News in immunology.

The field of immunology has undergone a very significant development in recent decades, which has been reflected especially in the beginning of this millennium in significant advances in the understanding of the immune system and in the application of this knowledge in practice. The progress and acceleration of research and advances in the field of immunology was further prompt by the unexpected onset of the COVID-19 pandemic in 2020. The intense scientific work has not only led to the development of our understanding of the immune response to viruses, but also to the rapid conversion of this knowledge into practical pandemic management on a global scale, as exemplified by the development of vaccines against SARS-Cov-2 virus. The pandemic era has further contributed to the acceleration of the application of not only biological discoveries but also technological approaches into practical applications, such as use of advanced mathematics, computer science and, more recently, artificial intelligence which are all are adding to the advances that are significantly moving the field of immunology forward. In this communication, we present specific advances in particular areas of immunopathology, which are mainly allergy, immunodeficiency, immunity and infection, vaccination, autoimmune diseases and cancer immunology.

Pathogenesis, immunology, and immune-targeted management of the multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS): EAACI Position Paper.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Nationwide observational study of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the Czech Republic.

The worldwide outbreak of the novel 2019 coronavirus disease (COVID-19) has led to recognition of a new immunopathological condition: paediatric inflammatory multisystem syndrome (PIMS-TS). The Czech Republic (CZ) suffered from one of the highest incidences of individuals who tested positive during pandemic waves. The aim of this study was to analyse epidemiological, clinical, and laboratory characteristics of all cases of paediatric inflammatory multisystem syndrome (PIMS-TS) in the Czech Republic (CZ) and their predictors of severe course. We performed a retrospective-prospective nationwide observational study based on patients hospitalised with PIMS-TS in CZ between 1 November 2020 and 31 May 2021. The anonymised data of patients were abstracted from medical record review. Using the inclusion criteria according to World Health Organization definition, 207 patients with PIMS-TS were enrolled in this study. The incidence of PIMS-TS out of all SARS-CoV-2-positive children was 0.9:1,000. The estimated delay between the occurrence of PIMS-TS and the COVID-19 pandemic wave was 3 weeks. The significant initial predictors of myocardial dysfunction included mainly cardiovascular signs (hypotension, oedema, oliguria/anuria, and prolonged capillary refill). During follow-up, most patients (98.8%) had normal cardiac function, with no residual findings. No fatal cases were reported.Conclusions: A 3-week interval in combination with incidence of COVID-19 could help increase pre-test probability of PIMS-TS during pandemic waves in the suspected cases. Although the parameters of the models do not allow one to completely divide patients into high and low risk groups, knowing the most important predictors surely could help clinical management.

Risk Factors for Severe COVID-19 and Hospital Admission in Patients With Inborn Errors of Immunity - Results From a Multicenter Nationwide Study.

Despite the progress in the understanding how COVID-19 infection may impact immunocompromised patients, the data on inborn errors of immunity (IEI) remain limited and ambiguous. Therefore, we examined the risk of severe infection course and hospital admission in a large cohort of patients with IEI. In this multicenter nationwide retrospective survey-based trial, the demographic, clinical, and laboratory data were collected by investigating physicians from 8 national referral centers for the diagnosis and treatment of IEI using a COVID-19-IEI clinical questionnaire. In total, 81 patients with IEI (including 16 with hereditary angioedema, HAE) and confirmed SARS-CoV-2 infection were enrolled, and were found to have a 2.3-times increased (95%CI: 1.44-3.53) risk ratio for hospital admission and a higher mortality ratio (2.4% vs. 1.7% in the general population). COVID-19 severity was associated with the presence of clinically relevant comorbidities, lymphopenia, and hypogammaglobulinemia, but not with age or BMI. No individuals with HAE developed severe disease, despite a hypothesized increased risk due to perturbed bradykinin metabolism. We also demonstrated a high seroconversion rate in antibody-deficient patients and the safety of anti-spike SARS CoV-2 monoclonal antibodies and convalescent plasma. Thus, IEI except for HAE, represent significant risk factors for a severe COVID-19. Therefore, apart from general risk factors, immune system dysregulation may also be involved in the poor outcomes of COVID-19. Despite the study limitations, our results support the findings from previously published trials.

Neutrophils mediate Th17 promotion in COVID-19 patients.

From the beginning of 2020, an urgent need to understand the pathophysiology of SARS-CoV-2 disease (COVID-19), much of which is due to dysbalanced immune responses, resonates across the world. COVID-19-associated neutrophilia, increased neutrophil-to-lymphocyte ratio, aberrant neutrophil activation, and infiltration of neutrophils into lungs suggest that neutrophils are important players in the disease immunopathology. The main objective of this study was to assess the phenotypic and functional characteristics of neutrophils in COVID-19 patients, with particular focus on the interaction between neutrophils and T cells. We hypothesize that the altered functional characteristics of COVID-19 patient-derived neutrophils result in skewed Th1/Th17 adaptive immune response, thus contributing to disease pathology. The expansion of G-MDSC and immature forms of neutrophils was shown in the COVID-19 patients. In the COVID-19 neutrophil/T cell cocultures, neutrophils caused a strong polarity shift toward Th17, and, conversely, a reduction of IFNγ-producing Th1 cells. The Th17 promotion was NOS dependent. Neutrophils, the known modulators of adaptive immunity, skew the polarization of T cells toward the Th17 promotion and Th1 suppression in COVID-19 patients, contributing to the discoordinated orchestration of immune response against SARS-CoV-2. As IL-17 and other Th17-related cytokines have previously been shown to correlate with the disease severity, we suggest that targeting neutrophils and/or Th17 represents a potentially beneficial therapeutic strategy for severe COVID-19 patients.

Disharmonic Inflammatory Signatures in COVID-19: Augmented Neutrophils' but Impaired Monocytes' and Dendritic Cells' Responsiveness.

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.

Searching for COVID-19 Antibodies in Czech Children-A Needle in the Haystack.

During the COVID-19 pandemics of 2020, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), both adults and children were shown to mount a specific antibody response to the virus. As infected children often exhibit mild symptoms or even remain asymptomatic, they are likely to be under tested for the direct presence of the virus. Mapping the SARS-CoV-2 antibodies frequency informs more accurately on the disease prevalence and helps guide the protective and therapeutic strategies. To date, only few seroprevalence studies included children. In the Czech Republic, in April 2020, the overall SARS-CoV-2 seroprevalence was estimated not to exceed 1.3%. In July and August, 2020, we screened 200 children (0-18 years of age), who attended the pediatric department of a large hospital in Prague for various COVID-19-unrelated reasons, for the presence of SARS-CoV-2 antibodies. Zero seropositive subjects were found. Therefore, we hereby report a low (<0.5%) seroprevalence amongst children in Prague, as of August, 2020.

Disharmonic Inflammatory Signatures in COVID-19: Augmented Neutrophils’ but Impaired Monocytes’ and Dendritic Cells’ Responsiveness

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis;however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.

Complex Immunometabolic Profiling Reveals the Activation of Cellular Immunity and Biliary Lesions in Patients with Severe COVID-19.

This study aimed to assess the key laboratory features displayed by coronavirus disease 2019 (COVID-19) inpatients that are associated with mild, moderate, severe, and fatal courses of the disease, and through a longitudinal follow-up, to understand the dynamics of the COVID-19 pathophysiology. All severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients admitted to the University Hospital in Motol between March and June 2020 were included in this study. A severe course of COVID-19 was associated with an elevation of proinflammatory markers; an efflux of immature granulocytes into peripheral blood; the activation of CD8 T cells, which infiltrated the lungs; transient liver disease. In particular, the elevation of serum gamma-glutamyl transferase (GGT) and histological signs of cholestasis were highly specific for patients with a severe form of the disease. In contrast, patients with a fatal course of COVID-19 failed to upregulate markers of inflammation, showed discoordination of the immune response, and progressed toward acute kidney failure. COVID-19 is a disease with a multi-organ affinity that is characterized by the activation of innate and cellular adaptive immunity. Biliary lesions with an elevation of GGT and the organ infiltration of interleukin 6 (IL-6)-producing cells are the defining characteristics for patients with the fulminant disease.