Primary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is the most common subtype. The treatment of... Show morePrimary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is the most common subtype. The treatment of this disease is based on skin-directed therapies eventually in association with biologic response modifiers in the early phases, whereas in patients with the advanced stages, several therapeutic strategies can be used including mono and/or poly-chemotherapy and bone marrow transplantation. In recent years, the identification of specific markers (phenotypical, immunological, and molecular) has led to the development of several studies (including two randomized phase III trials). The results of these studies are modifying our therapeutic strategy toward a personalized treatment approach in which the clinical characteristics of the patients and tumor-node-metastasis-blood stage are considered together with the expression of specific markers (i.e., a CD30-positive expression for the use of brentuximab vedotin). This review will provide a comprehensive scenario of the main phenotypical, molecular, and immunological markers related to MF pathogenesis and disease evolution, which could represent the target for the development of innovative effective treatments in this disease. Show less
BRD4 acts as an epigenetic reader to regulate gene transcription. It represents a valid therapeutic target in cancer, and several selective and potent small molecule inhibitors have been discovered... Show moreBRD4 acts as an epigenetic reader to regulate gene transcription. It represents a valid therapeutic target in cancer, and several selective and potent small molecule inhibitors have been discovered. A study by Le et al. (2020) published in Journal of Investigative Dermatology (2020) demonstrates that BRD4 inhibition reduces the invasive behavior of melanoma cells associated with matrix metalloproteinase-2 downregulation and increases phagocytosis by myeloid cells through SIRP alpha downregulation. Show less
The major histocompatibility complex haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which major... Show moreThe major histocompatibility complex haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which major histocompatibility complex-associated genetic susceptibility translates into autoimmune disease are not fully understood. Epidermolysis bullosa acquisita is an autoimmune skin-blistering disease driven by autoantibodies to type VII collagen. Here, we investigated autoantigen-specific plasma cells, CD4(+) T cells, and IgG fraction crystallizable glycosylation in murine epidermolysis bullosa acquisita in congenic mouse strains with the disease-permitting H2s or disease-nonpermitting H2b major histocompatibility complex II haplotypes. Mice with an H2s haplotype showed increased numbers of autoreactive CD4(+) T cells and elevated IL-21 and IFN-gamma production, associated with a higher frequency of IgG autoantibodies with an agalactosylated, proinflammatory N-glycan moiety. Mechanistically, we show that the altered antibody glycosylation leads to increased ROS release from neutrophils, the main drivers of autoimmune inflammation in this model. These results indicate that major histocompatibility complex II-associated susceptibility to autoimmune diseases acuminates in a proinflammatory IgG fraction crystallizable N-glycosylation pattern and provide a mechanistic link to increased ROS release by neutrophils. Show less
Bogaard, E. van den; Ilic, D.; Dubrac, S.; Tomic-Canic, M.; Bouwstra, J.; Celli, A.; Mauro, T. 2020
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and multiple organs of which the pathogenesis is poorly understood. Here we studied differentially expressed... Show moreSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and multiple organs of which the pathogenesis is poorly understood. Here we studied differentially expressed coding and non-coding genes in relation to SSc pathogenesis with a specific focus on antisense non-coding RNAs. Skin biopsy-derived RNAs from fourteen early SSc patients and six healthy individuals were sequenced with ion-torrent and analysed using DEseq2. Overall, 4901 genes with a fold change >1.5 and a false discovery rate < 5% were detected in patients versus controls. Upregulated genes clustered in immunological, cell adhesion and keratin-related processes. Interestingly, 676 deregulated non-coding genes were detected, 257 of which were classified as antisense genes. Sense genes expressed opposite of these antisense genes were also deregulated in 42% of the observed sense-antisense gene pairs. The majority of the antisense genes had a similar effect sizes in an independent North American dataset with three genes (CTBP1-AS2, OTUD6B-AS1 and AGAP2-AS1) exceeding the study-wide Bonferroni-corrected ρ-value (PBonf<0.0023, Pcombined = 1.1x10-9, 1.4x10-8, 1.7x10-6, respectively). In this study, we highlight that together with coding genes, (antisense) long non-coding RNAs are deregulated in skin tissue of SSc patients suggesting a novel class of genes involved in pathogenesis of SSc. Show less
Mieremet, A.; Rietveld, M.; Absalah, S.; Smeden, J.V.; Bouwstra, J.; Ghalbzouri, A. el 2016
