Characterization of autoinflammatory manifestations in NEMO deficiency and analysis of gene expression patterns in LRBA and CTLA-4 deficiencies

Sürücü, Naz
NEMO (NF-κB essential modulator, IKK-γ) deficiency that phenotypically manifests as ectodermal dysplasia with immune deficiency (EDA-ID) arises due to hypomorphic mutations in the ikbkg gene in males. Patients present with developmental impairment of ectodermal tissues accompanied with recurrent infections early in life. Herein, we investigated the underlying mechanistic conditions leading to paradoxical autoinflammatory manifestations in a case of NEMO deficiency, who later underwent HSCT. Consistent with the immune deficiency, the patient was unable to generate pro-inflammatory cytokines IL-1β and IL-6 in response to TLR stimulation. In contrast, the patient had inflammatory low-density granulocytes (LDG) as well as primed neutrophils in the circulation that potentially induced the clinical pathophysiology. Gene expression analysis conducted with the LDG and autologous neutrophil populations from the patient revealed increased expression of adhesion and inflammation related genes, indicating their potential to cross into the tissue and inflict damage. Furthermore, the patient exhibited an elevated type I IFN signature as evidenced by high IP-10 levels in the plasma in addition to excessive ISGylation of cellular proteins. The clinical autoinflammatory manifestations receded after HSCT parallel to the disappearance of the LDG population and the type I IFN signature, supporting their involvement in disease pathophysiology. Apart from this, we explored the gene expression profiles of CHAI and LATAIE patients, who started to receive abatacept therapy. Our preliminary data show coherence with the clinical phenotype of both disorders and display the improving effect of abatacept on the course of disease.


Low Density Granulocytes and Dysregulated Neutrophils Driving Autoinflammatory Manifestations in NEMO Deficiency
Yilmaz, Naz Surucu; et. al. (2022-01-01)
NF-kappa B essential modulator (NEMO, IKK-gamma) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations i...
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Tranilast is an antiallergic drug that interferes with proliferation and migration of vascular smooth muscle cell induced by platelet-derived growth factor (PDGF) and transforming growth factor-beta 1 (TGF-beta 1). We investigated the local effect of tranilast on neointimal hyperplasia using tranilastcoated prosthetic grafts. The inner sides of the thin-walled polytetrafluoroethylene (PTFE) grafts were coated with chitosan and tranilast containing chitosan solution. Wistar albino rats (32) were used in the ...
Citation Formats
N. Sürücü, “Characterization of autoinflammatory manifestations in NEMO deficiency and analysis of gene expression patterns in LRBA and CTLA-4 deficiencies,” Ph.D. - Doctoral Program, Middle East Technical University, 2022.