Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes

Abstract

The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

Fig 1. Association of time between T1D diagnosis and blood sampling with cytokine levels.

After the Bonferroni correction, the levels of IL-7 (A), TNF-ɑ (B), IL-8 (C), and IL-13 (D) showed a tendency to decrease with an increasing number of days between T1D diagnosis and blood sampling. Spearman’s rank correlation test was used.

Fig 2. Differences in cytokine levels between T1D patients with and without ketoacidosis.

Compared to T1D patients without ketoacidosis, patients with ketoacidosis had a tendency for higher IL-8 (A) and IL-10 levels after Bonferroni correction* (B). Lines represent median and interquartile range values. * P-values ≤ 0.0025 were considered statistically significant after Bonferroni correction in Mann-Whitney U-test.

Fig 3. Differences in cytokine levels between T1D patients with and without IA2A.

Compared to T1D patients without IA2A, T1D patients with IA2A showed a tendency for higher GM-CSF (A), IL-1β (B), TNF-ɑ (C), IFN-γ (D), and IL-10 (E) levels Bonferroni correction^*. Lines represent median and interquartile range values. ^* P-values ≤ 0.0025 were considered statistically significant after Bonferroni correction in Mann–Whitney U-test.

Fig 4. Differences in cytokine levels between T1D patients with and without ZnT8A.

Compared to T1D patients without ZnT8A, T1D patients with ZnT8A showed a tendency for higher GM-CSF (A) and IL-1β (B) levels after Bonferroni correction*. Lines represent median and interquartile range values. * P-values 0.05–0.0025 were considered as a tendency after Bonferroni correction in Mann–Whitney U-test.