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.

Tanja Milicic,Marija Macesic,Ljiljana Lukic,Ivanka Markovic,Nebojsa M Lalic,Natasa Rajkovic,Katarina Lalic,Jelena P Seferovic,Aleksandra Jotic,Milorad Civcic,Veljko Jeremic,Dušan Popadic,Jelena Stanarcic,Sandra Aleksic

doi:10.1155/2014/589360

Tanja Milicic, Marija Macesic + Show 12 more

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https://doi.org/10.1155/2014/589360

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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.

Highlights

It has been shown that first degree relatives (FDRs) of patients with type 1 diabetes (T1D) have at least 10 times higher relative risk of type 1 diabetics (T1D) than in the general population [1, 2]
We divided them into 2 subgroups according to presence/absence of autoantibodies; 17 of them was classified as high risk FDRs, who were persistently positive for the presence of glutamic acid decarboxylase (GADA) and tyrosine phosphatase insulinoma antigen-2 (IA-2A), while 34 FDRs were classified as low risk FDRs, negative for both autoantibodies
It has been suggested that human macrophages and B cells can express CD4, we gated on CD3+ cells, which is associated with T cells

Summary

Introduction

It has been shown that first degree relatives (FDRs) of patients with type 1 diabetes (T1D) have at least 10 times higher relative risk of T1D than in the general population [1, 2]. CXC chemokine receptor 3 (CXCR3) is selectively expressed on memory Th1 cells, while CC chemokine receptor 4 (CCR4) is expressed on memory Th2 cells [8, 9]. It was demonstrated that one of ligands for CXCR3 receptor is chemokine interferon γ inducible protein (IP-10) [9,10,11,12], while CCR4 receptor attracts the thymus and activation-regulated chemokine (TARC) [11]. It was shown that chemokine receptors, together with their ligands, might be involved in different Th1/Th2 cell migratory capacity and the extravasation of T cells into inflamed tissue [13, 14]

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