Psoriasis is a common chronic inflammatory disorder of the skin. To further understand the pathogenesis of psoriasis we have chosen to investigate the molecular genetic basis of the disorder. We have used a two-stage approach to search the human genome for the location of genes conferring susceptibility to psoriasis, using a total of 106 affected sibling pairs identified from 68 independent families. As over a third of the extended kindreds included affected relatives besides siblings, in addition to an analysis of allele sharing between affected sibling pairs, a novel linkage strategy was applied that extracts full non-parametric information. Four principal regions of possible linkage were identified on chromosomes 2, 8, 20 (p <0.005) and markers from the MHC region at 6p21 (p <0.0000006) for which significant evidence of linkage disequilibrium was also observed (p <0.00002). Whilst data from limited case control associations exist to implicate the MHC, the results of this genome wide analysis demonstrate that, at least in the population studied, a gene or genes located within the MHC and close to the class 1 HLA loci, represent the major determinant of the genetic basis of psoriasis.

SummaryLymphocyte trafficking is an essential process in immune and inflammatory functions which can be thought to contain at least two main components: adhesion and migration. Whereas adhesion molecules such as the sdectins are known to mediate the homing of leukocytes from the blood to the endothelium, the chemoattractant substances responsible for the migration of specific subsets of lymphocytes to sites of infection or inflammation are largely unknown. Here we show that two molecules in the chemokine (for chemoattractant cytokine) superfamily, human macrophage inflammatory protein lc~ (MIP-la) and MIP-lfl, do not share identical attractant activities for lymphocyte subpopulations. When analyzed in vitro in microchemotaxis experiments, HuMIP-1B tends to attract CD4 + T lymphocytes, with some preference for T cells of the naive (CD45RA) phenotype. HuMIP-lot, when tested in parallel with HuMIP-lfl, is a more potent lymphocyte chemoattractant with a broader range of concentration-dependent chemoattractant specificities. HuMIP-lo~ at a concentration of 100 pg/ml attracts B ceUs and cytotoxic T cells, whereas at higher concentrations (10 ng/ml), the migration of these cells appears diminished, and the migration of CD4 + T cells is enhanced. Thus, in this assay system, HuMIP-lc~ and -18 have differential attractant activities for subsets of immune effector cells, with HuMIP-la having greater effects than HuMIP-I~, particularly on B cells.

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SUMMARYLesions of the common inflammatory skin disease psoriasis are characterized by epidermal hyperproliferation, leucocyte adhesion molecule expression and leucocyte infillralion. The local release of proinflammatory cytokines. such as TNF-a, may play an iniporiant role in the induction of these events. We have, therefore, analysed aqueous extracts of lesional and uninvolved (clinically normal) stratum corneum for lhe presence of TNF-a immunoreactivity and biological activity. TNF-a immunoreactivity and bioactivity were consistently higher in lesional compared wilh uninvolved samples. By using an anti-TNF-a neutralizing antibody it was demonstrated that the biological activity measured was due to the presence of TNF-a alone. Concentrations of soluble TNF receptors {p55 and p75) were aiso higher in lesional stratum corneum extracts, with Ihe p55 form predominating. The plasma of psoriatic palients was also found to contain elevated concentrations of soluble p55 compared with normal controls. These results confirm the presence of inimunoreactive TNF-a and, for the fust time, conclusively demonstrate TNF-a biological activity and quantifiable concentrations ofsoluble TNF receptors (p55 and p75) in lesional psorialic samples. TNF-a recovery from stratum corneum probably reflects synthesis in deeper, viable layers, where il is likely lo exert its biological effects. Local and systemic release ofsoluble TNF receplors, in particular p55, may serve to regulate the effects of TNF-a in psoriasis.