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Epigenetic Priming in Immunodeficiencies.

ABSTRACT: Immunodeficiencies (IDs) are disorders of the immune system that increase susceptibility to infections and cancer, and are therefore associated with elevated morbidity and mortality. IDs can be primary (not caused by other condition or exposure) or secondary due to the exposure to different agents (infections, chemicals, aging, etc.). Most primary immunodeficiencies (PIDs) are of genetic origin, caused by mutations affecting genes with key roles in the development or function of the cells of the immune system. A large percentage of PIDs are associated with a defective development and/or function of lymphocytes and, especially, B cells, the ones in charge of generating the different types of antibodies. B-cell development is a tightly regulated process in which many different factors participate. Among the regulators of B-cell differentiation, a correct epigenetic control of cellular identity is essential for normal cell function. With the advent of next-generation sequencing (NGS) techniques, more and more alterations in different types of epigenetic regulators are being described at the root of PIDs, both in humans and in animal models. At the same time, it is becoming increasingly clear that epigenetic alterations triggered by the exposure to environmental agents have a key role in the development of secondary immunodeficiencies (SIDs). Due to their largely reversible nature, epigenetic modifications are quickly becoming key therapeutic targets in other diseases where their contribution has been known for more time, like cancer. Here, we establish a parallelism between IDs and the nowadays accepted role of epigenetics in cancer initiation and progression, and propose that epigenetics forms a "third axis" (together with genetics and external agents) to be considered in the etiology of IDs, and linking PIDs and SIDs at the molecular level. We therefore postulate that IDs arise due to a variable contribution of (i) genetic, (ii) environmental, and (iii) epigenetic causes, which in fact form a continuum landscape of all possible combinations of these factors. Additionally, this implies the possibility of a fully epigenetically triggered mechanism for some IDs. This concept would have important prophylactic and translational implications, and would also imply a more blurred frontier between primary and secondary immunodeficiencies.

SUBMITTER: Martinez-Cano J

PROVIDER: S-EPMC6635466 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Epigenetic Priming in Immunodeficiencies.

Martínez-Cano Jorge J Campos-Sánchez Elena E Cobaleda César C

Frontiers in cell and developmental biology 20190710

Immunodeficiencies (IDs) are disorders of the immune system that increase susceptibility to infections and cancer, and are therefore associated with elevated morbidity and mortality. IDs can be primary (not caused by other condition or exposure) or secondary due to the exposure to different agents (infections, chemicals, aging, etc.). Most primary immunodeficiencies (PIDs) are of genetic origin, caused by mutations affecting genes with key roles in the development or function of the cells of the ...[more]

PMID: 31355198

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.ResultsAmong 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR.ConclusionEpigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.Trial registrationClinicalTrials.gov NCT02901899.FundingUS Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.

Project description:BackgroundEosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia.MethodsA retrospective PubMed, and Google Scholar search using the terms "eosinophilia" and "every individual PID" as classified by Expert Committee of the International Union of Immunological Societies with the limit of the English language was performed. Results were assessed to capture case(s) which reported eosinophilia in the context of PID conditions. Absolute eosinophil counts (AEC) were retrieved from manuscripts whenever reported.ResultsIn addition to the typical PID conditions described with eosinophilia, we document that MHC class II deficiency, CD3γ deficiency, STAT1 deficiency (AD form), Kostmann disease, cyclic neutropenia, TCRα deficiency, Papillon-Lefevre syndrome, CD40 deficiency, CD40L deficiency, anhidrotic ectodermal dysplasia with immune deficiency, ataxia-telangiectasia, common variable immunodeficiency disorders (CVID), Blau syndrome, CARD9 deficiency, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA), chronic granulomatous disease, MALT1 deficiency and Roifman syndrome have been noted to have elevated eosinophils. Severe eosinophilia (>5.0 × 10(9)/L) was reported in Omenn syndrome, Wiskott Aldrich syndrome, ADA deficiency, autoimmune lymphoproliferative syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked, STAT3 deficiency, DOCK8 deficiency, CD40 deficiency, MHC II deficiency, Kostmann disease, Papillon-Lefevre syndrome, and CVID.ConclusionsThis literature review shows that there is an extensive list of PIDs which have been reported with eosinophilia. This list helps clinicians to consider an extended differential diagnoses when tasked with exclusion of PID as a cause for eosinophilia.

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Epigenetic Priming in Immunodeficiencies.

Publications

Epigenetic Priming in Immunodeficiencies.

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