Analysis of Ancestral and Functionally Relevant CD5 Variants in Systemic Lupus Erythematosus Patients

Cenit, María Carmen; Martínez-Florensa, Mario; Consuegra, Marta; Bonet, Lizette; Carnero‐Montoro, Elena; Armiger, Noelia; Caballero-Baños, Miguel; Arias, M.; Benitez, Daniel; Ortego-Centeno, Norbérto; Enrique, Rafael; Sabio, José Mario; García–Hernández, Francisco J.; Tolosa, Carles; Bosch, Elena; Martı́n, Javier; Lozano, Francisco

doi:10.1371/journal.pone.0113090

Cited by 16 publications

(28 citation statements)

References 47 publications

(57 reference statements)

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“…The second study evaluated two cohorts of melanoma patients and again showed a higher survival rate in those carrying the ancestral haplotype in homozygosis [68]. These findings were in agreement with previous work [69] reporting that the ancestral A471 variant translated into a lymphocyte hyper-responsiveness after TCR/CD3 crosslinking, reflected by higher thymidine incorporation and IL-2 and IFNγ release. This phenotype led to a worse autoimmune prognosis.…”

Section: Cd5 In Cancer Immunotherapysupporting

confidence: 86%

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

et al. 2017

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Scavenger receptors (SRs) are structurally heterogeneous cell surface receptors characterized by their capacity to remove extraneous or modified self-macromolecules from circulation, thus avoiding the accumulation of noxious agents in the extracellular space. This scavenging activity makes SRs important molecules for host defense and homeostasis. In turn, SRs keep the activation of the steady-state immune response in check, and participate as co-receptors in the priming of the effector immune responses when the macromolecules are associated with a threat that might compromise host homeostasis. Therefore, SRs built up sophisticated sensor mechanisms controlling the immune system, which may be exploited to develop novel drugs for cancer immunotherapy. In this review, we focus on the regulation of the anti-tumor immune response by two paradigmatic SRs: the lymphocyte receptor CD5 and the more broadly distributed scavenger receptor class B type 1 (SR-B1). Cancer immunity can be boosted by blockade of SRs working as immune checkpoint inhibitors (CD5) and/or by proper engagement of SRs working as innate danger receptor (SR-B1). Thus, these receptors illustrate both the complexity of targeting SRs in cancer immunotherapy and also the opportunities offered by such an approach. Keywords:Cancer immunotherapy r CD5 r Danger signal r Immune-checkpoint r Scavenger receptor r Scavenger receptor class B type 1 r Toll-like receptors IntroductionThe cancer-immunity cycle can be subverted by tumors at many steps, thus novel therapeutic interventions should be considered for all these possibilities [1]. This cycle starts with the release of tumor antigens and their subsequent capture by professional antigen-presenting cells (mainly, dendritic cells; DCs) for the activation of effector cells of the innate and adaptive immune Correspondence: Dr. Pedro Berraondo e-mail: pberraondol@unav.es system. This is a highly regulated process aimed at maintaining the integrity of the host without inducing significant side effects (e.g., inflammation or autoimmunity) [2]. Tissue homeostasis involves phagocytic processes to remove the excess of native or modified molecules from unviable or stressed cells, as well as from invading microbial agents [3]. Such molecules include lipids, whose intracellular levels should be carefully controlled to sustain proper cell metabolism; endogenous glyco-and lipo-proteins, damaged or * These authors contributed equally to this work. * * These authors are senior co-authors of this work. [4,5]. This phagocytic activity should be coupled to an alarm signal system that awakens other effector mechanisms of the immune system when the tissue damage cannot be controlled by the removal of the endogenous or exogenous molecules. To this end, the immune system has a myriad of specialized soluble or membrane-bound receptors called pattern recognition receptors (PRRs). These PRRs are non-polymorphic, nonclonally distributed, and germ-line encoded receptors recognizing microorganism-associated molecular patterns (MAMPs) -tha...

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Section: Cd5 In Cancer Immunotherapysupporting

confidence: 86%

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

et al. 2017

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“…Although little is known about the role of this SNP in CD5‐mediated functions, recent data have shown that B‐CLL patients that bare an ancestral haplotype with a proline instead of a leucine at position 224 (P224L) and an alanine instead of a valine at position 471 (A471V) present better prognosis and longer lifespan, and the same has been reported in melanoma patients . In this context, this SNP also appears to be biologically relevant in T cells, as suggested by a recent report showing that T lymphocytes carrying the ancestral 471 alanine have an enhanced proliferation and produce increased levels of IL‐2 and IFN‐γ when stimulated with anti‐CD3 antibodies …”

Section: Role Of Cd5 In B Cell Immunobiologymentioning

confidence: 86%

The multiple faces of CD5

Burgueño‐Bucio

Mier‐Aguilar

Soldevila

2019

Journal of Leukocyte Biology

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Since its discovery, over 30 years ago, CD5 has been used as a marker to identify T cells, B1‐a cells, and B cell chronic lymphocytic leukemia cells. Throughout the years, many studies have described the functional relevance of CD5 as a modulator of T and B cell receptor signaling. However, it has not been until recent years that CD5 has emerged as a functional receptor in other areas of the immune system. Here, we review some of the most important aspects of CD5 as a modulator of TCR and BCR signaling, cell survival receptor both in T and B cells during health and disease, as well as the newly discovered roles of this receptor in thymocyte selection, T cell effector differentiation, and immune tolerance. CD5 was found to promote T cell survival by protecting autoreactive T cell from activation‐induced cell death, to promote de novo induction of regulatory T cells in the periphery, to modulate Th17 and Th2 differentiation, and to modulate immune responses by modulating dendritic cell functions. CD5 is overexpressed in Tregs and Bregs, which are fundamental to maintain immune homeostasis. The newly established roles of CD5 in modulating different aspects of immune responses identify this receptor as an immune checkpoint modulator, and therefore it could be used as a target for immune intervention in different pathologies such as cancer, autoimmune diseases or infections.

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“…The rs2229177 variants together with another frequent SNP coding for a Pro to Leu substitution at the extracellular region of CD5 (rs2241002, NM_014207.3:c.671C > T, p.Pro224Leu) constitute different haplotypes, one of which (Pro224‐Val471) has been positively selected in East Asian populations . Functional analyses reveal that homozygous carriers of the ancestral Pro224‐Ala471 (CC) haplotype present higher in vitro T cell proliferative responses and a more severe clinical form of Systemic Lupus Erythematosus compared to homozygous individuals for the more recently derived Pro224‐Val471 (CT) haplotype . This finding suggests a link between differential regulation of T‐cell signaling by CD5 variants and distinct autoimmune disease outcome.…”

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confidence: 99%

Inherited functional variants of the lymphocyte receptor CD5 influence melanoma survival

Potrony

Carreras

Aranda

et al. 2016

Intl Journal of Cancer

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Despite the recent progress in treatment options, malignant melanoma remains a deadly disease. Besides therapy, inherited factors might modulate clinical outcome, explaining in part widely varying survival rates. T-cell effector function regulators on antitumor immune responses could also influence survival. CD5, a T-cell receptor inhibitory molecule, contributes to the modulation of antimelanoma immune responses as deduced from genetically-modified mouse models. The CD5 SNPs rs2241002 (NM_014207.3:c.671C>T, p.Pro224Leu) and rs2229177 (NM_014207.3:c.1412C>T, p.Ala471Val) constitute an ancestral haplotype (Pro224-Ala471) that confers T-cell hyper-responsiveness and worsens clinical autoimmune outcome. The assessment of these SNPs on survival impact from two melanoma patient cohorts (Barcelona, N=493 and Essen, N=216) reveals that p.Ala471 correlates with a better outcome (OR= 0.57, 95% CI=0.33-0.99, Adj. P=0.043, in Barcelona OR=0.63, 95% CI=0.40-1.01, Adj. P=0.051, in Essen). While, p.Leu224 was associated with increased melanoma-associated mortality in both cohorts (OR=1.87, 95% CI=1.07-3.24, Adj. P=0.030 in Barcelona and OR=1.84, 95% CI=1.04-3.26, Adj. P=0.037, in Essen). Furthermore survival analyses showed that the Pro224-Ala471 haplotype in homozygosis improved melanoma survival in the entire set of patients (HR=0.27, 95% CI 0.11 to 0.67, Adj. P=0.005). These findings highlight the relevance of genetic variability in immune-related genes for clinical outcome in melanoma.

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Analysis of Ancestral and Functionally Relevant CD5 Variants in Systemic Lupus Erythematosus Patients

Cited by 16 publications

References 47 publications

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

The multiple faces of CD5

Inherited functional variants of the lymphocyte receptor CD5 influence melanoma survival

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