The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope.

The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also triggers a cascade of SLE-associated cellular aberrations, including endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, necroptotic cell death, and production of pro-inflammatory cytokines.

HLA-G and the MHC Cusp Theory.

Human leukocyte antigens (HLA) are significant genetic risk factors in a long list of diseases. However, the mechanisms underlying these associations remain elusive in many cases. The best-characterized function of classical major histocompatibility complex (MHC) antigens is to allow safe presentation of antigenic peptides a self/non-self-discrimination process.

HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization.

Associations between particular human leukocyte antigen (HLA) alleles and susceptibility to-or protection from-autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit, but it is unclear whether HLA molecules might also have non-AP, disease-modulating effects. Here we demonstrate differential macrophage activation by HLA-DRB1 alleles known to associate with autoimmune disease risk or protection with resultant polarization of pro-inflammatory ("M1") versus anti-inflammatory ("M2") macrophages, respectively.

Uncovering a Shared Epitope-Activated Protein Citrullination Pathway.

Rheumatoid arthritis (RA) is closely associated with shared epitope (SE)-coding alleles and circulating anticitrullinated protein Abs (ACPA), but neither the respective pathogenic roles of SE and ACPA in RA nor the mechanisms underlying their coassociation are known. It was recently shown that the SE functions as a signal transduction ligand that activates a cell surface calreticulin-mediated, proarthritogenic, bone erosive pathway in an experimental model of RA. In this study, we demonstrate that stimulation of murine macrophages with LPS or DTT facilitated cell surface translocation of calreticulin, which in turn enabled increased SE-activated calcium signaling and activation of peptidylarginine deiminase with the resultant increased cellular abundance of citrullinated proteins.

Human Leukocyte Antigen-Disease Associations in Rheumatoid Arthritis.

The cause and pathogenesis of rheumatoid arthritis (RA) are influenced by environmental and genetic risk factors. Shared epitope-coding human leukocyte antigen (HLA)-DRB1 alleles increase RA risk and severity; however, the underlying mechanisms of action remain unclear. In contrast, several other DRB1 alleles protect against RA.

Altered expression of epidermal lipid bio-synthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition.

Background: The barrier dysfunction in atopic dermatitis (AD) skin correlates with stratum corneum (SC) lipid abnormalities including reduction of global lipid content, shorter ceramide (CER) as well as free fatty acid (FFA) chain length and altered CER subclass levels. However, the underlying cause of these changes in lipid composition has not been fully investigated.

Aim: We investigated whether the expression of CER and FFA biosynthesis enzymes are altered in AD skin compared with control skin and determine whether changes in enzyme expression can be related with changes in lipid composition.

A reciprocal HLA-Disease Association in Rheumatoid Arthritis and Pemphigus Vulgaris.

Human leukocyte antigens (HLA) have been extensively studied as being antigen presenting receptors, but many aspects of their function remain elusive, especially their association with various autoimmune diseases. Here we discuss an illustrative case of the reciprocal relationship between certain alleles and two diseases, rheumatoid arthritis (RA) and pemphigus vulgaris (PV). RA is strongly associated with alleles that encode a five amino acid sequence motif in the 70-74 region of the DR beta chain, called the shared epitope (SE), while PV is associated with the allele that encodes a different sequence motif in the same region.

Explant cultures of atopic dermatitis biopsies maintain their epidermal characteristics in vitro.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterised by various epidermal alterations. Filaggrin (FLG) mutations are a major predisposing factor for AD and much research has been focused on the FLG protein. Human skin equivalents (HSEs) might be useful tools for increasing our understanding of FLG in AD and to provide a tool for the screening of new therapies aimed at FLG replacement.

Exploring the potentials of nurture: 2(nd) and 3(rd) generation explant human skin equivalents.

Background: Explant human skin equivalents (Ex-HSEs) can be generated by placing a 4mm skin biopsy onto a dermal equivalent. The keratinocytes migrate from the biopsy onto the dermal equivalent, differentiate and form the epidermis of 1(st) generation Ex-HSEs. This is especially suitable for the expansion of skin material from which only small fragments of skin can be harvested e.

Barrier properties of an N/TERT-based human skin equivalent.

Human skin equivalents (HSEs) can be considered a valuable tool to study aspects of human skin, including the skin barrier, or to perform chemical or toxicological screenings. HSEs are three-dimensional skin models that are usually established using primary keratinocytes and closely mimic human skin. The use of primary keratinocytes has several drawbacks, including a limited in vitro life span and large donor-donor variation.

TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents.

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which the skin barrier function is disrupted. In this inflammatory AD environment, cytokines are upregulated, but the cytokine effect on the AD skin barrier is not fully understood. We aimed to investigate the influence of Th2 (IL-4, IL-13, IL-31) and pro-inflammatory (tumor necrosis factor alpha (TNF-α)) cytokines on epidermal morphogenesis, proliferation, differentiation, and stratum corneum lipid properties.

Intercellular skin barrier lipid composition and organization in Netherton syndrome patients.

Netherton syndrome (NTS) is a rare genetic skin disease caused by mutations in the serine protease inhibitor Kazal-type 5 gene, which encodes the lympho-epithelial Kazal-type-related inhibitor. NTS patients have profoundly impaired skin barrier function. As stratum corneum (SC) lipids have a crucial role in the skin barrier function, we investigated the SC lipid composition and organization in NTS patients.

Knock-down of filaggrin does not affect lipid organization and composition in stratum corneum of reconstructed human skin equivalents.

Human skin mainly functions as an effective barrier against unwanted environmental influences. The barrier function strongly relies on the outermost layer of the skin, the stratum corneum (SC), which is composed of corneocytes embedded in an extracellular lipid matrix. The importance of a proper barrier function is shown in various skin disorders such as atopic dermatitis (AD), a complex human skin disorder strongly associated with filaggrin (FLG) null mutations, but their role in barrier function is yet unclear.

Epidermal growth factor receptor activation and inhibition in 3D in vitro models of normal skin and human cutaneous squamous cell carcinoma.

The transmembrane tyrosine kinase epidermal growth factor receptor (EGFR) is considered a key player in the development of cutaneous squamous cell carcinoma (SCC), which is the second most common malignancy in white populations. Inhibition of EGFR with the small molecule tyrosine kinase inhibitor erlotinib is currently under clinical investigation in cutaneous SCC patients. In this study, we investigated the effects of EGFR activation and inhibition on normal and malignant in vitro human skin equivalents (HSEs).