tools for early diagnosis and an elucidation of the pathogenic mechanisms we investigated the expression kinetics of hemopoietic differentiation and class II alloantigens on both resident and passenger skin cells after bone marrow transplantation. HLA-DR antigens, which are found normally on the dendritic epidermal Langerhans cells only, are synthesized and expressed by keratinocytes within lesions of acute and chronic cutaneous graft-vs-host disease. Within non-lesional skin, however, during the course of cutaneous graft-vs-host eruptions, no clear cut expression of keratinocyte-bound HLA-DR antigens can be identified, suggesting that this phenomenon is locally restricted rather than generalized. Furthermore, our data indicate that within lesions clinically suggestive of cutaneous graft-vs-host disease but lacking diagnostic histopathologic criteria, KC-bound HLA-DR antigens can be readily identified. The second class II alloantigens investigated within the epidermis, the HLA-DQ antigens, were seen on Langerhans cells only and were not or only rarely detectable on keratinocytes. Several subtypes of CD3+ T lymphocytes were present in the epidermis of acute graft-versus-host lesions: one portion of CD3+ T lymphocytes also displayed the CD8 antigen; one portion, mainly localized within the basal layer, displayed the CD8 and/or the CD4 antigen; and one portion did not allow identification of CD8, CD4, or Leu7 antigens. In chronic cutaneous graft-versus-host lesions CD3+/CD8+ T lymphocytes predominated. CD1+ epidermal Langerhans cells were reduced in number and appeared rounded with blunt dendrites both in acute and chronic cutaneous graft-vs-host disease, but also, though to a lesser extent, within normal appearing skin from bone marrow transplanted patients without cutaneous graft-vs-host disease.
Human epidermal Langerhans' cells (LC) are HLA-DR+/DQ+, CD1+, CD4+ dendritic antigen-presenting leukocytes. Based on the observation that in certain human immunodeficiency virus type 1 (HIV-1) infected individuals, LC are the only epidermal cells to react with monoclonal antibodies against HIV-1 isolate termed human T-lymphotropic virus IIIB/83 core proteins p17 and p24, we have proposed that LC can serve as a target for HIV-1. This contention was strengthened by the ultrastructural finding of HIV-1-like particles in the close proximity of LC and by the demonstration of signs of moderate to severe LC damage. Detailed electron microscopic analysis of skin and mucosal biopsies from an AIDS patient with p17/p24-positive LC now revealed not only mature HIV-1-like virions in the extracellular space surrounding LC and in intracytoplasmic LC vacuoles, but also developmental forms of HIV-1-like particles budding from LC surface membranes. Using peripheral blood derived monocytes/macrophages as targets for HIV-1 isolation, a virus isolate, designated human T-lymphotropic virus III WR-SK/86, was recovered from skin tissue from this patient by cocultivation and identified as unique by nucleic acid hybridization analysis. These findings now conclusively show that HIV-1 replicates in and is released from LC and support the concept that antigen-presenting cells (mononuclear phagocytes, LC) can serve as a reservoir for the acquired immunodeficiency syndrome virus.
Epidermolysis bullosa acquisita is an immunologically mediated mechano-bullous dermatosis presenting with a variety of clinical appearances. In mild cases the skin lesions, serous blisters, erosions and scars are restricted to the extremities. Scarring alopecia, dystrophy and even loss of nails as well as extensive erosions of mucous membranes may complicate severe cases. The characteristic histopathological feature is a subepidermal blister, which is located within the dermis by electron microscopy. Linear deposits of IgG and C3 along the basement membrane zone have been found on the dermal side of the lamina densa by immunoelectron microscopy. This close anatomical relationship with anchoring fibrils strongly suggests a functional disturbance of these anatomical structures, leading to dermolytic blistering. Treatment with sulphones, in combination with cortico-steroids in the more severe cases, has resulted in long-term improvement in two of our three patients.
In a previous study we evaluated a microcrystalline preparation of 5-methoxypsoralen (5-MOP; Bergapten) for its photochemotherapeutic properties. Preliminary data indicated that the clinical efficacy of 5-MOP is comparable to that of 8-methoxypsoralen. 5-MOP appeared as a promising alternative photosensitizer for the management of psoriasis because of the almost complete lack of phototoxic and drug intolerance reactions that are frequently encountered in patients undergoing 8-MOP photochemotherapy. With a new liquid preparation of 5-MOP we have now extended our earlier investigation on a larger clinical scale and have correlated the clinical response with the bioavailability of the drug. Serum level determinations showed an absorption rate of only approximately 25% that of 8-MOP. When administered in the same dosage as 8-MOP, 5-MOP turned out to be significantly less effective; however, by doubling the oral dosage, comparable results in terms of clearing of psoriasis were obtained. Also with this high-dose 5-MOP regimen, no drug intolerance was noted and other side effects, such as severe erythema, pruritus, and nausea, occurred only rarely. We propose 5-MOP as a valuable alternative for photochemotherapy (PUVA) of PUVA-responsive diseases.