The Chemokine Receptor 5 Delta32 Polymorphism and Type 1 Diabetes, Behcet’s Disease, and Asthma: A Meta-analysis

IntroductionAutoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms.MethodsOur study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies.Results and conclusionsThe results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune response, but rather representing various events related to the formation of specific pathophysiological environment. Thus, our data suggest that while all of the studied diseases are affected by activation of common inflammatory processes, disease-specific variations in their relative balance are also identified.

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“…MS shares similarities with neurological manifestations of BD [ 55 ]. BD in turn has been reported to accompany T1D [ 56 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles

et al. 2017

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“…This variant has been strongly and repeatedly associated with resistance to HIV infection and slower HIV progression, as CCR5 is a common coreceptor for HIV entry into T-lymphocytes 16 . The CCR5 d32 allele has been suggested to confer a reduced risk of asthma in children in one study 17 although this has not been replicated 18 , 19 .…”

Section: Introductionmentioning

confidence: 95%

Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function

Adewoye¹,

Shrine²,

Odenthal-Hesse³

et al. 2018

Wellcome Open Res

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The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. We directly measured the complex structural variation of using the Paralogue Ratio Test and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for from the 1000 Genomes Project. We confirmed the gene dosage effect of copy number on mRNA expression levels. We found no evidence for association of copy number or CCR5del32 genotype with lung function. These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

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“…The meta-analysis included fourteen studies of which six were representative of T1DM and three of asthma. In relation to T1DM, CCR5∆32 was considered a protective factor while no association of CCR5∆32 with asthma susceptibility was found [114].…”

Section: Immune System Diseasesmentioning

confidence: 98%

“…The authors finally reported CCR5∆32 to be associated with protection regarding clinical course, but not disease susceptibility [113]. In a meta-analysis conducted using a mixed population, Song et al [114] aimed to investigate the role of CCR5∆32 in diabetes and asthma disease susceptibility. The meta-analysis included fourteen studies of which six were representative of T1DM and three of asthma.…”

Section: Immune System Diseasesmentioning

confidence: 99%

Metabolomics as an Approach to Characterise the Contrasting Roles of CCR5 in the Presence and Absence of Disease

Rautenbach

Williams

2020

IJMS

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Chemokine receptors such as C-C chemokine receptor 5 (CCR5) are activated through interaction with their ligands and are well known for their role in chemotaxis and signal transduction. While serving these roles, cellular responses are effected, hence the immune function of these molecules is established. Given the role of CCR5 in immune function and that the immune and metabolic systems are interlinked, subsequent immune-directed changes should be measurable at a metabolic level. Numerous investigations have reported on metabolic changes associated with CCR5 status in the presence of disease, so as to understand whether specific CCR5 genotypes, frequency and/or levels offer protection to the host or not. However, these metabolic changes were recorded using older conventional techniques. Depending on certain factors such as the disease model, the geography of the samples and/or the ethnic group under study, the role of CCR5 in disease differs. In addition, little is known about CCR5’s role in the absence of an enhanced inflammatory state, such as when infection persists. Metabolomics is defined as the study of metabolites and informs on metabolic changes within living organisms as induced by various stimuli, such as the interaction of CCR5 with its ligand. Since metabolomics reflects the underlying biochemical activity and state of cells/tissues, this review proposes it as a tool to clarify the contrasting roles of CCR5.

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The Chemokine Receptor 5 Delta32 Polymorphism and Type 1 Diabetes, Behcet’s Disease, and Asthma: A Meta-analysis

Abstract: This meta-analysis demonstrates that the CCR5-Δ32 polymorphism acts as a protective factor in T1D development in Europeans, and a risk factor for BD among HLA-B51 carriers. However, no association was found between the CCR5-Δ32 polymorphism and asthma.

Cited by 17 publications

References 36 publications

Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles

Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles

Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function

Metabolomics as an Approach to Characterise the Contrasting Roles of CCR5 in the Presence and Absence of Disease

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