High Risk First Degree Relatives of Type 1 Diabetics: An Association with Increases in CXCR3⁺T Memory Cells Reflecting an Enhanced Activity of Th1 Autoimmune Response

Abstract

We analyzed the level of (a) CXCR3+ (Th1) and CCR4+ (Th2) T memory cells (b) interferon-γ inducible chemokine (IP-10)(Th1) and thymus and activation-regulated chemokine (TARC)(Th2), in 51 first degree relatives (FDRs) of type 1 diabetics (T1D) (17 high risk FDRs (GADA+, IA-2+) and 34 low risk FDRs (GADA−, IA-2−)), 24 recent-onset T1D (R-T1D), and 18 healthy subjects. T memory subsets were analyzed by using four-color immunofluorescence staining and flowcytometry. IP-10 and TARC were determined by ELISA. High risk FDRs showed higher levels of CXCR3+ and lower level of CCR4+ T memory cells compared to low risk FDRs (64.98 ± 5.19 versus 42.13 ± 11.11; 29.46 ± 2.83 versus 41.90 ± 8.58%, resp., P < 0.001). Simultaneously, both IP-10 and TARC levels were increased in high risk versus low risk FDRs (160.12 ± 73.40 versus 105.39 ± 71.30; 438.83 ± 120.62 versus 312.04 ± 151.14 pg/mL, P < 0.05). Binary logistic regression analysis identified the level of CXCR3+ T memory cells as predictors for high risk FDRs, together with high levels of IP-10. The results imply that, in FDRs, the risk for T1D might be strongly influenced by enhanced activity of Th1 and diminished activity of Th2 autoimmune response.

Human immune phenotyping reveals accelerated aging in type 1 diabetes

“…Findings from murine models corroborate a role for CXCR3 in T cell trafficking to the islets and autoimmune diabetes development (76), indicating Th1 skewing as a globally dysregulated phenotype in T1D. Higher CXCR3 + memory T cell frequencies were shown in high-risk AAb+ REL compared with low-risk relatives (77), suggesting linkage to disease processes (77). CXCR3 + naive T cells are reportedly enriched in autoreactivity in mice and are thought to contain higher affinity (CD5 hi ) autoreactive TCRs (78).…”

Human immune phenotyping reveals accelerated aging in type 1 diabetes

“…Findings from murine models corroborate a role for CXCR3 in T cell trafficking to the islets and autoimmune diabetes development (76), indicating this Th1-skewing as a globally dysregulated phenotype in T1D. Milicic et al similarly reported higher CXCR3 + memory T cell frequencies in high-risk AAb+ REL as compared to low-risk relatives (77), suggesting linkage to disease processes (77). CXCR3 + naïve T cells have been previously described in mice, are reported to be enriched in autoreactivity, and are thought to contain higher-affinity (CD5 hi ) autoreactive TCRs (78).…”

Unidentified Polymorphism in Ip-10/CXCL10 Gene linked to Type 1 Diabetes

“…Simultaneously, both IP-10 and TARC levels were increased in high risk versus low risk FDRs. The level of CXCR3(+) T memory cells together with high levels of IP-10 might influence the risk for T1D [14].…”