Atopic dermatitis (AD) is a chronic and pruritic inflammatory skin disorder that is associated with susceptibility to bacterial or viral infections. The prevalence of atopic dermatitis has significantly increased in industrialized countries during the past three decades, affecting 15 to 30% of children and 2 to 10% of adults. Itching represents a predominant symptom of AD and substantially impairs the patient’s quality of life. Histologic features of acute skin lesions include edema (spongiosis) and a marked inflammatory infiltrate, while chronic skin lesions are characterized by skin thickening (acanthosis), skin markings (lichenification), and dry fibrotic papules. Deficiencies on the level of skin barrier function and innate and adaptive immunity contribute to the pathophysiology of AD, and might explain the susceptibility of AD patients to cutaneous pathogens.
A subgroup of patients (25%) has IgE antibodies against self-proteins from keratinocytes and endothelial cells, with IgE autoantibody levels correlating with disease severity (1). In these patients, early-onset atopic dermatitis, intense pruritus, recurrent bacterial skin infections, and high serum IgE levels are hallmarks of the disease. Thus, atopic dermatitis seems to stand at the frontier between allergy and autoimmunity.
Genomewide scans have highlighted several possible AD–related loci on chromosomes 3q21, 1q21, 16q, 17q25, 20p, and 3p26. The region of highest linkage was identified on chromosome 1q21, which harbors a family of epithelium-related genes called the epidermal differentiation complex. Most of the genetic regions associated with atopic dermatitis correspond to loci associated with psoriasis, although these two diseases are rarely linked. Several candidate genes have been identified in atopic dermatitis especially on chromosome 5q31-33. All of them encode cytokines involved in the regulation of IgE synthesis: IL-4, IL-5, IL-12, IL-13, and GM-CSF. Several recent studies have reported a strong association of loss of function mutations in the filaggrin gene (FLG.) with atopic eczema. Furthermore, the FLG defects have been linked to a specific type of allergic disease: a type of eczema with allergic sensitization and an increased risk of rhinitis and asthma. There is, however, no association between mutant FLG and allergic airway diseases without atopic dermatitis. FLG mutations are identified in 18-48% of European patients with atopic dermatitis (Fig. 1).
Psoriasis is a common, chronic skin disease, affecting approximately 2% of the population. Patients with psoriasis have significantly decreased quality of life and the combined costs of long-term therapy and social costs of the disease have a major impact on health care systems and on society in general. Psoriasis belongs within a spectrum of autoimmune-related diseases characterized by chronic inflammation in the absence of known infectious agents or antigens. Major challenges in the future include elucidation of the autoimmune nature of the inflammatory process and examination the role of environmental influences on disease initiation and progression.
Classic genomewide linkage analysis has identified at least nine chromosomal loci with statistically significant linkage to psoriasis; these loci are called psoriasis susceptibility 1 through 9 (PSORS1 through PSORS9) (2). The major genetic determinant of psoriasis is PSORS1, which probably accounts for 35 to 50% of the heritability of the disease. PSORS1 is located within the major histocompatibility complex (MHC) on chromosome 6p (Fig. 1). Three genes within the region are considered candidate genes: HLA-C (associated variant, HLA-Cw6) encodes a class I MHC protein. CCHCR1 (associated variant, WWCC) encodes the coiled-coil, x-helical rod protein 1, a ubiquitously expressed protein that is overexpressed in psoriatic epidermis. Corneodesmosin (CDSN) (associated variant, allele 5) encodes corneodesmosin, a protein that is uniquely expressed in the granular and cornified layers of the epidermis and is up-regulated specifically in psoriasis. Genomewide association scans have also identified variants in interleukin-23 receptor (IL23R) gene and in the untranslated region of the interleukin-12B (IL12B) (p40) gene as being indicators of psoriasis risk. IL23R variants are also associated with ankylosing spondylitis and psoriatic arthritis. Another gene, CDKAL1, has been shown to be associated with psoriasis as well as Crohn’s disease and type 2 diabetes mellitus.