CCR5Δ32 – A piece of protection in the inflammatory puzzle of multiple sclerosis susceptibility

Troncoso, Lian L.; Pontillo, Alessandra; Oliveira, Enedina Maria Lobato de; Finkelszteijn, Alessandro; Schneider, Silvete Maria Brandão

doi:10.1016/j.humimm.2018.04.015

Cited by 9 publications

(9 citation statements)

References 56 publications

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“…Subsequently, Troncoso et al (173) described a statistically significant higher CCR5D32 allele frequency in Euro-Brazilian controls (7.4%) compared to Euro-Brazilian patients (3.3%), suggesting a protective role of the variant on the development of multiple sclerosis. Besides, the frequency of the CCR5D32 was higher in Euro-Brazilian patients with progressive multiple sclerosis than Euro-Brazilian patients with relapse remitting multiple sclerosis (173). Both studies carried out in Brazil show that the CCR5D32 variant can influence both the susceptibility and the clinical outcome of multiple sclerosis.…”

Section: Ccr5d32 In Inflammatory Conditionsmentioning

confidence: 98%

“…Based on magnetic resonance imaging, Kaimen-Maciel et al (172) observed a decreased disease progression in patients bearing the CCR5D32 allele (172). Subsequently, Troncoso et al (173) described a statistically significant higher CCR5D32 allele frequency in Euro-Brazilian controls (7.4%) compared to Euro-Brazilian patients (3.3%), suggesting a protective role of the variant on the development of multiple sclerosis. Besides, the frequency of the CCR5D32 was higher in Euro-Brazilian patients with progressive multiple sclerosis than Euro-Brazilian patients with relapse remitting multiple sclerosis (173).…”

Section: Ccr5d32 In Inflammatory Conditionsmentioning

confidence: 99%

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CCR5Δ32 in Brazil: Impacts of a European Genetic Variant on a Highly Admixed Population

Kulmann-Leal

Ellwanger

2021

Front. Immunol.

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The genetic background of Brazilians encompasses Amerindian, African, and European components as a result of the colonization of an already Amerindian inhabited region by Europeans, associated to a massive influx of Africans. Other migratory flows introduced into the Brazilian population genetic components from Asia and the Middle East. Currently, Brazil has a highly admixed population and, therefore, the study of genetic factors in the context of health or disease in Brazil is a challenging and remarkably interesting subject. This phenomenon is exemplified by the genetic variant CCR5Δ32, a 32 base-pair deletion in the CCR5 gene. CCR5Δ32 originated in Europe, but the time of origin as well as the selective pressures that allowed the maintenance of this variant and the establishment of its current frequencies in the different human populations is still a field of debates. Due to its origin, the CCR5Δ32 allele frequency is high in European-derived populations (~10%) and low in Asian and African native human populations. In Brazil, the CCR5Δ32 allele frequency is intermediate (4-6%) and varies on the Brazilian States, depending on the migratory history of each region. CCR5 is a protein that regulates the activity of several immune cells, also acting as the main HIV-1 co-receptor. The CCR5 expression is influenced by CCR5Δ32 genotypes. No CCR5 expression is observed in CCR5Δ32 homozygous individuals. Thus, the CCR5Δ32 has particular effects on different diseases. At the population level, the effect that CCR5Δ32 has on European populations may be different than that observed in highly admixed populations. Besides less evident due to its low frequency in admixed groups, the effect of the CCR5Δ32 variant may be affected by other genetic traits. Understanding the effects of CCR5Δ32 on Brazilians is essential to predict the potential use of pharmacological CCR5 modulators in Brazil. Therefore, this study reviews the impacts of the CCR5Δ32 on the Brazilian population, considering infectious diseases, inflammatory conditions, and cancer. Finally, this article provides a general discussion concerning the impacts of a European-derived variant, the CCR5Δ32, on a highly admixed population.

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Section: Ccr5d32 In Inflammatory Conditionsmentioning

confidence: 98%

Section: Ccr5d32 In Inflammatory Conditionsmentioning

confidence: 99%

CCR5Δ32 in Brazil: Impacts of a European Genetic Variant on a Highly Admixed Population

Kulmann-Leal

Ellwanger

2021

Front. Immunol.

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“…2). The disease course has been reported to be less severe in carriers of the CCR5Δ32 allele, although contrasting results have been reported on the association between CCR5Δ32 and MS risk [99–101]. Both CCR2 and CCR5 are highly expressed within and around active MS lesions, mainly in infiltrating T cells and macrophages, and in resident microglia [99, 102].…”

Section: Ccr5 and Ccr2/ccl2 In The Pathogenesis Of Msmentioning

confidence: 99%

Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders

Fantuzzi

Tagliamonte

Gauzzi

et al. 2019

Cell. Mol. Life Sci.

111

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The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/ macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.

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“…However, recently the research involving the influence of CCR5 on different conditions has been intensified. Such studies address the CCR5 molecule per se (Castanheira et al, 2019; Jiao et al, 2018; Liu et al, 2018; Umansky, Blattner, Gebhardt, & Utikal, 2017), CCR5 pharmacological blockade (Moy et al, 2017; Pervaiz et al, 2019), CCR5 gene editing (Xie, Zhan, Ge, & Tang, 2019) and the genetic variant CCR5Δ32 (Fatima et al, 2019; Kaminski, Ellwanger, Sandrim, Pontillo, & Chies, 2019; Kletenkov et al, 2019; Słomiński et al, 2017; Toson et al, 2017; Troncoso et al, 2018). The resurgence of research involving these different aspects of CCR5 is due to two main factors: the advancement of gene‐editing technologies, which allow the exploration of the metabolic and pathophysiological effects of CCR5 editing (Allen et al, 2018; Qi et al, 2018; Vangelista & Vento, 2018; Xu et al, 2017), and the development of CCR5 blockers for clinical use (Vangelista & Vento, 2018).…”

Section: Introductionmentioning

confidence: 99%

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

Ellwanger

Kaminski

Rodrigues

et al. 2020

Int J Immunogenetics

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The CCR5 molecule was reported in 1996 as the main HIV‐1 co‐receptor. In that same year, the CCR5Δ32 genetic variant was described as a strong protective factor against HIV‐1 infection. These findings led to extensive research regarding the CCR5, culminating in critical scientific advances, such as the development of CCR5 inhibitors for the treatment of HIV infection. Recently, the research landscape surrounding CCR5 has begun to change. Different research groups have realized that, since CCR5 has such important effects in the chemokine system, it could also affect other different physiological systems. Therefore, the effect of reduced CCR5 expression due to the presence of the CCR5Δ32 variant began to be further studied. Several studies have investigated the role of CCR5 and the impacts of CCR5Δ32 on autoimmune and inflammatory diseases, various types of cancer, and viral diseases. However, the role of CCR5 in diseases caused by bacteria and parasites is still poorly understood. Therefore, the aim of this article is to review the role of CCR5 and the effects of CCR5Δ32 on bacterial (brucellosis, osteomyelitis, pneumonia, tuberculosis and infection by Chlamydia trachomatis) and parasitic infections (toxoplasmosis, leishmaniasis, Chagas disease and schistosomiasis). Basic information about each of these infections was also addressed. The neglected role of CCR5 in fungal disease and emerging studies regarding the action of CCR5 on regulatory T cells are briefly covered in this review. Considering the “renaissance of CCR5 research,” this article is useful for updating researchers who develop studies involving CCR5 and CCR5Δ32 in different infectious diseases.

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CCR5Δ32 – A piece of protection in the inflammatory puzzle of multiple sclerosis susceptibility

Cited by 9 publications

References 56 publications

CCR5Δ32 in Brazil: Impacts of a European Genetic Variant on a Highly Admixed Population

CCR5Δ32 in Brazil: Impacts of a European Genetic Variant on a Highly Admixed Population

Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

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