Established reference values are critical for the interpretation of immunologic assessments. In particular, the proportion and absolute counts of T- and B- cell subpopulations are subject to change with age and ethnicity. We aimed to establish age-specific reference values for lymphocyte subsets using updated immunophenotyping panels. We studied a total of 297 healthy Turkish subjects aged 0 to 50 years, stratified into major age brackets in a cluster factor of 10 per age-group. The predetermined age intervals contained randomly allocated participants enrolled over a period of 6 months, who were homogenously distributed by gender. We analyzed a complete blood count test and simultaneously with detailed immunophenotyping enumerated the percent and absolute cell counts of lymphocyte subsets. The percentage and absolute counts of lymphocyte subsets show a marked surge across the age-span. T helper, T cytotoxic, and the Natural Killer cell numbers were increasing from birth until 6 months, followed by a gradual decrease thereafter. B cell numbers were rising until 2 years, followed by a gradual decrease for the upcoming years, accompanied by a steady expansion of unclass-switched- and class-switched- B cells. We provide updated extensive reference intervals for lymphocyte subpopulations in Turkish people.

To establish local normative data of thyroid volume assessed by ultrasonography in subjects aged 0-55 years living in İstanbul, Turkey. Subjects without any known history of thyroid disease, of major surgery and/or chronic disease were enrolled in the study and evaluated by physical examination and thyroid ultrasonography. Thyroid gland and isthmus at usual location, each lateral lobe volume with three dimensions, ectopic thyroid tissue and echogenicity of the gland were assessed. Initially, 494 subjects were enrolled in the study. Subjects showing heterogeneous thyroid parenchyma (n=21) and/or nodule (n=51) in ultrasonography were excluded. Final analysis covered 422 subjects (216 males, 206 females). Thyroid volume was found to significantly correlate with height, weight, age and body surface area (r=0.661, r=0.712, r=0.772 and r=0.779, respectively; p<0.0001 for all). These correlations were even stronger in subjects younger than 18 years (r=0.758, r=0.800, r=0.815 and r=0.802, respectively; p<0.0001 for all). The study provides updated reference norms for thyroid volume in Turkish subjects which can be used in the diagnosis and follow-up of patients with thyroid diseases.

Polymerase δ is essential for eukaryotic genome duplication and synthesizes DNA at both the leading and lagging strands. The polymerase δ complex is a heterotetramer comprising the catalytic subunit POLD1 and the accessory subunits POLD2, POLD3, and POLD4. Beyond DNA replication, the polymerase δ complex has emerged as a central element in genome maintenance. The essentiality of polymerase δ has constrained the generation of polymerase δ–knockout cell lines or model organisms and, therefore, the understanding of the complexity of its activity and the function of its accessory subunits. To our knowledge, no germline biallelic mutations affecting this complex have been reported in humans. In patients from 2 independent pedigrees, we have identified what we believe to be a novel syndrome with reduced functionality of the polymerase δ complex caused by germline biallelic mutations in POLD1 or POLD2 as the underlying etiology of a previously unknown autosomal-recessive syndrome that combines replicative stress, neurodevelopmental abnormalities, and immunodeficiency. Patients’ cells showed impaired cell-cycle progression and replication-associated DNA lesions that were reversible upon overexpression of polymerase δ. The mutations affected the stability and interactions within the polymerase δ complex or its intrinsic polymerase activity. We believe our discovery of human polymerase δ deficiency identifies the central role of this complex in the prevention of replication-related DNA lesions, with particular relevance to adaptive immunity.

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients’ circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

Background: Genetic deficiencies of immune system, referred to as inborn errors of immunity (IEI), serve as a valuable model to study human immune responses. In a multicenter prospective cohort, we evaluated the outcome of SARS‐CoV‐2 infection among IEI subjects and analyzed genetic and immune characteristics that determine adverse COVID‐19 outcomes.Methods: We studied 34 IEI patients (19M/15F, 12 [min: 0.6‐max: 43] years) from six centers. We diagnosed COVID‐19 infection by finding a positive SARS‐CoV‐2 PCR test (n = 25) and/or a lung tomography scoring (CORADS) ≥4 (n = 9). We recorded clinical and laboratory findings prospectively, fitted survival curves, and calculated fatality rates for the entire group and each IEI subclass.Results: Nineteen patients had combined immune deficiency (CID), six with predominantly antibody deficiency (PAD), six immune dysregulation (ID), two innate immune defects, and one in the autoinflammatory class. Overall, 23.5% of cases died, with disproportionate fatality rates among different IEI categories. PAD group had a relatively favorable outcome at any age, but CIDs and IDs were particularly vulnerable. At admission, presence of dyspnea was an independent risk for COVID‐related death (OR: 2.630, 95% CI; 1.198–5.776, p < .001). Concerning predictive roles of laboratory markers at admission, deceased subjects compared to survived had significantly higher CRP, procalcitonin, Troponin‐T, ferritin, and total‐lung‐score (p = .020, p = .003, p = .014, p = .013, p = .020; respectively), and lower absolute lymphocyte count, albumin, and trough IgG (p = .012, p = .022, p = .011; respectively).Conclusion: Our data disclose a highly vulnerable IEI subgroup particularly disadvantaged for COVID‐19 despite their youth. Future studies should address this vulnerability and consider giving priority to these subjects in SARS‐Cov‐2 therapy trials.