Studies Of The Mechanism of Epidermal Injury By A Staphylococcal Epidermolytic Toxin

Experimental animal models of the two forms of toxic epidermal necrolysis have been reviewed: a murine model of staphylococcal-induced epidermolysis and a hamster model of graft-versus-host disease. In the former, a protein exotoxin, epidermolysin, has been purified and characterized. The exotoxin has a molecular weight of approximately 30,000 and causes a split beneath the granular layer. It is effective at 3 × 10-12 moles. Epidermolysin does not require an intact complement system for its action since B10D2 mice deficient in C5 or mice injected with the decomplementing agent in cobra venom factor were susceptible to its epidermolytic effects. Neither are immunocompetent thymocytes required for the action of the toxin since hairless, athymic adult (nu/nu) mice are susceptible. A few reports of epidermolysis due to an exotoxin of group I Staphylococcus aureus have appeared. This toxin is antigenically different from the exotoxin of group II organisms.A model of drug-induced toxic epidermal necrolysis has been described in hamsters, but the toxic principle released from sensitized lymphoid cells has not yet been characterized

Biochemistry of Transglutaminases and Cross-Linking in the Skin

Transglutaminase is a calcium-dependent enzyme found widely in nature. It catalyzes the formation of α-(γ-glutamyl)lysine bonds that participate in processes varying from fibrin clot formation to epidermal cell envelope formation. Epidermal transglutaminase is localized to the granular layer of the epidermis. It catalyzes the covalent cross-linking of a soluble cytoplasmic substrate into large polymers to form the cornified envelope that lines the inner membrane of keratinocytes in the stratum corneum, The soluble precursor from epidermis has been named keratolinin, and from keratinocyte culture, it has been named involucrin. Hair follicle transglutaminase is biochemically and immunochemically distinct from its epidermal counters part. It has been localized to the inner root sheath and medulla of the hair follicle, The substrate of hair follicle transglutaminase has been poorly defined but appears to be rich in the amino acid citrulline, Transglutaminase has been shown to be an important marker of normal differentiation. There is a rise in its activity at the time of keratinization, and transglutaminase activity has been shown to be greatly decreased in basal cell epithelioma and in psoriasis. Keratinocyte cell culture has proven most helpful in delineating the processes of normal differentiation and keratinization, since the formation of the cell envelope in culture appears to parallel the formation in vivo

Psoriasis Vulgaris: A Genetic Approach

Evidence for a genetic contribution in psoriasis comes from direct examination of a large segment of the population in an isolated island environment, epidemiologic and questionnaire studies presented to psoriatic patients, twin studies collected from the literature and from twin registries, and splitsibship analysis. The concordance of psoriasis in monozygotic twins was 65–72%, whereas psoriasis in dizygotic twins was 15–30%. Determination of concordance in older twin pairs from a national twin registry in Denmark revealed nearly 90–100% heritability. In order to link psoriasis with known markers within the human genome, serologic studies have been carried out with a variety of blood group and polymorphic protein antigens. A weak association with the MNS and Lewis Blood Groups Systems (relative risk, 3.5) has been identified. Stronger associations with class I B locus and class II D locus genes (relative risk, 8–12) have also been determined by studies of the human lymphocyte-antigen system. Finally, a strong association with HLA Cw6 has been determined; this marker is thought to be in linkage disequilibrium with B and D locus genes previously associated with psoriasis. The relative risk of developing psoriasis in HLA Cw6 positive individuals is about 24. A few large kindred have been reported in the dermatology literature. These support the hypothesis of autosomal dominant inheritance with penetrance of approximately 60%. In cooperation with The National Psoriasis Foundation, we have now identified over 90 families with psoriasis in three generations. We have begun the process of ascertainment, the construction of family trees, and the collection of leukocyte DNA for linkage analysis with established restriction fragment polymorphisms (RFLP). Our initial assessment is being directed to four RFLP that span approximately 30 centiMorgans of the short arm of human chromosome 6. Although karyotyping is uncommoly done in patients because of psoriasis, we now seek evidence of translocation of chromosome 6 in association with psoriasis

Flaujeac trait: deficiency of human plasma kininogen

trait or Fletcher trait, in that the intrinsic coagulation pathway, plasma fibrinolytic pathway, kinin-forming system, permeability factor of dilution (PF/dil) phenomenon were abnormal. The defect in each assay was reconstituted by a factor separable from Hageman factor or Fletcher factor. This substance was an a-globulin with an approximate mol wt of 170,000. Flaujeac plasma did not release a kinin upon incubation with kallikrein and was deficient in total kininogen antigen. Antiserum to kininogen inhibited the activity of the factor in solution. Flaujeac factor was identified as a kininogen of high molecular weight (HMW-kininogen). The mean total kininogen antigen in four children of the proposita was 51 % (range 34-62%) of normal. A functional coagulation assay of HMW-kininogen in the children was 34 % (range 23-55%). The results were consistent with autosomal recessive inheritance. The plasma pathways of intrinsic coagulation, fibrinolysis, kinin formation, and PF/dil generation are dependent upon HMW-kininogen. We believe this is the first demonstration of biological function for a kininogen apart from its role as a substrate for kallikreins