Genome-wide transcriptional profiling in human squamous cell carcinoma of the skin identifies unique tumor-associated signatures.

The elucidation of specific genetic changes associated with human cancer pathogenesis has focused efforts to relate such changes to the neoplastic phenotype. To further our understanding of the genetic basis of human squamous cell carcinoma (SCC) of the skin, this study used a genome-wide (12 627 sequences) approach to determine transcriptional signatures in lesional and nonlesional sites from five SCC patients. Several novel genes involving the p53 pathway, anti-apoptotic pathways, signal transduction, structural loss and DNA replication, including BCL2A1, MUC4, PTPN11 (SHP2) and FGF9, are upregulated in SCC and could warrant further study regarding their role in disease pathogenesis. SCC pathology is likely combinatorial in nature involving the compounded changes from several cellular processes.

Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris.

Early studies of genetic susceptibility to pemphigus vulgaris (PV) showed associations between human leukocyte antigen (HLA) DR4 and DR6 and disease. The emergence of DNA sequencing techniques has implicated numerous DRB1 and DQB1 loci in various populations, leading to confusion regarding which exact alleles confer susceptibility. The strong linkage disequilibrium among DR and DQ HLA alleles further complicates the investigation of the true susceptibility loci. In this study, we report genotyping data for the largest sampling of North American Caucasian non-Jewish and Ashkenazi Jewish PV patients studied to date and compare our data with other population studies. To pinpoint true susceptibility, alleles among overrepresented sequences, we applied a step-wise reductionist analysis through (1) determination of the degree of linkage disequilibrium (LD) between purportedly associated alleles, (2) haplotype frequencies comparisons, and (3) primary sequence comparisons of disease-associated versus non-disease-associated alleles to identify crucial differences in amino acid residues in putative peptide binding pockets. Collectively, our data provide extended support for the hypothesis that the HLA associations in Caucasian PV patients map to DRB1*0402 and DQB1*0503 alone. Further structure-function studies will be required to define the exact mechanisms of HLA-mediated control of susceptibility and resistance to disease.

Modeling the bound conformation of Pemphigus vulgaris-associated peptides to MHC Class II DR and DQ alleles.

BACKGROUND: Pemphigus vulgaris (PV) is a severe autoimmune blistering disorder characterized by the presence of pathogenic autoantibodies directed against desmoglein-3 (Dsg3), involving specific DR4 and DR6 alleles in Caucasians and DQ5 allele in Asians. The development of sequence-based predictive algorithms to identify potential Dsg3 epitopes has encountered limited success due to the paucity of PV-associated allele-specific peptides as training data. RESULTS: In this work we constructed atomic models of ten PV associated, non-associated and protective alleles. Nine previously identified stimulatory Dsg3 peptides, Dsg3 96-112, Dsg3 191-205, Dsg3 206-220, Dsg3 252-266, Dsg3 342-356, Dsg3 380-394, Dsg3 763-777, Dsg3 810-824 and Dsg3 963-977, were docked into the binding groove of each model to analyze the structural aspects of allele-specific binding. CONCLUSION: Our docking simulations are entirely consistent with functional data obtained from in vitro competitive binding assays and T cell proliferation studies in DR4 and DR6 PV patients. Our findings ascertain that DRB1*0402 plays a crucial role in the selection of specific self-peptides in DR4 PV. DRB1*0402 and DQB1*0503 do not necessarily share the same core residues, indicating that both alleles may have different binding specificities. In addition, our results lend credence to the hypothesis that the alleles DQB1*0201 and *0202 play a protective role by binding Dsg3 peptides with greater affinity than the susceptible alleles, allowing for efficient deletion of autoreactive T cells.

The role of T cells in cutaneous autoimmune disease.

T cells assume a fundamental function in immunosurveillance and maintenance of the cutaneous immune barrier, yet derangement of their requisite role effects a range of cutaneous autoimmune diseases with significant associated morbidity. While blistering skin diseases, such as pemphigus vulgaris (PV), pemphigus foliaceus (PF) and bullous pemphigoid (BP) are mediated by antibodies directed against autoantigens found in the skin, recent evidence has shown that T cell activation is crucial for the initiation and coordination of this humoral response. Non-blistering skin diseases, such as alopecia areata (AA), vitiligo (VL) and psoriasis (PS) are increasingly believed to be directly mediated by the activities of autoreactive T cells. Here, we examine T lymphocyte control of antibody-mediated and cell-mediated processes involved in the pathoimmunology of the above mentioned skin diseases.