Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity?

Abstract

Multiple genome-wide association studies have shown that the single-nucleotide polymorphism (SNP) rs2281808 TT variant, present within the signal regulatory protein gamma (SIRPG) gene, is associated with autoimmune diseases, such as type 1 diabetes. SIRPγ is the only SIRP expressed on T cells. The role of SIRPγ in human T-cells or the effect of the TT variant are poorly understood. In this short report, we demonstrate the rather unusual finding that this intronic SNP is associated with a reduction of SIRPγ expression on T cells, both in healthy subjects as well as patients with type 1 diabetes. Using this information, we propose that a simple flow cytometric detection of SIRPγ could be a potential diagnostic testing approach for the presence of SNP in the appropriate clinical context.

Altered expression of SIRPγ on the T-cells of relapsing remitting multiple sclerosis and type 1 diabetes patients could potentiate effector responses from T-cells

“…SIRPγ staining on the T-cells of HD and T1D subjects has already been published before [8,11]. Representative staining of SIRPγ on T-cells of RRMS subjects including low vs. high SIRPγ gates is shown in Fig 2A. We found that overall SIRPγ expression on T-cells of RRMS and T1D patients was significantly lower than T-cells from HD irrespective of the rs2281808 genotype.…”

“…SIRPγ staining on the T-cells of HD and T1D subjects has already been published before [ 8 , 11 ]. Representative staining of SIRPγ on T-cells of RRMS subjects including low vs. high SIRPγ gates is shown in Fig 2A .…”

The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes

“…Nevertheless, we hypothesize that T1D-associated SNPs in the SIRPG locus contribute towards the decrease of SIRPγ expression on T cells and NK cells, potentially disrupting CD47 signaling and the downstream regulation that constrains the activation and proliferation of these subsets ( Figure 2B ). The impacts of T1D-associated SIRPG SNPs on T cell phenotype have been studied at the polyclonal level, but these observations must be validated in autoreactive islet-specific T cell clones ( 6 , 7 ). SIRPγ low CD8 + T cells isolated from healthy human donors demonstrated an effector gene signature characterized by increased TBX21 , EOMES , IFNG , and GZMB expression, and possessed lower activation thresholds, determined through anti-CD3 titration in vitro , as compared to SIRPγ high CD8 + T cells ( 6 ).…”

“…Among these variants, those associated with SIRPG (signal regulatory protein gamma), which encodes the receptor-like transmembrane protein SIRPγ, have been proposed to modulate T cell and natural killer (NK) cell activation ( 5 – 7 ). SIRPG contains two SNPs associated with risk for T1D ( 5 , 8 – 12 ): rs2281808 [C>T, intronic, minor allele frequency (MAF): 0.27, odds ratio (OR): 1.11] and rs6043409 (G>A, Ala263Val, MAF: 0.20, OR 1.13).…”

“…These processes may be augmented if SIRPα and/or CD47 expression are decreased. (B) SIRPγ and CD47 are co-expressed in T and natural killer (NK) cells ( 5 – 7 , 31 ). CD47 ligation is hypothesized to inhibit T and NK cell activation via inhibition of unknown downstream elements of the zeta chain of T cell receptor-associated protein kinase 70 (ZAP70) activation, inhibition phosphorylation of the mitogen-associated protein kinase (MEK), and inhibition of phosphorylation of the extracellular signal-regulated kinases (ERK) ( 26 , 34 – 37 ).…”