AID and APOBECs span the gap between innate and adaptive immunity

Moris, Arnaud; Murray, Shannon Marie; Cardinaud, Sylvain

doi:10.3389/fmicb.2014.00534

Cited by 69 publications

(65 citation statements)

References 168 publications

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“…In addition, the IL-18 receptor subunit IL18R1 and activation-induced cytidine deaminase (AICD) genes were more highly expressed in CD4+ ILC1. Although the best characterized role for AICD is in B cell class switching, several reports also suggest that it is involved in innate antiviral immunity (53). These data indicate that a small set of genes do differentiate CD4+ from CD4− ILC1.…”

Section: Resultsmentioning

confidence: 99%

CD4+ Group 1 Innate Lymphoid Cells (ILC) Form a Functionally Distinct ILC Subset That Is Increased in Systemic Sclerosis

Roan

Stoklasek

Whalen

et al. 2016

The Journal of Immunology

107

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Innate lymphoid cells (ILC) are a heterogeneous group of cellular subsets that produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of antigen. In this study, we define distinct patterns of surface marker and cytokine expression among the ILC subsets that may further delineate their migration and function. Most notably, we found that the subset previously defined as ILC1 contains CD4+ CD8−, CD4− CD8+ and CD4− CD8− populations. Although all ILC1 subsets shared characteristics with Th1 cells, CD4+ ILC1 also demonstrated significant phenotypic and functional heterogeneity. We also show that the frequencies of CD4+ ILC1 and NKp44+ ILC3, but not CD4− ILC1 or ILC2, are increased in the peripheral blood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular pathology as well as immune dysregulation. Furthermore, we demonstrate that CD4+ and CD4− ILC1 are functionally divergent based on their IL-6Rα expression, and that the frequency of IL-6Rα expression on ILC is altered in SSc. The distinct phenotypic and functional features of CD4+ and CD4− ILC1 suggest that they may have differing roles in the pathogenesis of immune-mediated diseases such as systemic sclerosis.

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Section: Resultsmentioning

confidence: 99%

CD4+ Group 1 Innate Lymphoid Cells (ILC) Form a Functionally Distinct ILC Subset That Is Increased in Systemic Sclerosis

Roan

Stoklasek

Whalen

et al. 2016

The Journal of Immunology

107

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“…Although the nature and temporal development of the immune processes associated with the observed expression changes detected by GSEA are of great interest, this technique provides limited resolution to characterize the associated phenomena, and additional study is required. However, given the canonical function of APOBEC enzymes in the immune system (47,48), several potential mechanisms for this observation could be considered arising from either tumor or immune cell intrinsic effects of the A3B del polymorphism. The previously described association of A3B del with a somatic hypermutation phenotype (17) and recent interest in the relationship between somatic mutational burden and antitumor immune response prompted us to examine the differences in gene expression profiles between the hypermutated and nonhypermutated breast cancers.…”

Section: Discussionmentioning

confidence: 99%

APOBEC3Bexpression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Cescon

Haibe‐Kains

Mak

2015

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

124

121

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Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3B del ), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B del individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B del breast cancers, which seems to be related to hypermutation arising in A3B del carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B del require additional study, these findings nominate the A3B del polymorphism as a potential predictor for cancer immunotherapy.cancer | mutagenesis | cellular proliferation T he recent application of next generation sequencing technologies to characterize the landscape of somatic alterations in solid tumors has yielded major insights into the genes and pathways operant in various cancers. In addition, these studies have enabled the identification of distinct patterns of DNA base alterations that reflect underlying mutational processes (1-6). One of the major discoveries of this effort was the high prevalence of C > T transitions occurring in a preferred sequence motif (TCW, thymine/cytosine/adenine or thymine). This pattern is consistent with the deaminase activity of the AID/APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of enzymes, and thus, its identification invoked an endogenous mutator as a significant contributor to the somatic mutational burden across several cancer types (2-9). Based on the sequence motifs, expression levels, and subcellular localization of APOBEC family members, APOBEC3B (A3B) has been implicated as the likely mutator (6-8).Analyses of cell line and tumor datasets have shown that A3B gene expression is up-regulated in malignant vs. normal tissues and epithelial cell lines and have shown correl...

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“…However, it is possible that this partitioning is a relict of an ancient AID role against viral infections, played now by the APOBEC enzymes, which evolved from AID 122 . Cytoplasmic retention might have later evolved to minimize AID off-targeting activity in the nucleus.…”

Section: Keeping Aid Off-targeting Activity At Baymentioning

confidence: 99%

Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity

et al. 2016

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As B cells engage in the immune response they express the deaminase AID to initiate the hypermutation and recombination of immunoglobulin genes, which are crucial processes for the efficient recognition and disposal of pathogens, However, AID must be tightly controlled in B cells to minimize off-targeting mutations, which can drive chromosomal translocations and the development of B cell malignancies, such as lymphomas. Recent genomic and biochemical analyses have begun to unravel the crucial question of how AID-mediated deamination is targeted outside immunoglobulin genes. Here, we discuss the transcriptional and topological features that are emerging as key drivers of AID promiscuous activity.

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AID and APOBECs span the gap between innate and adaptive immunity

Cited by 69 publications

References 168 publications

CD4+ Group 1 Innate Lymphoid Cells (ILC) Form a Functionally Distinct ILC Subset That Is Increased in Systemic Sclerosis

CD4+ Group 1 Innate Lymphoid Cells (ILC) Form a Functionally Distinct ILC Subset That Is Increased in Systemic Sclerosis

APOBEC3Bexpression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity

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