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Frontiers in Immunology 2019Recent studies suggest an important role of immunoglobulin E (IgE) as an alternative pathogenic pathway in the development of bullous pemphigoid (BP), as the most...
Recent studies suggest an important role of immunoglobulin E (IgE) as an alternative pathogenic pathway in the development of bullous pemphigoid (BP), as the most frequent subepidermal blistering disease of the skin Use of IgE targeted therapies, such as omalizumab, has been shown promising in recent studies. The aim of this study was to assess the effect of omalizumab on FcεRI and IgE expression on circulating basophils and on lesional intradermal cells in BP to generate insight into the immunological effects of omalizumab in BP. We report two cases of BP patients treated with omalizumab. Efficacy of treatment was assessed clinically 4 months after initiation of the therapy. Lesional and non-lesional skin biopsies where taken before and 4 weeks after initiation of omalizumab therapy. In addition, FcεRI expression on circulating cells and IgE levels in serum and in the skin samples, as well as anti-BP180 and anti-BP230 in serum and eosinophils and basophils counts in blood were assessed before and during treatment. Both patients showed a marked improvement after 4 months, with no adverse effects. Down-regulation of FcεRI, IgE in lesional skin and on circulating basophils were observed in parallel with clinical improvement. The current case study supports the role of omalizumab in the treatment of a subset of BP patients. Our observations suggest that omalizumab represents a valuable therapeutic option in the management of BP patients. Its efficacy might be related to reduction in FcεRI+ and IgE+ basophils and intradermal cells.
Topics: Aged; Anti-Allergic Agents; Autoantibodies; Autoantigens; Basophils; Dystonin; Eosinophils; Humans; Immunoglobulin E; Leukocyte Count; Middle Aged; Non-Fibrillar Collagens; Omalizumab; Pemphigoid, Bullous; Receptors, IgE; Skin; Treatment Outcome; Collagen Type XVII
PubMed: 31474990
DOI: 10.3389/fimmu.2019.01919 -
Acta Dermato-venereologica Nov 2019
Topics: Adrenal Cortex Hormones; Autoantibodies; Drug Resistance; Drug Therapy, Combination; Dystonin; Histamine Antagonists; Humans; Immunoglobulin G; Immunosuppressive Agents; Laminin; Male; Middle Aged; Pemphigoid, Bullous; Remission Induction; Treatment Outcome
PubMed: 31449311
DOI: 10.2340/00015555-3294 -
Annals of Surgery Oct 2019To understand role of barrier molecules in melanomas.
OBJECTIVE
To understand role of barrier molecules in melanomas.
BACKGROUND
We have reported poor patient survival and low immune infiltration of melanomas that overexpress a set of genes that include filaggrin (FLG), dystonin (DST), junction plakoglobin (JUP), and plakophilin-3 (PKP3), and are involved in cell-cell adhesions. We hypothesized that these associations are causal, either by interfering with immune cell infiltration or by enhancing melanoma cell growth.
METHODS
FLG and DST were knocked out by CRISPR/Cas9 in human DM93 and murine B16-F1 melanoma cells. PKP3 and JUP were overexpressed in murine B16-AAD and human VMM39 melanoma cells by lentiviral transduction. These cell lines were evaluated in vitro for cell proliferation and in vivo for tumor burden, immune composition, cytokine expression, and vascularity.
RESULTS
Immune infiltrates were not altered by these genes. FLG/DST knockout reduced proliferation of human DM93 melanoma in vitro, and decreased B16-F1 tumor burden in vivo. Overexpression of JUP, but not PKP3, in B16-AAD significantly increased tumor burden, increased VEGF-A, reduced IL-33, and enhanced vascularity.
CONCLUSIONS
FLG and DST support melanoma cell growth in vitro and in vivo. Growth effects of JUP were only evident in vivo, and may be mediated, in part, by enhancing angiogenesis. In addition, growth-promoting effects of FLG and DST in vitro suggest that these genes may also support melanoma cell proliferation through angiogenesis-independent pathways. These findings identify FLG, DST, and JUP as novel therapeutic targets whose down-regulation may provide clinical benefit to patients with melanoma.
Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Cytokines; Dystonin; Filaggrin Proteins; Flow Cytometry; Fluorescent Antibody Technique; Humans; Intermediate Filament Proteins; Melanoma; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; gamma Catenin
PubMed: 31425296
DOI: 10.1097/SLA.0000000000003522 -
The Journal of Investigative Dermatology Dec 2019Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important... (Randomized Controlled Trial)
Randomized Controlled Trial
Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important for pathogenesis. Given the adverse effects of standard treatment (glucocorticoids, immunosuppressants), there is an unmet need for safe and effective therapies. In this phase 1 trial, we evaluated the safety and activity of BIVV009 (sutimlimab, previously TNT009), a targeted C1s inhibitor, in 10 subjects with active or past bullous pemphigoid (NCT02502903). Four weekly 60 mg/kg infusions of BIVV009 proved sufficient for inhibition of the classical complement pathway in all patients, as measured by CH50. C3c deposition along the dermal-epidermal junction was partially or completely abrogated in 4 of 5 patients, where it was present at baseline. BIVV009 was found to be safe and tolerable in this elderly population, with only mild to moderate adverse events reported (e.g., headache, fatigue). One serious adverse event (i.e., fatal cardiac decompensation) occurred at the end of the post-treatment observation period in an 84-year-old patient with a history of diabetes and heart failure, but was deemed unlikely to be related to the study drug. This trial provides the first results with a complement-targeting therapy in bullous pemphigoid, to our knowledge, and supports further studies on BIVV009's efficacy and safety in this population.
Topics: Aged; Aged, 80 and over; Autoantigens; Complement C3; Complement Pathway, Classical; Dermis; Dystonin; Epidermis; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 31229501
DOI: 10.1016/j.jid.2019.04.025 -
The Journal of Investigative Dermatology Sep 2019Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion...
Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion molecules, known as BP180 and BP230. Homologues to these proteins are found in the brain, and it is hypothesized that neurologic disease leads to the production of autoantibodies that can cross-react with their cutaneous forms. To better understand the link between BP and neurologic disease, we evaluated primary demographic features (age, sex, race, ethnicity, and elapsed time between onset of skin symptoms and BP diagnosis), severity of BP, and IgG and IgE autoantibody levels in BP control individuals and patients with BP with preceding Parkinson disease, dementia, and stroke. The main findings of this study are that patients with BP with preceding neurologic disease have a shorter elapsed time between onset of skin disease and BP diagnosis and that patients with preceding Parkinson disease or dementia, but not stroke, are significantly older than patients with BP without neurologic disease. However, no significant differences in clinical presentation, BP severity scores, or autoantibody (IgG and IgE) responses were observed among the groups. These findings suggest that, despite the age difference, the clinical phenotype of BP is not affected by preceding neurologic disease.
Topics: Age Factors; Age of Onset; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Comorbidity; Dementia; Dystonin; Female; Humans; Incidence; Male; Middle Aged; Non-Fibrillar Collagens; Parkinson Disease; Pemphigoid, Bullous; Risk Factors; Severity of Illness Index; Sex Factors; Stroke; Time Factors; Collagen Type XVII
PubMed: 30876802
DOI: 10.1016/j.jid.2019.01.034