[CHARACTERIZATION OF THE ADAPTIVE IMMUNE REPERTOIRE USING NEXT GENERATION SEQUENCING: RECENT DISCOVERIES IN THE FIELD OF PRIMARY IMMUNODEFICIENCY, AND THE UPCOMING FUTURE].

INTRODUCTION: A powerful adaptive immune system, which includes cellular (T lymphocytes) and humoral (B lymphocytes) immunity, depends on its ability to recognize and protect against millions of different foreign antigens. It does so through an enormous diverse array of T-cell and B-cell receptors, collectively referred to as the adaptive immune repertoire. Using high-throughput sequencing as next generation sequencing (NGS) led to multiple breakthroughs in the field of molecular medicine. It has increased our ability to characterize the immune repertoire in primary immunodeficiency (PID) and to identify defects in diversification processes among other parameters as well. Human inborn errors of immunity represent a unique genotype-phenotype model that enable the study of critical genes' and proteins' role in disease and health. Recent studies regarding immune repertoire profiling of PID allowed us to better define genotype-phenotype correlations in diseases with wide clinical spectrum, the underlining patho-mechanism causing the specific genetic disease, the common features of similar diseases as well as the unique molecular signature for each genetic disease. Immune repertoire knowledge is an integral part of PID research, and aids in improving diagnosis and designing personalized treatment. Nevertheless, NGS has created some challenges that emphasize the need for technologies such as cloud-based platforms like Kusto, enabling scalable data analysis and the incorporation of artificial intelligence techniques.

The Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Patients Hospitalized with Acute Pulmonary Embolism.

Early risk stratification is essential for determining the appropriate therapeutic management approach of pulmonary embolism (PE). This study aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in patients hospitalized with acute pulmonary embolism by investigating its association with mortality in a large-scale population diagnosed and hospitalized with acute PE. We retrieved all consecutive patients hospitalized in an internal medicine department or an intensive care unit in a tertiary medical center from December 2007 to April 2021 with a discharge diagnosis of pulmonary embolism. A total of 2072 patients were included. Patients with above-median NLR (i.e., 5.12) had a higher 30-day mortality risk (adjusted odds ratio (aOR), 2.82; 95% confidence interval (CI) 2.14-3.70) and higher one-year mortality risk (aOR, 2.51; 95% CI 2.04-3.08). Similar trends were demonstrated in a sub-analysis of patients without cancer and hemodynamically stable (i.e., systolic blood pressure over 90 mmHg). Furthermore, the median hospital length of stay in patients with an elevated NLR was higher, and so was the in-hospital mortality rate. Elevated NLR in acute PE is associated with a worse short-term and long-term prognosis and with a longer duration of hospitalization.

Folate Levels in Patients Hospitalized with Coronavirus Disease 2019.

We aimed to investigate the prevalence of decreased folate levels in patients hospitalized with Coronavirus Disease 2019 (COVID-19) and evaluate their outcome and the prognostic signifi-cance associated with its different levels. In this retrospective cohort study, data were obtained from the electronic medical records at the Sheba Medical Center. Folic acid levels were available in 333 out of 1020 consecutive patients diagnosed with COVID-19 infection hospitalized from January 2020 to November 2020. Thirty-eight (11.4%) of the 333 patients comprising the present study population had low folate levels. No significant difference was found in the incidence of acute kidney injury, hypoxemia, invasive ventilation, length of hospital stay, and mortality be-tween patients with decreased and normal-range folate levels. When sub-dividing the study population according to quartiles of folate levels, similar findings were observed. In conclusion, decreased serum folate levels are common among hospitalized patients with COVID-19, but there was no association between serum folate levels and clinical outcomes. Due to the important role of folate in cell metabolism and the potential pathologic impact when deficient, a follow-up of folate levels or possible supplementation should be encouraged in hospitalized COVID-19 patients. Fur-ther studies are required to assess the prevalence and consequences of folate deficiency in COVID-19 patients.

Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects.

The T cell receptor (TCR) signaling pathway is an ensemble of numerous proteins that are crucial for an adequate immune response. Disruption of any protein involved in this pathway leads to severe immunodeficiency and unfavorable clinical outcomes. Here, we describe an infant with severe immunodeficiency who was found to have novel biallelic mutations in SLP76. SLP76 is a key protein involved in TCR signaling and in other hematopoietic pathways. Previous studies of this protein were performed using Jurkat-derived human leukemic T cell lines and SLP76-deficient mice. Our current study links this gene, for the first time, to a human immunodeficiency characterized by early-onset life-threatening infections, combined T and B cell immunodeficiency, severe neutrophil defects, and impaired platelet aggregation. Hereby, we characterized aspects of the patient's immune phenotype, modeled them with an SLP76-deficient Jurkat-derived T cell line, and rescued some consequences using ectopic expression of wild-type SLP76. Understanding human diseases due to SLP76 deficiency is helpful in explaining the mixed T cell and neutrophil defects, providing a guide for exploring human SLP76 biology.