RESUMO
Schimke immuno-osseous dysplasia is a rare multisystemic disorder caused by biallelic loss of function of the SMARCAL1 gene that plays a pivotal role in replication fork stabilization and thus DNA repair. Individuals affected from this disease suffer from disproportionate growth failure, steroid resistant nephrotic syndrome leading to renal failure and primary immunodeficiency mediated by T cell lymphopenia. With infectious complications being the leading cause of death in this disease, researching the nature of the immunodeficiency is crucial, particularly as the state is exacerbated by loss of antibodies due to nephrotic syndrome or immunosuppressive treatment. Building on previous findings that identified the loss of IL-7 receptor expression as a possible cause of the immunodeficiency and increased sensitivity to radiation-induced damage, we have employed spectral cytometry and multiplex RNA-sequencing to assess the phenotype and function of T cells ex-vivo and to study changes induced by in-vitro UV irradiation and reaction of cells to the presence of IL-7. Our findings highlight the mature phenotype of T cells with proinflammatory Th1 skew and signs of exhaustion and lack of response to IL-7. UV light irradiation caused a severe increase in the apoptosis of T cells, however the expression of the genes related to immune response and regulation remained surprisingly similar to healthy cells. Due to the disease's rarity, more studies will be necessary for complete understanding of this unique immunodeficiency.
Assuntos
Reparo do DNA , Osteocondrodisplasias , Doenças da Imunodeficiência Primária , Humanos , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/imunologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/imunologia , Reparo do DNA/genética , DNA Helicases/genética , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/genética , Linfócitos T/imunologia , Arteriosclerose/genética , Arteriosclerose/etiologia , Arteriosclerose/imunologia , Masculino , Feminino , Embolia Pulmonar/genética , Embolia Pulmonar/etiologia , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/genética , Transtornos do Crescimento/genética , Transtornos do Crescimento/etiologia , Raios Ultravioleta/efeitos adversos , Criança , Apoptose/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologiaRESUMO
The aim of this study was to investigate the impact of thymic dysplasia on the phenotypic and functional characteristics of T cells in patients with 22q11.2 deletion syndrome, including T-cell phenotype, transcriptional profile, cytokine production, as well as the possibility of utilizing IL-7 to recover their numbers and function. We found a strong bias towards Th1 response in pediatric and young adult 22q11.2DS patients, expansion of CXCR5+ follicular helper cells and CXCR3+CCR6- Th1 cells, increased production of cytokines IFN-γ, IL-10, IL-2, IL-21 and TNF-α. This Th1 skew was primarily driven by expanded terminally differentiated T cells. IL-7 further reduced naive T cells, increased cytokine production and caused an upregulation of exhaustion markers. Thus, Th1 bias in T cell populations persists from infancy into adolescence and is accompanied by accelerated maturation of T cells into memory stages. This phenotype is exacerbated by IL-7 which causes further decrease in naïve T cells in vitro.