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Objective: To investigate whether angiogenic biomarker concentrations differ between women who deliver small-for-gestational-age (SGA) infants (<10th centile birth weight for gestational age) compared with controls, because identifying SGA risk early could improve outcomes. Methods: This case-control study compared serum concentrations of angiogenic biomarkers before 24 weeks of pregnancy from 62 women who delivered SGA infants (cases) and 62 control women from an urban Zambian cohort. Odds of delivering an SGA infant were calculated using conditional logistic regression. Results: Placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sEng) in controls were 37.74 pg/mL (interquartile range [IQR] 23.12– 63.15), 2525.18 pg/mL (IQR 1502.21–4265.54) and 2408.18 pg/mL (IQR 1854.87– 3017.94), respectively. SGA cases had higher PlGF (40.50 pg/mL, IQR 22.81–67.94) and sFLT-1 (2613.06 pg/mL, IQR 1720.58–3722.50), and lower sEng (2038.06 pg/mL, IQR 1445.25–3372.26). Participants with sEng concentration below and concomitant sFLT-1 concentration above their respective thresholds (n = 40) had five-fold higher odds of SGA (adjusted odds ratio 4.77, 95% confidence interval 1.61–14.1; P = 0.005). Conclusion: Biomarker concentrations were similar between cases and controls. Participants with concomitant low sEng and high sFLT-1 had the highest odds of SGA, suggesting that a combination of biomarkers may better for predicting SGA than single biomarkers. [ABSTRACT FROM AUTHOR]

Background: Maternal HIV increases the risk of adverse birth outcomes including preterm birth, fetal growth restriction, and stillbirth, but the biological mechanism(s) underlying this increased risk are not well understood. We hypothesized that maternal HIV may lead to adverse birth outcomes through an imbalance in angiogenic factors involved in the vascular endothelial growth factor (VEGF) signaling pathway.Methods: In a case-control study nested within an ongoing cohort in Zambia, our primary outcomes were serum concentrations of VEGF-A, soluble endoglin (sEng), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFLT-1). These were measured in 57 women with HIV (cases) and 57 women without HIV (controls) before 16 gestational weeks. We used the Wilcoxon rank-sum and linear regression controlling for maternal body mass index (BMI) and parity to assess the difference in biomarker concentrations between cases and controls. We also used logistic regression to test for associations between biomarker concentration and adverse pregnancy outcomes (preeclampsia, preterm birth, small for gestational age, stillbirth, and a composite of preterm birth or stillbirth).Results: Compared to controls, women with HIV had significantly lower median concentrations of PlGF (7.6 vs 10.2 pg/mL, p = 0.02) and sFLT-1 (1647.9 vs 2055.6 pg/mL, p = 0.04), but these findings were not confirmed in adjusted analysis. PlGF concentration was lower among women who delivered preterm compared to those who delivered at term (6.7 vs 9.6 pg/mL, p = 0.03) and among those who experienced the composite adverse birth outcome (6.2 vs 9.8 pg/mL, p = 0.02). Median sFLT-1 concentration was lower among participants with the composite outcome (1621.0 vs 1945.9 pg/mL, p = 0.04), but the association was not significant in adjusted analysis. sEng was not associated with either adverse birth outcomes or HIV. VEGF-A was undetectable by Luminex in all specimens.Conclusions: We present preliminary findings that HIV is associated with a shift in the VEGF signaling pathway in early pregnancy, although adjusted analyses were inconclusive. We confirm an association between angiogenic biomarkers and adverse birth outcomes in our population. Larger studies are needed to further elucidate the role of HIV on placental angiogenesis and adverse birth outcomes. [ABSTRACT FROM AUTHOR]

Disease-causing variants in key immune homeostasis genes can lead to monogenic autoimmune diabetes. Some individuals carrying disease-causing variants do not develop autoimmune diabetes, even though they develop another autoimmune disease. We aimed to determine whether type 1 diabetes polygenic risk contributes to phenotypic presentation in monogenic autoimmune diabetes. We used a 67 single nucleotide polymorphism type 1 diabetes genetic risk score (T1D-GRS) to determine polygenic risk in 62 individuals with monogenic autoimmune diabetes and 180 control individuals with nonautoimmune neonatal diabetes (NDM). We used population-based control participants (n = 10,405) and individuals with type 1 diabetes (n = 285) as a comparator. Individuals with monogenic autoimmune diabetes had higher T1D-GRSs compared with individuals with nonautoimmune NDM (mean 11.3 vs. 9.8; P = 1.7 × 10−5) and controls (mean 10.3; P = 7.5 × 10−6), but the levels were markedly lower than those for individuals with type 1 diabetes (14.9; P = 3.3 × 10−21). These differences were explained by individuals with monogenic autoimmune diabetes having higher class II HLA genetic risk, specifically from the DRB1* 03:01 -DQA1 *05:01 -DQB1 *02:01 haplotype (DR3-DQ2) (P < 0.01). In the presence of monogenic autoimmunity, the polygenic class II HLA susceptibility contributes to development of autoimmune diabetes. This suggests a role of class II HLA in targeting the dysregulated immune response toward the β-cell. Article Highlights: There is variability in early-onset autoimmune diabetes presentation in individuals with monogenic autoimmunity; the mechanism(s) underlying this is unclear. We examined whether type 1 diabetes (T1D) polygenic risk contributes to clinical phenotype in monogenic autoimmune diabetes. Individuals with monogenic autoimmune diabetes had higher T1D genetic risk scores compared with control cohorts, driven largely by increased presence of T1D-risk DR3-DQ2 haplotype. Established T1D polygenic risk alleles, particularly class II HLA genes, contribute to clinical presentation in monogenic autoimmunity. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells abundantly express the immunoreceptor programmed cell death protein 1 (PD-1), and the impact of PD-1 deficiency on antibody (Ab)-mediated immunity in mice is associated with compromised Tfh cell functions. Here, we revisited the role of the PD-1-PD-L1 axis on Ab-mediated immunity. Individuals with inherited PD-1 or PD-L1 deficiency had fewer memory B cells and impaired Ab responses, similar to Pdcd1 −/− and Cd274 −/− Pdcd1lg2 −/− mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following in vitro activation. PD-1- or PD-L1-deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc-target genes in vivo , and PD-1 deficiency or neutralization of PD-1 or PD-L1 impeded c-Myc expression and Ab production in human B cells isolated in vitro. Furthermore, B cell-specific deletion of Pdcd1 prevented the physiological accumulation of memory B cells in mice. Thus, PD-1 shapes optimal B cell memory and Ab-mediated immunity through B cell-intrinsic and B cell-extrinsic mechanisms, suggesting that B cell dysregulation contributes to infectious and autoimmune complications following anti-PD-1-PD-L1 immunotherapy. [Display omitted] • Impaired B cell memory in PD-1- and PD-L1-deficient humans and mice deficient in PD-1 signaling • PD-1 deficiency but not PD-L1 deficiency disrupts Tfh cell phenotype and function • Human PD-1-PD-L1 axis promotes antibody responses in a B cell-intrinsic manner • B cell-specific deletion of PD-1 triggers striking phenotypic alterations in mice Ogishi, Kitaoka, et al. examine humans deficient in PD-1 and PD-L1 as well as associated mouse models and find that PD-1 and PD-L1 promote B cell memory and antibody responses through both T cell-dependent and B cell-intrinsic mechanisms. Their findings provide insight into the mechanisms underlying the infectious and autoimmune complications associated with anti-PD-1-PD-L1 immunotherapy. [ABSTRACT FROM AUTHOR]