Case 1: A 61-year-old Japanese woman presented with a history of refractory AD since adolescence. She had complaints of allergic rhino-conjunctivitis. Her mother had no history of allergic disease. She showed lichenified eczema on the face, neck, upper trunk, upper extremities, and knee folds. She had been treated with topical corticosteroids until her 30s, but had not achieved complete remission and became fearful of using corticosteroids. She was therefore, managed using a topical moisturizer, tacrolimus, and oral antihistamines, resulting in moderate improvements.

Case 2: An 84-year-old Japanese man presented with a history of prolonged AD since his 50s. He showed lichenified eczema on the face, neck, upper trunk, and upper extremities. Immunohistochemical analysis of skin biopsy specimens showed an allergic etiology of the skin lesions, with inflammatory infiltration of numerous immunoglobulin (Ig)E-positive cells (mainly comprising IgE+CD1a+ epidermal dendritic cells, IgE+CD11c+ dermal dendritic cells and IgE+ mast cells) in the lichenified eczema [1]. He had complaints of bronchial asthma since adolescence. He also had experienced symptoms of allergic rhino-conjunctivitis and chronic obstructive pulmonary disease (COPD) since his 70s. He had been treated with topical moisturizer and tacrolimus, oral antihistamines for AD, and an oral corticosteroid, montelukast, a bronchodilator, and inhaled corticosteroid/b-agonist for asthma and COPD, resulting in marked improvements.

HLA genotyping was mainly determined using a polymerase chain reaction (PCR)-reverse-sequence specific oligonucleotide method by the Tissue Typing Department (BML, Tokyo, Japan). In FLG genotyping, we genotyped the six loss-of-function variants (c.3321delA, p.Gln1790X, p.Ser2554X, p.Ser2889X, p.Ser3296X, and p.Lys4022X). Determination of c.3321delA was made by size, using fluorescently labeled PCR and an Applied Biosystems 3130 Genetic Analyzer (Life Technologies, Tokyo, Japan), and p.Gln1790X, p.Ser2554X, p.Ser2889X, p.Ser3296X, and p.Lys4022X using a Taqman Assay-by-Design system for single-nucleotide polymorphism genotyping (Life Technologies). Genotype results were confirmed by direct sequencing with BigDye^® Terminator v3.1 Cycle Sequencing Kit (Life Technologies). All study protocols were approved by the ethics committees of both the Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology and the University of Tsukuba. Both patients provided written informed consent for the genetic study. Clinical characteristics and results of the genetic analyses for these two cases are summarized in Table 1 and Table 2, respectively.

The comparison of clinical and genetic features between Cases 1 and 2 yielded some interesting findings. In this father and daughter pair with elderly AD, the common genetic background underlying the pathogenesis of AD may represent a haplotype for major histocompatibility complex (MHC) class II (i.e., HLA-DRB1*1501-DQA1*0102-DQB1*0602-DPB1*0501). The allele HLA-DRB1*1501 in this haplotype has been reported as a gene encoding an immunodominant epitope of Dermatophagoides pteronyssinus-1 and D. pteronyssinus-2, which induces sensitization of specific T cells and IgE against D. pteronyssinus in patients with AD [2,3] and asthma [4] . HLA-DRB1*1501/ D. pteronyssinus-1 and- 2 MHC class II tetramers are therefore frequently used for clinical research in the phenotyping of house dust mite (HDM)-allergens-specific T cells in AD patients [2,3]. In addition, the alleles HLA-DQA1*0102-DQB1*0602 in this haplotype have also been reported as susceptibility genes for major antigen-presenting molecules for D. farinae-1-derived peptides to T cells in Japanese atopic individuals [5]. Actually, both HDM-allergens represented the major allergens in the present kindred cases.

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