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Drug eruptions are probably the most frequent of all manifestations of drug sensitivity. They occur in about 2% of treatment courses and are commoner in women, the elderly and in patients with the acquired immunodeficiency syndrome (AIDS), especially from sulphonamides such as in co-trimoxazole1. Drugs most often incriminated are listed in Table 1. The prevalence of a history of penicillin allergy has been estimated as up to 10%, and reactions to sulphonamides may affect 5% of those treated. Potentially fatal conditions such as Stevens–Johnson syndrome and toxic epidermal necrolysis are fortunately rare (0.5–1.8 cases per million per year)2. Adverse drug reactions may reflect immunological drug allergy or, more usually, non-immunological mechanisms. Idiosyncratic reactions are independent of dose, unrelated to the pharmacological action of the drug and may have a genetic basis3. This article lists the commonest clinical patterns of drug eruptions (excluding contact dermatitis) and reviews their management. more...

Difficulties may arise in the diagnosis of patients with clinical features suggestive of plasma cell dyscrasia-related amyloidosis (amyloidosis L), but without evidence of a paraprotein. We have employed gene rearrangement methodology to demonstrate the clonality of bone marrow cells not only in a patient with myeloma-associated systemic amyloidosis, but also in a patient with "primary" systemic amyloidosis without overt myeloma or a detectable paraprotein. Furthermore, we have shown the clonality of the amyloid-producing plasma cells within a skin nodule of a patient with primary localized cutaneous amyloidosis; by contrast, clonal rearrangement was not detected in bone marrow cells from this patient. This finding provides definitive proof that organlimited nodular primary localized cutaneous amyloid deposits arise in relation to cutaneous plasmacytomas. Gene rearrangement studies may enable early diagnosis and initiation of treatment in patients with systemic amyloidosis L, as well as their differentiation from patients with organ-limited nodular cutaneous amyloidosis, who do not require aggressive therapy. more...

Amyloid deposits, regardless of clinicopathologic type or tissue involvement, are composed of a loose meshwork of 7.5- to 10-nm fibrils. 1 During the course of purification of extracted amyloid fibril preparations, a further amyloid tissue protein, quite separate from the fibrillar component of amyloid deposits, was identified. 2,3 This novel amyloid tissue protein was termed amyloid P (plasma)-component, or protein AP (AP), because of its antigenic identity to an α-globulin present in the blood of normal individuals. 4–6 AP is a glycoprotein found in tissue deposits of all forms of amyloid in which it has been sought, irrespective of the chemical nature of the amyloid fibril protein, with the single exception of certain intracortical amyloids. 7,8 AP is indistinguishable from, and derived from, the normal plasma glycoprotein serum amyloid P-component (SAP). 7,9,10 A protein which cross-reacts immunochemically with SAP has been shown to be a normal matrix glycoprotein of glomerular basement membrane; we have shown in immunohistochemical studies that this normal tissue form of amyloid P-component (TAP) is also invariably associated with elastic fiber microfibrils in normal, adult, human skin and other tissues. 11,12 This chapter will summarize and review our current knowledge of the biology of amyloid P-component, including its potential role in the maintenance of normal connective-tissue architecture, and the deposition of amyloid deposits. more...

Thy-1 + Ly-5 + dendritic cells have recently been described as a resident cell population in murine epidermis, but their ontogeny and function are unknown. We therefore investigated the origin and turnover of epidermal Thy- 1 + cells utilizing chimeric mice. Lethally x- irradiated AKR/J (Thy-1.1 + ) and AKR/Cum (Thy-1.2 + mice were reconstituted with allogeneic bone marrow cells with or without thymocytes from congenic AKR/ Cum or AKR/J mice, respectively. The density of residual indigenous Thy-1.1 + cells in AKR/J chimeras and Thy-1.2 + cells in AKR/Cum chimeras was substantially reduced following x-irradiation, as determined by immunofluorescence staining of epidermal sheets. Epidermal repopulation by allogeneic Thy-1 + dendritic epidermal cells was first observed at 5 weeks in AKR/J chimeras and at 7 weeks in AKR/Cum chimeras and progressed slowly. Repopulation was not enhanced by increasing the number of allogeneic bone marrow cells injected from 2 × 10 7 to 10 8 cells or by the addition of 8 × 10 7 allogeneic thymocytes to the donor inoculate. Epidermal repopulation by allogeneic Thy-1.2 + cells was not seen in AKR/J mice reconstituted with syngeneic bone marrow cells and allogeneic Thy-1.2 + AKR/Cum thymocytes. Taken together, these results indicate that Thy-1 + dendritic epidermal cells are derived from the bone marrow and suggest that they are not related to conventional peripheral T-lymphocytes. more...

Contact dermatitis accounts for up to 40% of all occupationally acquired illnesses, with an incidence conservatively estimated at 70,000 new cases per year in the United States, resulting in a cost, in terms of health care and lost productivity, of $22 million annually. If, as suspected, there is gross underrecording of cases, the true cost may lie in the range of $222 million to $1 billion. 1 Atopy is the single greatest risk factor for the development of contact dermatitis; the relative odds of developing occupational skin disease are 13.5 times greater in atopic subjects, 2 who account for 93% of lost jobs, 79% of lost workdays, and 88% of compensation payments. 3 These figures do not, of course, take into account contact dermatitis occurring outside the workplace; up to 3% of the population may be affected by hand eczema alone. 4 The figures also exclude reference to many of the types of plant dermatitis discussed in this issue. Although the majority of contact dermatitis is the result of exposure to irritants, allergic contact dermatitis accounts for a substantial proportion of cases. Despite the clinical importance of allergic contact dermatitis, our knowledge of its pathogenesis—in particular, regarding why a given individual becomes sensitized to a specific contact allergen—remains comparatively restricted. This paper will review what is known about pathologic mechanisms involved in the development of allergic contact dermatitis, incorporating recent information on the immunologie function of normal skin. Recent data on the mechanisms of action of agents that modulate the induction or expression of allergic contact dermatitis, such as topical corticosteroids, mid-range ultraviolet light irradiation (UV-B), and 8-methoxypsoralen plus long-wave ultraviolet light irradiation (PUVA), also will be discussed. more...

Basic principles of production of monoclonal antibodies are discussed in this paper. In order to illustrate the usefulness of such production, studies of a new monoclonal antibody designated KF-2 which defines a unique cell-surface antigen found exclusively in the stratum spinosum of man and lower primates are recounted. more...

The distribution of amyloid P component (AP) in normal human skin was investigated by a light and electron microscopic immunoperoxidase technique, using antibodies to serum amyloid P component (SAP). AP, or an immunologically cross-reactive protein, was found to be specifically localized to the microfibrils of papillary oxytalan fibers and to the peripheral microfibrillar mantle surrounding the elastin core of mature elastic fibers in the reticular dermis; collagen fibers were not stained with anti-SAP, AP was not detected in the dermal-epidermal basement membrane or in the basement membranes surrounding dermal papillary blood vessels and eccrine structures. These findings, which establish the detailed distribution of normal tissue AP in the skin, provide a basis for further studies of the function and behavior of this protein in health and disease. more...

The basement membrane zone (BMZ) of human skin is a complex structure which contains several well-defined components including bullous pemphigoid antigen, laminin, type IV collagen, and proteoglycan. Characterization of additional basement membrane (BM) constituents has been limited by their relative inaccessibility, insolubility, and low tissue concentration. We have produced a murine monoclonal antibody that has enabled us to define a unique constituent of the BMZ of human stratified squamous epithelia. The monoclonal antibody (KF-1) was raised by standard techniques using suction blister-derived trypsinized human epidermal cells as the antigen. Indirect immunofluorescence and immunoperoxidase staining of human and rhesus monkey tissues with KF-1 produced linear BMZ staining of stratified squamous epithelia. Glandular and vascular BMs were not stained. Immunoelectron microscopic studies of normal human skin and esophagus showed specific binding of KF-1 to the lamina densa of the BMZ, a localization identical to that of type LV collagen. However, unlike type IV collagen, which is not species specific and is found in all BMs, the antigen defined by KF-1 is collagenase-resistant and is specific for primate stratified squamous epithelia. These findings confirm the existence of regional variation in BM composition, and demonstrate for the first time that the lamina densa of stratified squamous epithelial BMs contains a constituent other than type IV collagen. more...

Vitronectin is a multifunctional human plasma glycoprotein that is also found in constant association with elastic tissue fibers in normal adults. We have investigated the nature of the association of vitronectin with elastic tissue, and compared it to that of other elastic fiber-associated proteins, namely fibrillin and amyloid P component. Samples of normal human dermis were incubated with a variety of extraction agents, including high molar salt solution, non-ionic detergent (Nonidet P-40), the reducing agents dithiothreitol or 2-mercaptoethanol, and the chaotropic agents sodium dodecyl sulfate or guanidine hydrochloride. Vitronectin purified from serum typically migrates as two bands of 75 and 65 kD. By contrast, immunoblotting studies of residual dermal material after extraction with the various agents revealed only lower molecular weight (58, 50, 42, 35, and 27 kD) anti-vitronectin reactive bands. Although these bands may represent degradation products of vitronectin generated as a result of the extraction procedure, we cannot exclude the possibility that tissue vitronectin is distinct from plasma vitronectin. Anti-vitronectin reactive polypeptides co-migrating with the 58-, 50-, and 42-kD bands were solubilized following extraction with sodium dodecyl sulfate or guanidine hydrochloride, but not with the other extraction agents. Immunofluorescence studies using residual dermal material after extraction with guanidine hydrochloride demonstrated a marked reduction in elastic fiber staining intensity with anti-vitronectin and anti-amyloid P component, but not with anti-fibrillin. Thus the majority, if not all of dermal vitronectin, is, like amyloid P component, non-covalently associated with, and not an integral constituent of, elastic fibers. more...

The mechanisms involved in the modulation of cutaneous immune responses by UV radiation have been extensively investigated; by contrast, few studies have addressed the effects of x-irradiation on epidermal immune function. We therefore investigated the effect of x-irradiation of mice on: (a) the density of epidermal Ia+ Langerhans cells (LC) in immunofluorescence studies, (b) epidermal cell (EC) allostimulatory capacity in the allogeneic EC-lymphocyte reaction (ELR), and (c) production of epidermal cell-derived thymocyte activating factor (ETAF). C3H/He and BALB/c mice were irradiated with 900, 1,800, 2,700, or 3,600 rad from a 137Cs source, and sacrificed 10 h or 3 days later. X-irradiation of mice 10 h previously only slightly decreased the density of epidermal Ia+ LC and did not affect the capacity of their EC to stimulate allogeneic responder lymphocytes in the ELR. X-irradiation of mice 3 days previously, however, resulted in a dose-dependent decrease in the density of Ia+ LC. This decrease was accompanied by a substantial reduction in EC allostimulatory capacity in the ELR at all doses of x-irradiation. ETAF production by cultured EC from mice x-irradiated 3 days previously was also found to be diminished at all doses of x-irradiation. Trypan blue exclusion studies demonstrated that the observed decreases in EC allostimulatory capacity and ETAF production were not the result of a generalized lethal effect of x-irradiation on EC. The reduction in EC allostimulatory capacity following in vivo x-irradiation could not be reversed by addition of exogenous ETAF or interleukin-1 in the ELR. Taken together, these results indicate that x-irradiation decreases the density of Ia+ LC, impairs LC alloantigen-presenting function, and reduces ETAF production. Thus cutaneous x-irradiation may affect inflammatory and neoplastic processes not only by its antimitotic activity, but also by a direct effect on EC which subserve immunologic functions. more...

The monoclonal antibody, KF- 1, identifies a noncollagenous constituent of the lamina densa of the basement membrane zone (BMZ) of skin. In order to determine whether this BMZ constituent is affected in epidermolysis bullosa (EB), a mechanobullous skin disease often resulting in marked disfigurement, we have examined skin from patients with various forms of this disease for binding by KF-1 as well as for binding by polyclonal antibodies to laminin, type IV collagen, and bullous pemphigoid antigen, three other known BMZ components of normal skin. In all specimens from patients with simplex and junctional forms of EB, all four antibodies bound normally. In contrast, absent or diminished KF-1 binding was noted in all skin specimens from patients with dystrophic EB; antibodies directed against the other BMZ constituents, however, bound normally. This suggests that KF-1 may play a role in the structural integrity of normal skin and its absence or diminution may be important in the pathogenesis of lesion formation in dystrophic EB. more...