Epithelial cell interactions with matrices are critical to tissue organization. Indirect immunofluorescence and immunoprecipitations of cell lysates prepared from stratified cultures of human epidermal cells showed that the major integrins expressed by keratinocytes are ad3,4 (also called a644) and a2pl/a3.l1. The adP4 integrin is localized at the surface of basal cells in contact with the basement membrane, whereas a2fil/a3fl1 integrins are absent from the basal surface and are localized only on the lateral surface of basal and spinous keratinocytes. Anti-fl4 antibodies potently inhibited keratinocyte adhesion to matrigel or purified laiinin, whereas anti-fl1 antibodies were ineffective. Only anti-fl4 antibodies were able to detach established keratinocyte colonies. These data suggest that aEP4 mediates keratinocyte adhesion to basal lamina, whereas the ,BI subfamily is involved in cell-cell adhesion of keratinocytes.

In this paper we report that the integrin complex alpha 1/beta 1, a laminin/collagen receptor, is expressed on cultured foreskin microvascular endothelium, but is absent on endothelial cells from large vessels such as the aorta and umbilical and femoral veins. The restricted expression of integrin alpha 1/beta 1 to microvascular endothelium was also demonstrated in vivo, by immunohistochemical staining of human tissue sections. Alpha 1 specific antibodies reacted strongly with endothelial cells of small blood vessels and capillaries in several tissues, but not with endothelium of vein and arteries of umbilical cord. Expression of integrin alpha 1 can be induced in cultured umbilical vein endothelial cells by treatment with 5 ng/ml tumor necrosis factor alpha (TNF alpha). Induction of alpha 1 subunit expression also occurred after treatment of umbilical vein endothelium with 10(-5) M retinoic acid or with 10 nM PMA; Maximal induction of alpha 1 integrin was reached after 48 h of treatment and costimulation with TNF alpha and PMA resulted in a synergistic effect. The induction of alpha 1 integrin changed the adhesive properties of umbilical vein endothelial cells, by increasing the adhesiveness to collagen, laminin, and laminin fragment P1, while adhesion to fibronectin and laminin fragment E8 remained constant. The alpha 1 integrin is thus a marker of a specific population of endothelial cells and its expression confers distinctive properties of interaction with the underlying basal membrane.

Retinoic acid (RA) is known to induce differentiation of neuroblastoma cells in vitro. Here we show that treatment of two human neuroblastoma cell lines, SY5Y and IMR32, with RA resulted in a fivefold increase of the integrin alpha 1/beta 1 expression. The effect was selective because expression of the alpha 3/beta 1 integrin, also present in these cells, was not increased. The up-regulation of the alpha 1/beta 1 differentiated SY5Y cells correlated with increased neurite response to laminin. In fact, RA-treated SY5Y cells elongated neurites on laminin-coated substratum more efficiently compared with untreated cells or cells treated with nerve growth factor, insulin, or phorbol 12-myristate 13-acetate. These three agents induced partial morphological differentiation but did not increase alpha 1 integrin expression. Neurite extension in RA-treated cells was more efficient on laminin than on fibronectin or collagen type I and was inhibited with beta 1 integrin antibodies on all three substrates. Affinity chromatography experiments showed that alpha 1/beta 1 is the major laminin receptor in both untreated and RA-treated SY5Y cells. These data show that RA, a naturally occurring morphogen implicated in embryonic development, can selectively regulate the expression of integrin complexes in neuronal cells and suggest an important role of the alpha 1/beta 1 laminin receptor in the morphological differentiation of nerve cells.

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SUMMARY The association of HLA-A,B,C, DR polymorphisms and of Bf and GLO with coeliac disease was analysed in 100 Italian children. Primary involvement of HLA-DR3 and DR7 is apparent, while specificities of nearby loci are probably associated secondarily, because of linkage disequilibrium. Direct assessment of D/DR genotype through family studies and mixed lymphocyte cultures led to the recognition of two high risk genotypes DR3/3 and DR3/7, and of two lower risk genotypes DR3/X and DR7/X. The different weight of the HLA-dependent genetic factors is to some extent correlated with the clinical and immunological parameters, suggesting that the low-risk genotypes induce a milder expression of coeliac disease. Furthermore, other genetic factors, such as sex, appear to contribute to the penetrance of the disease, especially in the case of DR3/X and DR7/X. Both genetic and environmental factors contribute to the onset and to clinical progression of coeliac disease. The role of genetic factors has long been substantiated by a high concordance rate in monozygotic twins, and an increased incidence of overt malabsorption or of asymptomatic histological lesions in first-degree relatives.' 2 More recently, the association between markers of the HLA system and coeliac disease has provided new evidence of the importance of genetic factors in this disease. 8 Different genetic models have been put forward, which propose dominant or recessive expression of HLA-linked gene(s), or in addition assume the involvement of non-HLA gene(s).9 I() In susceptible individuals, exposure to dietary gluten, or to purified gliadin fractions under experimental conditions, is the leading known environmental factor. Clinical and/or histological improvement on a gluten-free diet and relapse after gluten challenge have thus been established as fixed diagnostic criteria.11 Nevertheless, the protean nature of the clinical picture is adequately shown by the significant proportion of atypical cases.'2 As part of an ongoing study, the present report (1) provides further evidence of the association of