Clinical and HLA genotype analysis of immune checkpoint inhibitor-associated diabetes mellitus: a single-center case series from China.

Objective: To investigate the clinical characteristics and HLA genotypes of patients with immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in China. Methods: We enrolled 23 patients with ICI-DM and 51 patients with type 1 diabetes (T1D). Clinical characteristics of the patients were collected. HLA-DRB1, HLA-DQA1, and HLA-DQB1 genotyping was conducted via next-generation sequencing. Results: The ICI-DM patients had a male predominance (70.6%), a mean body mass index (BMI) of 21.2 ± 3.5 kg/m2, and a mean onset of ICI-DM in 5 (IQR, 3-9) cycles after ICI therapy. Most (78.3%) ICI-DM patients were treated with anti-PD-1, 78.3% presented with diabetic ketoacidosis, and all had low C-peptide levels and received multiple insulin injections. Compared to T1D patients, ICI-DM patients were significantly older (57.2 ± 12.4 vs 34.1 ± 15.7 years) and had higher blood glucose but lower HbA1c levels (P<0.05). Only two (8.7%) ICI-DM patients were positive for islet autoantibodies, which was lower than that in T1D patients (66.7%, P<0.001). A total of 59.1% (13/22) of ICI-DM patients were heterozygous for an HLA T1D risk haplotype, and DRB1*0901-DQA1*03-DQB1*0303 (DR9) and DRB1*0405-DQA1*03-DQB1*0401 were the major susceptible haplotypes. Compared to T1D, the susceptible DR3-DQA1*0501-DQB1*0201 (DR3) and DR9 haplotypes were less frequent (17.7% vs 2.3%; P=0.011 and 34.4% vs 15.9%; P=0.025), whereas the protective haplotypes (DRB1*1101-DQA1*05-DQB1*0301 and DRB1*1202-DQA1*0601-DQB1*0301) were more frequent in ICI-DM patients (2.1% vs 13.6%; P=0.006 and 4.2% vs 15.9%; P=0.017). None of the ICI-DM patients had T1D-associated high-risk genotypes DR3/DR3, DR3/DR9, and DR9/DR9. Among the 23 ICI-DM patients, 7 (30.4%) presented with ICI-associated fulminant type 1 diabetes (IFD), and 16 (69.6%) presented with ICI-associated type 1 diabetes (IT1D). Compared to IT1D patients, IFD patients exhibited marked hyperglycemia and low C-peptide and HbA1c levels (P<0.05). Up to 66.7% (4/6) of IFD patients were heterozygous for reported fulminant type 1 diabetes susceptibility HLA haplotypes (DRB1*0405-DQB1*0401 or DRB1*0901-DQB1*0303). Conclusion: ICI-DM shares similar clinical features with T1D, such as acute onset, poor islet function and insulin dependence. However, the lack of islet autoantibodies, the low frequencies of T1D susceptibility and high frequencies of protective HLA haplotypes indicate that ICI-DM represents a new model distinct from classical T1D.

Memory T cells delay the progression of atherosclerosis via AMPK signaling pathway.

BACKGROUND: Memory T cells play a key role in the development of atherosclerosis (AS). This study aimed to investigate the role of AMPK signaling pathway of spleen memory T cells in the pathogenesis of AS in high-fat diet (HFD) fed mice. METHODS: Mice were divided into 5 groups: normal group, AS group, AS + solvent group, AS + Compound C (AMPK inhibitor) group and AS + A-769662 (AMPK agonist) group. HFD animals were intraperitoneally treated with Compound C at 20 mg/kg thrice weekly or A-769662 at 30 mg/kg once daily for 15 weeks. Then, the degree of AS was assessed, and the proportion of memory T cell was determined by flow cytometry. RESULTS: AS was evident in the aorta of HFD mice. The areas of plaque formation in both AS + Compound C group and AS + A-769662 group reduced as compared to the AS group and AS + solvent group. After intervention of AMPK activity, the proportion of memory T cells in the spleen reduced as compared to the AS group and AS + solvent group; the pro proportion of memory T cells in HFD groups was markedly higher than in the normal group and this increase was more evident in the AS + Compound C than in the AS + A-769662 group. CONCLUSIONS: The decreased memory T cells can improve AS, which may be related to the AMPK signaling pathway. Thus, AMPK in the memory T cells may serve as a target in the prevention and treatment of AS.

Imbalance of T-helper 1/T-helper 2 cytokines and impaired glucose tolerance among patient with acute coronary syndrome.

PURPOSE: The balance between T helper (Th) cells Th1- and Th2-related cytokines plays a key role in the clinical process of acute coronary syndrome (ACS) and type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). The objective of this study was to assess the status of Th1/Th2 cytokines in patients with ACS and T2D or IGT. METHODS: A total of 201 ACS patients were enrolled in the study. All ACS patients were divided into three groups: Group I-patients with normal glucose tolerance (NGT), Group II-patients with IGT and Group III-patients with T2D. We measured circulating Th1/Th2-type cytokines (interleukin [IL]-4, IL-13, interferon-gamma [IFN-γ], and tumor-necrosis factor-alpha [TNF-α]) using enzyme-linked immunosorbent assay and calculated the ratio of Th1/Th2. RESULTS: Significant elevations in serum levels of IL-4, IL-13, IFN-γ, and TNF-α were found in ACS-T2D and ACS-IGT groups compared to that in both ACS-NGT group and healthy individuals. Higher serum levels of IL-4, IL-13, and TNF-α were found in ACS-NGT group than that in the control group. Furthermore, IL-4 and IFN-γ concentrations were significantly higher in ACS-T2D patients than in ACS-IGT patients. IFN-γ/IL-4, IFN-γ/IL-13, and TNF-α/IL-4 ratios as markers of Th1/Th2 ratio were significantly higher for the ACS-T2D group and ACS-IGT group as compared to that in the ACS-NGT group and control group (P < 0.05). CONCLUSION: Shifts in the balance of Th1/Th2 toward a predominance of Th1 may represent more severe inflammatory status in ACS patients with type T2D or IGT.

Effects of arterial blood on the venous blood vessel wall and differences in percentages of lymphocytes and neutrophils between arterial and venous blood.

Vascular sclerosis mostly occurs in arteries and is mainly related to anatomic structure and hemodynamics of artery. This study aimed to investigate effects of arterial blood on vein wall and explore differences of composition between arterial and venous blood.Ultrasound was used to examine the distal venous structure of arteriovenous fistula in uremia patients. Immunohistochemistry was used to study the pathology of the distal vein. Twelve patients were divided into control group and trial group. Patients received an arteriovenous fistula within 1 month in control group. Patients had undergone this surgery ≥2 years before in the trial group. Blood samples were collected from the aortic, arterial, and venous vessels of 51 patients who had taken coronary angiography and analyzed with blood routine rest, biochemical, and immunological measures to compare the differences of blood composition between artery and vein. This study was registered with the China Clinical Trial Center website under registration number ChiCTR-OOC-16008085.In the trial group, the vascular wall of distal veins of fistula were thickened and hardened. No significant differences of blood composition were found between the aortic and radial arterial blood. However, the differences in the percentages of lymphocytes and neutrophils between arterial and venous blood were significant (Pa = .0095, Pb = .01).Under smooth hemodynamic conditions, arterial blood caused hardening of the venous wall. Arterial and venous blood differed in the percentage of lymphocyte and neutrophils. This may contribute to the vascular sclerosis that is observed in arteries more often than veins.

A novel mutation in autoimmune regulator gene causes autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive disease due to mutations in the autoimmune regulator (AIRE) gene, which encodes a transcription factor that induces the expression of peripheral tissue-specific antigens in medullary thymic epithelial cells. AIM: The purpose of this study was to identify the underlying genetic cause in a Chinese family diagnosed with APECED. METHOD: Peripheral blood samples were collected from family members. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. The functional consequence of the mutations was analyzed by cell transfection and in vitro assays. RESULTS: A novel c.483_484insC mutation in exon 4 was identified, which resulted in a frame shift predicted to generate a truncated protein containing the first 163 AIRE amino acids followed by 52 aberrant amino acids. Confocal immunofluorescence microscopy of COS-7 cells transfected with wild-type and mutant AIRE constructs showed that wild-type AIRE protein was localized mainly in the nucleus, while mutant AIRE was localized mainly in the cytoplasm. A luciferase reporter assay showed that the identified mutation dramatically inhibited the transactivation activity of AIRE in vitro. CONCLUSION: We identified a novel AIRE mutation which alters the intracellular location and transcription activity of AIRE, and has implications in the pathogenesis of APECED.