Complement. Second of two parts.

Age-related macular degeneration (AMD), a blinding disorder that compromises central vision, is characterized by the accumulation of extracellular deposits, termed drusen, between the retinal pigmented epithelium and the choroid. Recent studies in this laboratory revealed that vitronectin is a major component of drusen. Because vitronectin is also a constituent of abnormal deposits associated with a variety of diseases, drusen from human donor eyes were examined for compositional similarities with other extracellular disease deposits. Thirty-four antibodies to 29 different proteins or protein complexes were tested for immunoreactivity with hard and soft drusen phenotypes. These analyses provide a partial profile of the molecular composition of drusen. Serum amyloid P component, apolipoprotein E, immunoglobulin light chains, Factor X, and complement proteins (C5 and C5b-9 complex) were identified in all drusen phenotypes. Transcripts encoding some of these molecules were also found to be synthesized by the retina, retinal pigmented epithelium, and/or choroid. The compositional similarity between drusen and other disease deposits may be significant in view of the recently established correlation between AMD and atherosclerosis. This study suggests that similar pathways may be involved in the etiologies of AMD and other age-related diseases.

Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease

Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions. We investigated 53 patients with clinical sensitivity to anticonvulsants by exposing their lymphocytes in vitro to drug metabolites generated by a murine hepatic microsomal system. The diagnosis of a hypersensitivity reaction was corroborated by in vitro rechallenge for each drug (phenytoin, n = 34; phenobarbital, n = 22; carbamazepine, n = 25) when cytotoxicity (% dead cells) exceeded 3 SD above the mean result for controls. Cross-reactivity among the drugs was noted. 7 out of 10 patients who had received all three anticonvulsants had adverse reactions to each. 40 out of 50 patients tested to all three drugs in vitro were positive to each. Adverse reactions were indistinguishable among anti-convulsants. Skin rash (87%), fever (94%), hepatitis (51%), and hematologic abnormalities (51%) were common clinical features of each drug. 62% of reactions involved more than two organs. Cells from patients' parents exhibited in vitro toxicity that was intermediate between values for controls and patients. In vitro testing can help diagnose hypersensitivity to anticonvulsants. Cells from patients may also be used for prospective individualization of therapy to decrease risk of adverse reaction. Cross-reactivity among the major anticonvulsants is common and should be considered before deciding on alternative therapy.

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Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk.

Immunosuppressive drugs have revolutionized organ transplantation and improved the therapeutic management of autoimmune diseases. The development of immunosuppressive drugs and understanding of their action traditionally has been focused on lymphocytes, but recent evidence indicates that these agents interfere with immune responses at the earliest stage, targeting key functions of dendritic cells (DCs). Here, we review our present understanding of how classical and new immunosuppressive agents interfere with DC development and function. This knowledge might provide a rational basis for the selection of immunosuppressive drugs in different clinical settings and for the generation of tolerogenic DCs in the laboratory.

Dendritic cells: emerging pharmacological targets of immunosuppressive drugs.

In a double-blind trial, 21 patients with severe plaque psoriasis were randomly assigned to receive oral cyclosporine, 14 mg/kg/d, or its vehicle. After four weeks of therapy the 11 cyclosporine recipients had the following response to treatment: two had total clearing and six improved markedly, two moderately, and one minimally; whereas ten vehicle-treated patients showed no change or minimal improvement. Vehicle-treated patients, after a switch to cyclosporine for four weeks, demonstrated impressive improvement similar to that seen in patients who initially received only cyclosporine. Moderate or marked improvement or total clearing was noted in 17 (81%) of 21 and 20 (95%) of 21 after one and four weeks of therapy, respectively. Mitotic figures and leukotriene B4 levels in lesions decreased 86% and 64%, respectively, after seven days of cyclosporine therapy. Mononuclear (including activated T cells) and polymorphonuclear leukocyte infiltrates were markedly reduced in lesions of all patients after seven days of cyclosporine therapy. These results suggest that (1) psoriasis may have an immunologic basis mediated by activated T cells and/or other immune cells; (2) if a long-term regimen with a favorable efficacy—side effect ratio can be determined, cyclosporine would be a significant advance in the treatment of psoriasis. ( JAMA 1986;256:3110-3116)

Cyclosporine improves psoriasis in a double-blind study.

Summary
We describe five patients who showed a distinctive pattern of late onset hyperkeratosis and acanthosis of palms and fingers. The epidermal thickening gave rise to a rugose appearance with broadened rete ridges bounded by deep sulci (tripe palms). One of these patients had malignant acanthosis nigricans, two also had carcinomata with the palmar changes as a forme fruste of acanthosis nigricans and two patients had pruriginous dcrmatoses with palmar changes of diffuse lichenification which were reversible. The relationship between palmar-plantar keratoderma and malignancy is discussed.

Acanthosis palmaris: tripe palms. A distinctive pattern of palmar keratoderma frequently associated with internal malignancy.

We have investigated the mechanisms by which topical corticosteroids modulate cutaneous immune reactions in man. Volunteers applied clobetasone butyrate 0.05% (Eumovate; EV), betamethasone valerate 0.1% (Betnovate; BV), clobetasol propionate 0.05% (Dermovate; DV), and control vehicles twice daily to forearm skin for 7 days. Steroid therapy significantly decreased the number of HLA-DR/T6 (CD1a) positive Langerhans cells (LCs) per mm2 in suction blister-derived epidermal sheets, expressed as a mean percentage of controls, as follows: EV 69.2%; BV 67.3%; DV 37.8%. LC antigen presenting capacity was determined in the allogeneic and autologous epidermal cell-lymphocyte reactions. The LC-dependent allostimulatory capacity of epidermal cells, expressed as a mean percentage of controls, was also significantly reduced by steroid therapy: EV 45.1%; BV 41.9%; DV 23.4%. Following therapy with clobetasol propionate 0.05%, the capacity of epidermal cells to present tetanus toxoid to, and to augment concanavalin A mediated lymphocyte stimulation of, autologous lymphocytes was reduced to 33.6% and 19.7% respectively of controls. Depression of epidermal cell allostimulatory capacity was not the result of a steroid-induced decrease in the production of epidermal cell-derived thymocyte activating factor (ETAF)/interleukin 1 by keratinocytes, since it could not be reversed by addition of exogenous interleukin 1. Indomethacin, added to block any potential prostaglandin synthesis during the culture period, did not restore the allostimulatory capacity of epidermal cells from steroid-treated sites. Addition of epidermal cells from DV-treated sites depressed the capacity of control epidermal cells to stimulate lymphocytes in the allogeneic epidermal-lymphocyte reaction. Our results demonstrate that the anti-inflammatory action of topical corticosteroids in man is associated not only with a reduction in the number of HLA-DR/T6 positive LCs, but also with a marked decrease in Langerhans cell-dependent T lymphocyte activation. The effects of the different steroids on both of these parameters correlated with their potency as determined in the standard occlusive vasoconstrictor assay. Topical corticosteroids are widely used for the treatment of inflammatory skin disorders, and inhibit not only the elicitation phase, but also the induction phase, of allergic contact dermatitis reactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of topical corticosteroid therapy on Langerhans cell antigen presenting function in human skin.

HLA-DR4 may determine expression of actinic prurigo in British patients.

Fluorescence Microscopic and Flow Cytometric Analysis of Bone Marrow-Derived Cells in Human Epidermis: A Search for the Human Analogue of the Murine Dendritic Thy-1+ Epidermal Cell

Summary

Three patients who developed toxic epidermal necrolysis whilst receiving carbamazepine are described. Two patients experienced severe oropharyngeal ulceration and extensive cutaneous necrolysis with subsequent transient alopecia, nail shedding and persistent ulceration of the tongue. Histology of the skin revealed changes resembling those found in not only erythema multiforme and toxic epidermal necrolysis but also homograft rejection and the acute graft-versus-host reaction, suggesting that cutaneous damage was mediated by ‘aggressor lymphocytes’ sensitized to epidermal cells.

S.M. Breathnach

Papers

Acanthosis palmaris: tripe palms. A distinctive pattern of palmar keratoderma frequently associated with internal malignancy.

Effects of topical corticosteroid therapy on Langerhans cell antigen presenting function in human skin.

HLA-DR4 may determine expression of actinic prurigo in British patients.

Fluorescence Microscopic and Flow Cytometric Analysis of Bone Marrow-Derived Cells in Human Epidermis: A Search for the Human Analogue of the Murine Dendritic Thy-1+ Epidermal Cell

Carbamazepine (‘Tegretol’) and toxic epidermal necrolysis: report of three cases with histopathological observations