piperidines and Immunologic-Deficiency-Syndromes

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflammatory disorder. Cutaneous manifestations of CANDLE syndrome include characteristic recurring violaceous annular plaques comprised of an immature dermal mononuclear cell infiltrate. In CANDLE syndrome, deleterious genetic mutations inhibit proteasome-immunoproteasome function, resulting in cellular accumulation of ubiquitinated waste proteins that activate type I interferon signaling to drive inflammation. We describe a report of successful treatment of a 12-year-old girl with CANDLE syndrome with tofacitinib.

Topics: Child; Female; Fever; Humans; Immunologic Deficiency Syndromes; Lipodystrophy; Piperidines; Pyrimidines; Skin Diseases; Sweet Syndrome

Interleukin-6 signal transducer (IL6ST) encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through Janus kinase signal transducers and activators of transcription pathway (JAK/STAT) activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of the Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular, small monoallelic in-frame deletions of which the most prevalent is the IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been described. Herein, we report a pediatric proband with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphy associated with the IL6ST Tyr186_Tyr190del variant present constitutively. Tyr186_Tyr190del was found by exome sequencing and was shown to be de novo (absent in proband's parents and siblings) and mosaic (present in approximately 15-40% of cells depending on the tissue studied-blood, urine sediment, hair bulbs and buccal swab). Functional studies were performed in the Epstein-Barr virus-immortalized patient's B cell lymphoblastoid cell line, which carried the variant in approximately 95% of the cells. Western blot showed that the patient's cells exhibited constitutive hyperphosphorylation of Tyr705 in STAT3, which is indicative of IL6-independent activation of GP130. Interestingly, the STAT3 phosphorylation could be inhibited with ruxolitinib as well as tofacitinib, which are clinically approved JAK1 and JAK3 (to lesser extent JAK2 and JAK1) inhibitors, respectively. Given our results and the recent reports of ruxolitinib and tofacitinib use for the treatment of diseases caused by direct activation of STAT3 or STAT1, we speculate that these drugs may be effective in the treatment of our patient's condition.

Topics: Child; Cytokine Receptor gp130; Exome Sequencing; Hereditary Autoinflammatory Diseases; Humans; Immunologic Deficiency Syndromes; Male; Nitriles; Pedigree; Phosphorylation; Piperidines; Poland; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Pyrazoles; Pyrimidines; Sequence Deletion; Signal Transduction; STAT3 Transcription Factor; White People

Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.

Topics: Adenine; B-Cell CLL-Lymphoma 10 Protein; B-Lymphocytes; CARD Signaling Adaptor Proteins; Cell Line; Diploidy; Exons; Genes, Dominant; Genetic Variation; Guanylate Cyclase; Humans; Immunologic Deficiency Syndromes; Jurkat Cells; Lymphoma; NF-kappa B p50 Subunit; Piperidines; Polymorphism, Single Nucleotide; Primary Immunodeficiency Diseases; Sensitivity and Specificity

Topics: Adolescent; Adult; Child; Female; Gain of Function Mutation; Humans; Immunologic Deficiency Syndromes; Janus Kinases; Male; Nitriles; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrroles; STAT1 Transcription Factor; STAT3 Transcription Factor; Treatment Outcome

Despite antibiotics, infection remains a significant problem in surgical patients. The reasons are multiple, and include acquired immunologic deficiencies that are seen in malnutrition, sepsis, trauma, and burns. Two immunomodulators, thymopentin (TP-5) and CP-46,665, have been shown to improve survival in infectious animal models of such deficiencies. We investigated the mechanism of action in guinea pigs subjected to a burn of 30% of the total body surface area. These animals received 0.3 mg/kg of thymopentin, 0.3 mg/kg of CP-46,665, or saline solution. Neutrophils, macrophages, and serum samples were obtained from the animals and tested for their ability to phagocytose and kill Pseudomonas aeruginosa. The serum was tested for its ability to opsonize Escherichia coli. Thymopentin was found to improve neutrophil function on postburn days 2 and 4 and to improve macrophage function on postburn day 4. CP-46,665 was found to improve both macrophage function and opsonization on postburn day 2.

Topics: Adjuvants, Immunologic; Animals; Burns; Disease Models, Animal; Female; Guinea Pigs; Immunologic Deficiency Syndromes; Macrophages; Neutrophils; Opsonin Proteins; Peptide Fragments; Phagocytosis; Piperidines; Pseudomonas aeruginosa; Thymopentin; Thymopoietins; Thymus Hormones; Time Factors

Topics: Abnormalities, Drug-Induced; Animals; Cats; Cattle; Chromosome Aberrations; Chromosome Disorders; Disease Models, Animal; Dogs; Ehlers-Danlos Syndrome; Freemartinism; Genetic Diseases, Inborn; Genetic Linkage; Heart Defects, Congenital; Humans; Immunologic Deficiency Syndromes; Karyotyping; Leukocytes; Mercury Poisoning; Mink; Mosaicism; Nicotiana; Piperidines; Plant Extracts; Plant Poisoning; Plants, Medicinal; Plants, Toxic; Sheep; Swine; Veratrum