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

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2022-2-9

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Sürücü, Naz

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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.

Subject Keywords

Autoinflammation, CHAI, LATAIE, low-density granulocytes (LDG), NEMO deficiency

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https://hdl.handle.net/11511/96383

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Graduate School of Natural and Applied Sciences, Thesis

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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.