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Recent studies have highlighted that human resident memory T cells (TRM) are functionally distinct from circulating T cells. Thus, it can be postulated that skin T cells age differently from blood-circulating T cells. We assessed T-cell density, diversity, and function in individuals of various ages to study the immunologic effects of aging on human skin from two different countries. No decline in the density of T cells was noted with advancing age, and the frequency of epidermal CD49a+ CD8 TRM was increased in elderly individuals regardless of ethnicity. T-cell diversity and antipathogen responses were maintained in the skin of elderly individuals but declined in the blood. Our findings demonstrate that in elderly individuals, skin T cells maintain their density, diversity, and protective cytokine production despite the reduced T-cell diversity and function in blood. Skin resident T cells may represent a long-lived, highly protective reservoir of immunity in elderly people.

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Acne inversa, also known as hidradenitis suppurativa (HS), is a neglected, prevalent, chronic, stigmatizing, and debilitating inflammatory skin disease. HS patients suffer from deep, painful, recurrent abscesses that drain malodorous fluid and lead to disfiguring scars that can limit mobility of the arms and legs. People with African ancestry have a more than twofold increased risk of HS. A lack of effective therapies and limited knowledge about HS pathogenesis contribute to unmet needs. Unlike other common inflammatory skin diseases, there never has been a genome-wide association study (GWAS) conducted for HS. We performed a GWAS of HS using data obtained from the electronic MEdical Records & GEnomics (eMERGE) network of electronic health record linked biorepositories. Cases were identified by the presence of at least one diagnosis code for HS (ICD-9 705.83). Controls were identified as having no record of any immune mediated disease as defined by 28,419 ICD codes. Principal component analysis was used to estimate ancestry from a set of 40,156 SNPs. Our final cohort consisted of 455 HS cases and 1,178 controls with comparable multi-ethnic ancestry (l¼1.06). Genotype data for 40 million variants was tested for association, adjusting for five principle components and run using PLINK (v1.9). Six loci approached the threshold for genome-wide significance (p<5x10-8), with p-values that ranged between 2.0x10-7 and 9.9x10-7 , and effect estimates (2.36>OR>1.43) that suggest a moderate expansion in sample size will allow us to exceed genome-wide significance. There was no evidence for HLA association supporting classification of HS as inflammatory rather than autoimmune. Our group is constructing multi-ethnic replication cohorts that will allow us to expand this study in the near future.

Lichen sclerosus (LS) is an acquired inflammatory condition that mainly affects anogenital skin. Evidence for serum autoantibodies to glycoprotein extracellular matrix protein 1 (ECM1) in a substantial number of patients may hold clue in understanding the pathogenic signature of LS. Indirect immunofluorescence staining on confocal laser scanning microscope using sera from LS patients (n¼23; 1 male and 22 female) displayed that 9 (39.1%) of them exhibit intense immunoreactivity in the lower epidermis and dermal vessels of normal skin substrate, consistent with the staining pattern of affinity-purified IgG from LS sera and rabbit anti-ECM1 antibody. To address the relationship between in vivo ECM1 dysfunction and molecular events in the LS skin, we generated human dermal fibroblasts with siRNA-knockdown for ECM1 and analyzed transcription profiles by cDNA microarray. Comparison with siRNAuntreated fibroblasts identified 3,035 differentially expressed genes. Functional assessment assigned that 1,471 upregulated and 1,564 downregulated genes are related to proteins binding with cellular components, divalent cations, enzymes, and nucleotides. Criteria employing in vivo localization and proposed function of ECM1 in the skin narrowed to 49 upregulated genes, including COL4A, laminin A, fibronectin, MMPs, CTGF, PDGFA and its receptor, SMAD, and TGFB receptor. Realtime RT-PCR and ELISA supported the upregulation of paneled genes and corresponding proteins. Laminin 332 and type IV collagen, the representatives upregulated by ECM1 silencing, revealed unique expression pattern on immunohistochemistry using LS skin. Moreover, type VII collagen, which did not satisfy the ECM1sliencing upregulation but showed abnormal expression pattern in the LS skin, bound to ECM1 recombinant protein. Impaired ECM1 function may thus cause increased expression and selective disassembly of basement membrane, vascular, and extracellular matrix molecules, as well as growth factors facilitating fibroblast proliferation, contributing to the LS skin pathology. 014 Differentiation between control subjects and patients with chronic spontaneous urticaria based on the ability of anti-IgE autoantibodies to induce FcεRI crosslinking, as compared to anti-FcεRIa autoantibodies

Mast cells (MCs) are crucial cells in the development of various types of diseases, including allergy, atopic dermatitis and hair disorders. Corticotropin releasing hormone (CRH) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. However, CRH and its receptors (CRHR) have been recently identified within the skin and reported to play important roles in local cutaneous HPA axis. MCs are also reported to act as CRH mediated stress sentinels in tissue. We have previously shown that CRH induces connective tissue type (CT)-MC degranulation and promotes maturation. Here, we investigated whether CRH can also affect mucosal type (M)-MC biology by using human nasal polyp organ culture. The expression of both CRH and CRHR was detected within nasal polyp samples by immunohistochemistry and RT-PCR. CRH treatment in the organ culture increased the expression of ACTH receptor as well as glucocorticosteroid receptor in situ. Kit or tryp-tase+ M-MCs of isolated nasal polyps was shown to express CRHR by double immunofluorescence. CRH treatment significantly increased tryptase+ M-MC number and induced degranulation in situ. This was partially abrogated by the co-administration of stem cell factor (SCF) neutralizing antibody and CRHR antagonist, antalarmin. Just as human hair follicles organ culture, CRH also increased SCF expression within the epithelium of organ cultured nasal polyp samples. In contrast to CT-MC, CRH treatment significantly increased tryptase+ M-MC proliferation in situ. Furthermore, the effect of CRH on M-MCs degranulation and number was partially diminished by CRHR gene knockdown in situ. These results indicate that CRH induces both cutaneous and mucosal type neuroinflammation by promoting MC activity and increasing the number of it and that blockade of SCF and CRHR might be a novel future target for treating stress-induced disorders including atopic dermatitis and asthma.

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