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Phenotypic and functional characterization of leukocytes in patients with immune system dysregulation
Fejtková, Martina ; Kanderová, Veronika (advisor) ; Vlková, Marcela (referee) ; Balounová, Jana (referee)
Inborn errors of immunity (IEI) are a heterogenic group of diseases of the immune system causing dysregulations of both innate and adaptive immunity. New altered immune-related genes are discovered every year, nowadays reaching over 400. (Tangye et al., 2020) Here three new autoinflammatory disorders of IEI patients are described. Toll-like receptors (TLR) 7 and 8 are endosomal receptors in the innate immune response against external pathogens and endogenous autoantigens. A dysregulation in TLR7 and TLR8 in mice causes autoimmunity and inflammation, however, in humans, the immunopathology of TLR8 and TLR7 remains unclear. We identified a novel X-linked c.1715G>T mutation in TLR8 that leads to autoimmune haemolytic anaemia and autoinflammation in male twins caused by dysregulation in TLR8 and TLR7 response especially in myeloid cells (low TLR8 protein expression, cross-reactivity of TLR8 for TLR7 ligands and enhanced TLR7 response). Hematopoietic cell kinase (HCK) belongs to the Src family of kinases and is involved in myeloid cell migration, adhesion and degranulation. Kinase activity in the immune response must be strictly regulated. In HCK, this regulation is based on C-terminal inhibitory tyrosine, which when phosphorylated, HCK kinase activity is switched off. We identified a heterozygous...
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