Is the CCR5 Δ 32 Mutation Associated with Immune System-Related Diseases?

Abstract

Hypersensitivity and autoimmunity are the main features of immune system-related diseases such as type 2 diabetes (T2D), multiple sclerosis (MS), and asthma. It has been established that chemokines play key roles in the activation and regulation of immune cell migration which is important in the pathogenesis of the diseases mentioned. CC chemokines receptor 5 or CCR5 is a receptor for RANTES, MIP-1α, and MIP-1β and is expressed by several immune cells including NK cells, T lymphocytes, and macrophages. It plays key roles in the regulation of migration and activation of the immune cells during immune responses against microbe and self-antigens during autoimmunity and hypersensitivity disorders. Therefore, any alteration in the sequence of CCR5 gene or in its expression could be associated with immune system-related diseases. Previous studies revealed that a 32-base pair deletion (Δ 32) in exon 1 of the CCR5 gene led to downregulation of the gene. Previous studies demonstrated that not only CCR5 expression was altered in autoimmune and hypersensitivity disorders, but also that the mutation is associated with the diseases. This review addresses the recent information regarding the association of the CCR5 Δ 32 mutation in immune-related diseases including T2D with and without nephropathy, MS, and asthma. Based on the collected data, it seems that the CCR5 Δ 32 mutation can be considered as a risk factor for MS, but not asthma and T2D with and without nephropathy.

CCR5Δ32 (rs333) polymorphism is associated with the susceptibility to systemic lupus erythematosus in female Brazilian patients

“…CCR5 is a receptor expressed by several immune cells and is upregulated by proinflammatory cytokines [4]. In SLE, the inflammatory process is initiated by lymphocytic infiltration into tissue spaces, and the biological distribution of lymphocytes appears to be determined by the expression of chemokines receptors, including CCR5 [35,36].…”

“…In the absence of CCR5 +/+ cells, CCL3, CCL4, and CCL5 can induce the recruitment of pathogenic monocytes and T cells via the activation of their alternate receptor, CCR3 and CCR1, which is abundantly expressed on these cell types [4,42]. This augmented CCR1-and CCR3-dependent infiltration of immune cells can lead to the exacerbate tissue injury, as shown in models of hepatic and renal inflammation [41].…”

“…The SLE etiology is multifactorial with an involvement of genetic and environmental factors and chemokines, and their receptors are implicated in the pathogenesis of the chronic inflammatory processes of the disease [4][5][6].…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…Moreover, individuals with this mutation appear to be otherwise healthy apart from an as yet unconfirmed increase in susceptibility to West Nile infection [214] and hepatitis B virus infection [215] . These statements have raised the concern of whether CCR5 is implicated in immune system-related diseases [216] . An interesting discussion in this topic can be read in [217] .…”

Specificity for a CCR5 Inhibitor Is Conferred by a Single Amino Acid Residue

“…CCR5 has thus been implicated in the pathophysiology of numerous inflammatory diseases including rheumatoid arthritis, multiple sclerosis, psoriasis, atherosclerosis, and hepatitis (35,47,48). Several studies attempted to link CCR5 to several of these diseases by looking for an association with the CCR5⌬32 deletion, which results in a truncated receptor that does not get expressed on the cell surface (49). Results from these studies are inconsistent and generally have failed to show a relationship with this CCR5 polymorphism.…”