Absence of γ-Chain in Keratinocytes Alters Chemokine Secretion, Resulting in Reduced Immune Cell Recruitment

Nowak, Karolin; Linzner, Daniela; Thrasher, Adrian J.; Lambert, Paul F.; Di, Wei; Burns, Siobhan O.

doi:10.1016/j.jid.2017.05.024

Cited by 13 publications

(13 citation statements)

References 59 publications

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“…One hypothesis attributes the intrinsic defect of keratinocytes to the lack of HPV clearance. A keratinocyte cell line deficient for IL2RG showed a reduced chemokine response after IL-15 stimulation, resulting in reduced dendritic and CD4 T-cell migration [40]. This hypothesis is in agreement with the low frequency of overlapping CD8 clonotypes in wart + skin.…”

Section: Discussionsupporting

confidence: 80%

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

et al. 2022

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The first successful European hematopoietic stem cell transplantation (HSCT) was performed in 1968 as treatment in a newborn with IL2RG deficiency using an HLA-identical sibling donor. Because of declining naive T and natural killer (NK) cells, and persistent human papilloma virus (HPV)-induced warts, the patient received a peripheral stem cell boost at the age of 37 years. NK and T cells were assessed before and up to 14 years after the boost by flow cytometry. The boost induced renewed reconstitution of functional NK cells that were 14 years later enriched for CD56dimCD27+ NK cells. T-cell phenotype and T-cell receptor (TCR) repertoire were simultaneously analyzed by including TCR Vβ antibodies in the cytometry panel. Naive T-cell numbers with a diverse TCR Vβ repertoire were increased by the boost. Before and after the boost, clonal expansions with a homogeneous TIGIT and PD-1 phenotype were identified in the CD27− and/or CD28− memory population in the patient, but not in the donor. TRB sequencing was applied on sorted T-cell subsets from blood and on T cells from skin biopsies. Abundant circulating CD8 memory clonotypes with a chronic virus-associated CD57+KLRG1+CX3CR1+ phenotype were also present in warts, but not in healthy skin of the patient, suggesting a link with HPV. In conclusion, we demonstrate in this IL2RG-deficient patient functional NK cells, a diverse and lasting naive T-cell compartment, supported by a stem cell boost, and an oligoclonal memory compartment half a century after HSCT.

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Section: Discussionsupporting

confidence: 80%

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

et al. 2022

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“…32106). In addition, primary keratinocytes were isolated from skin biopsy and cultured as described in Nowak et al (68). Coimmunoprecipitation studies were conducted as described above with the amendment of 500 μg of protein lysate, 2 μg of NOP10 antibody (Abcam, catalog no.…”

Section: Methodsmentioning

confidence: 99%

Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis

Balogh

Chandler

Varga

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations inDKC1,NOP10, orNHP2cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males withDKC1p.Glu206Lys and two children with homozygousNOP10p.Thr16Met. Females with heterozygousDKC1p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin–NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin–NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafishdkc1mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.

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“…That led us to hypothesize that seroconversion failure to intradermal vaccine is also due to mutated keratinocytes in the skin, with impaired chemotactic functions, not corrected by HSCT. 37,38 This finding suggests that while intradermal vaccination may enhance seroconversion in most immunocompromised vaccinees, X-SCID patients who underwent HSCT may not benefit from intradermal vaccination.…”

Section: Discussionmentioning

confidence: 99%

Safety and Immunogenicity of 3 Doses of BNT162b2 and CoronaVac in Children and Adults with Inborn Errors of Immunity

Leung

Duque

et al. 2022

Preprint

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Background Safety and immunogenicity of 3 doses of BNT162b2 and CoronaVac in adult and pediatric patients with inborn errors of immunity (IEIs) remain unknown. Intradermal vaccination may improve immunogenicity in immunocompromised patients. Our study (NCT04800133) aimed to determine the safety and immunogenicity in patients with IEIs receiving a 3-dose primary series of mRNA vaccine BNT162b2 (age 12+) or inactivated whole-virion vaccine CoronaVac (age 3+) in Hong Kong, including Omicron BA.1 neutralization, in a nonrandomized manner. Intradermal vaccination was also studied. Methods Thirty-nine patients were vaccinated, including 16 with homologous intramuscular 0.3ml BNT162b2 and 17 with homologous intramuscular 0.5ml CoronaVac. Two patients received 3 doses of intradermal 0.5ml CoronaVac, and 4 patients received 2 doses of intramuscular BNT162b2 and the third dose with intradermal BNT162b2. Adverse reactions and adverse events were tracked for 7 and 28 days after each dose. Antibody responses assessed included binding IgG antibody to wild-type (WT) spike receptor-binding domain (S-RBD IgG) and surrogate neutralization activity to WT and BA.1 viruses. T cell responses were examined by intracellular cytokine staining following stimulation with SARS-CoV-2 peptide pool(s). Results No safety concerns were identified. Inadequate antibody responses were found after 2 doses in patients with humoral immunodeficiencies and especially so against BA.1. Dose 3 of either vaccine increased S-RBD IgG response. T cell responses against SARS-CoV-2 antigens were detected in vaccinated IEI patients. Intradermal third dose vaccine led to high antibody response in 4 patients. Conclusions The primary vaccination series of BNT162b2 and CoronaVac in adults and children with IEIs should include 3 doses for optimal immunogenicity.

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Absence of γ-Chain in Keratinocytes Alters Chemokine Secretion, Resulting in Reduced Immune Cell Recruitment

Cited by 13 publications

References 59 publications

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis

Safety and Immunogenicity of 3 Doses of BNT162b2 and CoronaVac in Children and Adults with Inborn Errors of Immunity

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