Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Regulatory T Cells

Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection.

/pdf/longitudinal-observation-and-decline-of-neutralizing-npugyx3tjj.pdf

Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans.

COVID-19 and the human innate immune system.

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.

OBJECTIVE: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS-CoV-2 infection. The Task Force also provided recommendations for children with hyperinflammation during COVID-19, the acute, infectious phase of SARS-CoV-2 infection. METHODS: The Task Force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and discussion through webinars. A 9-point scale was used to determine the appropriateness of each statement (1-3, inappropriate; 4-6, uncertain; 7-9, appropriate), and consensus was rated as low (L), moderate (M), or high (H) based on dispersion of the votes along the numeric scale. Approved guidance statements had to be classified as appropriate with moderate or high levels of consensus, which were pre-specified prior to voting. RESULTS: The first version of the guidance was approved by the Task Force in June 2020 and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion but is meant to be modified as additional data become available.

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2.

Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1—multisystem inflammatory syndrome in children (MIS-C)—which comprises multiorgan dysfunction and systemic inflammation2–13. We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections14,15, and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness1 and appears distinct from Kawasaki disease. Characterization of a cohort of children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection provides insights into the immunopathogenic features of the disease.

/pdf/peripheral-immunophenotypes-in-children-with-multisystem-2tx42c2v24.pdf

Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.

1 Immunophenotyping of circulating leukocytes reveal non-specific activation of innate and adaptive immune systems in Multi-system Inflammatory Syndrome of Childhood Temporally Associated with SARS-Cov-2 Infection: Descriptive cohort study Michael J. Carter1,2 # PhD; Matthew Fish3,4,5 # MSc; Aislinn Jennings3,4,# MSc; Katie J. Doores4 PhD; Paul Wellman2 BSc, Jeffrey Seow4 PhD; Sam Acors4 PhD; Emma Timms5, Julia Kenny1,2 PhD; Stuart Neil4 PhD; Michael H. Malim4 DPhil; Shane M. Tibby2* MD; Manu Shankar-Hari3,4* PhD # Denote equal contributions *Corresponding authors

https://www.preprints.org/manuscript/202007.0252/v1/download

Immunophenotyping of Circulating Leukocytes Reveal Non-specific Activation of Innate and Adaptive Immune Systems in Multi-System Inflammatory Syndrome of Childhood Temporally Associated with SARS-Cov-2 Infection: Descriptive Cohort Study

Emma Timms

Papers

Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.

Immunophenotyping of Circulating Leukocytes Reveal Non-specific Activation of Innate and Adaptive Immune Systems in Multi-System Inflammatory Syndrome of Childhood Temporally Associated with SARS-Cov-2 Infection: Descriptive Cohort Study