Raivo Uibo

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder characterized by antiphospholipid antibody-mediated inflammatory environment at the maternal–fetal interface. It leads to significant complications, including pre-fetal or fetal demise, preeclampsia, and placental insufficiency. Pregnancy leads to significant changes in the immune profile that facilitate fetal tolerance while ensuring protection from infections. A controlled inflammation at the maternal–fetal interface is essential during implantation as trophoblasts need to invade the endometrial lining. However, excessive inflammation can disrupt this balance and contribute to pregnancy-related complications. Consequently, the increased activation of the innate immune system is counteracted by the tolerogenic responses of the adaptive immune system. There is a shift from T helper (Th) 1 to Th2 responses from the first to the third trimester of pregnancy. This is associated with a decrease in lymphopoiesis, together with a prolonged B cell lifespan. Thus, during pregnancy, antibody-producing B cells are prone to activation, potentially leading to a loss of tolerance. Changes in B cell function, antigen presentation, and antibody affinity are seen in women with antiphospholipid syndrome. It is essential to understand the defects in B cell regulation in OAPS as they are likely to induce a breach in immune homeostasis. Herein, we will review the role of B cell tolerance in OAPS, including a discussion of potential novel therapeutic effects to improve maternal and fetal health.

This study aimed to compare the immunological and immunogenetic profiles over a spectrum of childhood- and adulthood-onset T1D at diagnosis. The cross-sectional study involved participants with recently diagnosed T1D (n = 168), aged 2.9–68.2 years. HLA-II alleles, single nucleotide polymorphisms (SNP) (rs2476601, rs3087243, rs1990760, rs13266634), thyroid and coeliac disease-related autoantibodies and anti-enterovirus antibodies (anti-EV) were analysed regarding the diabetes-associated autoantibodies’ (DAA) status and the age of participants. In the longitudinal study, 19 immune checkpoint gene expression levels in children (n = 25) aged 3.6–14.5 years were measured at diagnosis and 1 year after diagnosis. The duration of symptoms before diagnosis was age-dependent. Older age increased the odds of being single DAA-positive (OR 1.05; 95% CI 1.02–1.09), while anti-EV IgG positivity increased the odds of being multiple DAA-positive (adjusted OR 4.42; 95% CI 1.62–12.04). The DAA-negative T1D participants were older than the DAA-positive individuals. The checkpoint gene expression levels between the two time points were similar, but exhibited more pronounced variability at the time of diagnosis. These results confirm immunological variability in recent-onset T1D cases between children and adults and stress the importance of further research to define the comprehensive immunological profile of the disease age-related subgroups.

Molecular mimicry has been proposed to be a possible mechanism of induction of autoimmunity. In some cases, it is believed that such events could lead to a disease such as Type 1 diabetes (T1D). One of the primary MHC-I epitopes in the non-obese diabetic (NOD) mouse model of T1D has been identified as a peptide from the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) protein. In humans, the most common MHC-I model allele is HLA-A02; based on this, the study here identified a potential HLA-A0201-restricted human IGRP epitope as YLKTNLFLFL and also found a homologous A0201-restricted peptide in an Enterococcal protein. Using cells obtained from healthy human donors, it was seen that after a 2-week incubation with the synthetic bacterial protein, healthy A0201⁺ donor CD8⁺ cells displayed increased staining for human IGRP-peptide-dextramer. On the other hand, in control cultures, no significant levels of dextramer-staining CD8⁺ T-cells were detectable. From these outcomes, it is possible to conclude that certain bacterial proteins may initiate CD8⁺ T-cell-mediated immune reaction toward homologous human antigens.

Aims/Introduction We aimed to assess the distribution of transcription factor 7-like 2 gene TCF7L2 (rs7903146) polymorphism and to find possible associations between TCF7L2 and the characteristics of type 1 diabetes. Materials and Methods We studied 190 newly diagnosed type 1 diabetes patients (median age 12.7 years, range 2.0-72.5) and 246 controls (median age 23.8 years, range 1.4-81.5) for TCF7L2 single nucleotide polymorphism. We determined anti-islet autoantibodies, random C-peptide levels, diabetes associated HLA DR/DQ haplotypes and genotypes in all patients. Results There were no differences in the distribution of TCF7L2 single nucleotide polymorphism between patients and controls. However, patients with in type 1 diabetes, after adjusting for age and sex, subjects carrying C allele were at risk for a C-peptide level lower than 0.5 nmol/L (OR 5.65 [95% CI: 1.14-27.92]) and for zinc transporter 8 autoantibody positivity (5.22 [1.34-20.24]). Participants without T allele were associated with a higher level of islet antigen-2 autoantibodies (3.51 [1.49-8.27]) and zinc transporter 8 autoantibodies (2.39 [1.14-4.99]). Conclusions The connection of TCF7L2 polymorphism with zinc transporter 8 and islet antigen-2 autoantibodies and C-peptide levels in patients supports the viewpoint that TCF7L2 is associated with the clinical signs and autoimmune characteristics of type 1 diabetes. The mechanisms of the interaction between the TCF7L2 risk genotype and anti-islet autoantibodies need to be studied further.

Enteroviruses (EV) are among the leading environmental triggers of childhood‐onset type 1 diabetes (T1D). Our aim was to determine the prevalence of antibodies against EV and their association with T1D in different age groups (n = 62), including young adults, and to compare these data with results from HLA‐matched control participants (n = 62). IgA, IgG, and IgM antibodies against EV were detected. IgA EV antibodies were present in 46.8% of participants with T1D (median level 10.9 EIU) and in 11.3% of controls (median level 3.4 EIU). IgA EV positivity and higher level of IgA EV antibodies were both significant risk factors for T1D (odds ratio (OR) 8.33; 95% confidence interval (CI) 2.52–27.6; p = 0.0005 and OR 1.04; 95% CI 1.01–1.06; p = 0.0105, respectively). Importantly, the prevalence of IgA EV antibodies in the subgroups of both children and young adults was also significantly different between participants with T1D and their matched controls (p = 0.0089 and p = 0.0055, respectively). Such differences were not seen for IgG and IgM EV antibodies. However, IgG EV antibodies were associated with 65 kDa glutamic acid decarboxylase antibodies, but not with zinc transporter 8 and protein tyrosine phosphatase IA2 antibodies. The genotype frequency of PTPN22 (rs2476601) and IFIH1 (rs1990760) was not associated with EV positivity. This study showed that EV infections may be an important disease‐promoting factor of T1D not only in childhood‐onset but also in adult‐onset T1D. However, to further confirm this association, direct virological studies are needed in the latter T1D group.

Aims/Introduction: Gestational diabetes (GDM) is characterized by low‐grade systemic inflammation, which manifests as changes in the levels of cytokines in the blood. We aimed to investigate plasma immune mediators during gestational weeks 23–28 in 213 women at risk for GDM, and to find associations between GDM and its complications.Materials and Methods: We quantified the levels of adipokines: adiponectin, leptin, plasminogen activator inhibitor‐1 and resistin; chemokines: C‐C motif chemokine ligand 2 (CCL2), CCL4, C‐X‐C motif chemokine ligand 8 (CXCL8) and CXCL10; and cytokines: granulocyte‐macrophage colony‐stimulating factor, interferon‐γ, interleukin (IL)‐1β, soluble (s)IL‐1RI, IL‐2, sIL‐2Ra, IL‐4, IL‐5, IL‐6, IL‐7, IL‐10, IL‐12(p70), IL‐13, IL‐15, IL‐17A, IL‐17F, IL‐21, IL‐22, IL‐23, IL‐27, transforming growth factor (TGF)‐β1, TGF‐β2, TGF‐β3, tumor necrosis factor‐α and soluble tumor necrosis factor receptor 2 using the Milliplex®MAP Magnetic Bead assay on Luminex®200™, and compared the results with clinical data from pregnancy and post‐partum follow up.Results: Lower levels of adiponectin and higher levels of CCL2 (Wilcoxon test, P = 3.4E‐03 and P = 0.03, respectively) were found in women with GDM. IL‐27 levels were associated with lower odds of GDM (adjusted logistic regression 0.90, P = 2.4E‐03), and showed a risk association with glutamic acid decarboxylase autoantibody positivity (adjusted odds ratio 1.13, P = 2.8E‐03). Similarly, higher IL‐22 levels increased the odds of glutamic acid decarboxylase autoantibody positivity (adjusted odds ratio 4.23, P = 0.04). TGF‐β1 was associated with post‐partum fasting glucose levels, and CCL4 with post‐partum C‐peptide levels (linear regression, P = 0.04 and P = 0.01, respectively). Women who developed pregnancy complications had higher levels of CXCL10 and CCL4 (linear regression, P = 7.0E‐04 and P = 0.01, respectively).Conclusions: Plasma adiponectin and CCL2 concentrations distinguish women with GDM. IL‐27 and IL‐22 levels might select women with an autoimmune reaction, whereas increased TGF‐β1 and CCL4 are associated with post‐partum glucose and insulin metabolism.

The incidence of type I diabetes has been increasing worldwide at an annual rate of approximately 3%. One of the strategies to treat type I diabetes is islet transplantation, in which damaged β-cells are replaced with new islets. To improve β-cells’ expansion and pseudoislet formation, studies are focusing on using extracellular-matrix-resembling substrates. We evaluated the potential of salmon fibrinogen and chitosan electrospun scaffold as cell substrate for cultivating MIN-6 cells. The morphology of cells, insulin secretion and gene expression was evaluated and compared with other substrates (nanofibrous scaffold, microporous scaffold and tissue culture polystyrene). We found that all tested 3D conditions favored the pseudoislet formation of MIN-6 cells. The insulin secretion of MIN-6 cells after stimulation with high-glucose media shows approximately a 9-fold increase compared to the control group when a fibrinogen/chitosan-based electrospun scaffold was used for cultivation. The differences in insulin secretion were corroborated by differences in gene expression. The differences in insulin secretion could probably be attributed to the differences in the mechanical and/or chemical nature of the tested substrates.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10⁻⁸) with GDM, mapping to/near MTNR1B (P = 4.3 × 10⁻⁵⁴), TCF7L2 (P = 4.0 × 10⁻¹⁶), CDKAL1 (P = 1.6 × 10⁻¹⁴), CDKN2A-CDKN2B (P = 4.1 × 10⁻⁹) and HKDC1 (P = 2.9 × 10⁻⁸). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.