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Inherited human c-REL deficiency disrupts adaptive immunity

ABSTRACT: Inherited human c-REL deficiency disrupts adaptive immunity

PROVIDER: PRJNA703721 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13758480_1.fastq.gz	Fastqsanger.gz
	SRR13758480_2.fastq.gz	Fastqsanger.gz
	SRR13758481_1.fastq.gz	Fastqsanger.gz
	SRR13758481_2.fastq.gz	Fastqsanger.gz
	SRR13758482_1.fastq.gz	Fastqsanger.gz

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Inherited human c-REL deficiency disrupts adaptive immunity

Project description:Various inborn errors of the canonical NF-kB pathway underlie different forms of human immunodeficiency. However, no patients with autosomal recessive complete deficiencies of RelA, c-REL, or NF-kB1, the three core members of the canonical NF-kB pathway, have yet been identified. We report a child homozygous for a loss-of-expression mutation of REL, encoding c-REL, which is expressed principally in myeloid and lymphoid cells. The distribution of myeloid subsets is normal in this patient, but in vitro-derived monocytes and cDC1s, unlike cDC2s, have impaired IL-12 and IL-23 production. The patient has low frequencies of memory CD4+ T cells, Th1*, Th2, Tregs, and almost no memory B cells. The frequencies of the other lymphoid subsets are normal. The patient’s naïve and memory CD4+ T cells produce only small amounts of IL-2, and the addition of this interleukin rescues their proliferation in response to mitogens, but not to antigens, in vitro. However, we found that HLA-syngeneic control cDCs rescued the proliferation of these cells in response to recall antigens. The production of key effector cytokines, such as IL-4, IL-17A, and IFNg, by memory CD4+ T cells was also highly impaired ex vivo, as was the differentiation of naïve CD4+ T cells into Th1 and Th17 cells in vitro. Both the survival and proliferation of the patient’s naïve B cells were found to be compromised, preventing B-cell differentiation into immunoglobulin (Ig)-secreting plasmablasts in vitro. As a consequence of this pleiotropic effect, this child suffered from severe viral, mycobacterial, fungal, and parasitic infections, while IgG substitution treatment prevented pyogenic infections. The immunological and infectious phenotypes were of hematopoietic origin, as they were cured by hematopoietic stem cell transplantation. Inherited human c-REL deficiency impairs multiple core functions of DCs, T cells, and B cells, thereby disrupting adaptive immunity to multiple infections.

2021-08-31 | GSE167185 | GEO

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents [EBV B-cells]

Project description:We investigated transcriptional responses following in vitro stimulation of EBV-B cells derived from a patient with inherited c-Rel deficiency.

2021-08-31 | GSE164345 | GEO

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents [primary T and B cells]

Project description:We investigated transcriptional responses following in vitro stimulation of peripheral blood naive CD4+ T cells and naive B cells obtained from a patient with inherited c-Rel deficiency. Samples from unrelated healthy donors and a patient with CD40 deficiency were analyzed for comparison.

2021-08-31 | GSE166872 | GEO

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents

Project description:Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents

| PRJNA702154 | ENA

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents [EBV B-cells]

Project description:Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents [EBV B-cells]

| PRJNA690078 | ENA

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.

Project description:We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

| S-EPMC8409595 | biostudies-literature

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents [primary T and B cells]

Project description:Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents [primary T and B cells]

| PRJNA702159 | ENA

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to a variety of infectious agents

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-08-31 | GSE166873 | GEO

Stepwise Neofunctionalization of c-Rel during Vertebrate Evolution (ChIP-Seq)

Project description:Adaptive immunity and the five vertebrate NF-kB/Rel family members first appeared in cartilaginous fish, suggesting that NF-kB family expansion allowed the acquisition of new functions to regulate adaptive immune responses. Transcriptome profiling revealed that, even in macrophages, the NF-kB family member, c-Rel, most potently regulates a cytokine gene linked to adaptive immunity, Il12b, with limiting roles at key regulators of innate immunity. Neofunctionalization of c-Rel to regulate Il12b depends on its unique DNA-binding properties, which we examined using structural, biochemical, functional, and genomic approaches. Among our findings was functional c-Rel homodimer binding to motifs with little resemblance to canonical NF-kB motifs. To determine whether c-Rel’s unique binding properties drove c-Rel-RelA divergence, we compared binding properties in various vertebrate species. c-Rel-RelA binding properties diverged in mammals and amphibians but were comparable in earlier vertebrates, suggesting that divergent DNA binding emerged relatively late during vertebrate evolution to support increasing complexity of adaptive immune regulation.

2023-11-29 | GSE243010 | GEO

Stepwise Neofunctionalization of c-Rel during Vertebrate Evolution (RNA-Seq)

2024-03-11 | GSE243011 | GEO