Phenotypic and mechanistic clues to inborn errors of immunity

Elina A. Tuovinen

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Sammanfattning

Inborn Errors of Immunity (IEI) are a heterogenic group of disorders caused by germline alterations in genes that regulate the development and function of the immune system. Currently, almost 500 monogenic causes for IEIs are reported, and the list is constantly growing. The spectrum of the diseases is widening as more causative genes are detected and more reports on the effects of different genetic variants on phenotypes accumulate. Since different genetic variants can lead to similar phenotypes, IEIs can present a diagnostic challenge. Furthermore, more atypical, or unexpected phenotypes are being reported. For better diagnostics and treatment, studying the pathogenic mechanisms of different genetic variants on molecular level is essential. In this study, we aimed to broaden the spectrum of IEIs by focusing on both the detailed characterization of a single patient with variant in IL2RG (interleukin-2 receptor gamma chain) and on studying a larger cohort of patients carrying different pathogenic variants in NFKB1. In the first original publication, we reported two unrelated patients with hemizygous novel hypomorphic IL2RG c. 172C>T;p.(Pro58Ser) variant leading to atypical X-linked severe combined immunodeficiency (X-SCID) phenotype. The index patient presented with recurrent respiratory tract infections, and bronchiectasis was diagnosed at age seven. He displayed normal numbers of T, B, and NK cells but increased numbers of γδ T cells, but had, unlike patients with typical (X-)SCID, not required hematopoietic stem cell transplant. We studied the index patient’s IL2RG-mediated signaling and protein interactions. We detected abnormal plasma membrane targeting leading to reduced cell surface expression and IL2RG-mediated signaling. In the second original publication, we further characterized the expanded γδ T cell population of the index patient of the first original publication. We studied extensively the function and phenotype of these cells and found that they displayed normal IL2RG surface expression, intact IL2RG-mediated signaling, and enhanced killing ability. With IL2RG mRNA sequencing, we discovered a novel, second-site c.534C>A; p.(Phe178Leu) somatic reversion mosaicism restricted to patient’s γδ T cells only. Further studies with a human embryonic kidney cell line (HEK293) induced to express different IL2RG variants showed that this novel variant enhances the plasma membrane targeting of IL2RG, partly correcting defective plasma membrane targeting caused by the c. 172C>T;p.(Pro58Ser) variant. In the third original publication, we examined a Finnish cohort of 31 individuals carrying pathogenic NFKB1 variants. The cohort consisted of six families with five different NFKB1 variants. Contrary to previous reports, we observed high prevalence of autoinflammatory complications, low prevalence of hypogammaglobulinemia/common variable immunodeficiency, and incomplete penetrance even with advanced age. Frequently, patients with inflammation are assessed by other specialties. Our study was the first larger cohort in NFKB1 haploinsufficiency, where recruitment was based on family screening, not on screening of patients with antibody deficiency. This study shows that the spectrum of IEIs is ever broadening. Defining pathogenic mechanisms on genetic and molecular levels helps to guide treatment, screening, and genetic counseling. Determining genotype to phenotype associations requires studies both on molecular and population level, and international registries should be established and utilized in the process.
Originalspråkengelska
Handledare
  • Kere, Juha, Handledare
  • Seppänen, Mikko, Handledare
  • Grönholm, Juha, Handledare
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-9202-8
Elektroniska ISBN978-951-51-9203-5
StatusPublicerad - 2023
MoE-publikationstypG5 Doktorsavhandling (artikel)

Bibliografisk information

M1 - 120 s. + liitteet

Vetenskapsgrenar

  • 3111 Biomedicinska vetenskaper
  • 1184 Genetik, utvecklingsbiologi, fysiologi

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