The role of skewed immune responses in the resolution of viral infection, allergic disease, and sterile injury

The immune system evolved to protect the host from external pathogens as well as manage host internal processes including tissue repair after damage. This thesis explores different aspects of immune responses in the context of viral infection, allergic disease, and internal, sterile muscle injury. Firstly, the characterization of peripheral blood immune cells in patients admitted to the intensive care unit (ICU) due to an infection with SARS-CoV-2, the virus that causes COVID-19, uncovered immune biomarkers, specifically serum IL-10 and CD11cˡºʷ classical monocytes, that are predictive of disease outcome. The unprecedented and ongoing burden caused by the COVID-19 pandemic makes this research timely and critical to assist with ICU patient management. Secondly, the characterization of immune cells in archived umbilical cord blood revealed biomarkers predictive of the development of childhood allergic disease, which occurs commonly and severely and for which disease origin is unclear. Our findings suggest that alterations in naive CD8 T cells and monocytes are already established prior to birth in children who, by the age of 5, develop a combined wheeze and atopy phenotype. The stages of prenatal immune development are rarely explored in the context of allergic disease development and may be a new avenue for early disease detection and prevention. Lastly, the characterization and manipulations of type-2 immune responses in mouse models of sterile acute and chronic skeletal muscle injury showed that type-2 immune cells are largely expendable in normal tissue regeneration but accelerate muscle pathology. Specifically, IL-33- induced type-2 immunity promoted prominent influx of ILC2s and eosinophils in acutely injured skeletal muscle with no discernable impact on muscle regeneration but accelerated fibrosis deposition in mdx mice – a model of Duchenne muscular dystrophy. These findings add to our understanding of how the immune system supports normal tissue function and how tissue is damaged in disease, which is fundamental for future development of disease treatments and preventative measures.Medicine, Faculty ofExperimental Medicine, Division ofGraduat

Group 2 Innate Lymphoid Cells: Central Players in a Recurring Theme of Repair and Regeneration

Innate lymphoid cells (ILCs) are recently discovered innate counterparts to the well-established T helper cell subsets and are most abundant at barrier surfaces, where they participate in tissue homeostasis and inflammatory responses against invading pathogens. Group 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression profiles with type-2 helper T cells and are primarily associated with immune responses against allergens and helminth infections. Emerging data, however, suggests that ILC2s are also key regulators in other inflammatory settings; both in a beneficial context, such as the establishment of neonatal immunity, tissue repair, and homeostasis, and in the context of pathological tissue damage and disease, such as fibrosis development. This review focuses on the interactions of ILC2s with stromal cells, eosinophils, macrophages, and T regulatory cells that are common to the different settings in which type-2 immunity has been explored. We further discuss how an understanding of these interactions can reveal new avenues of therapeutic tissue regeneration, where the role of ILC2s is yet to be fully established.Applied Science, Faculty ofMedicine, Faculty ofOther UBCBiomedical Engineering, School ofExperimental Medicine, Division ofMedical Genetics, Department ofMedicine, Department ofReviewedFacult

Prognostic peripheral blood biomarkers at ICU admission predict COVID-19 clinical outcomes

The COVID-19 pandemic continues to challenge the capacities of hospital ICUs which currently lack the ability to identify prospectively those patients who may require extended management. In this study of 90 ICU COVID-19 patients, we evaluated serum levels of four cytokines (IL-1b, IL-6, IL-10 and TNFa) as well as standard clinical and laboratory measurements. On 42 of these patients (binned into Initial and Replication Cohorts), we further performed CyTOF-based deep immunophenotyping of peripheral blood mononuclear cells with a panel of 38 antibodies. All measurements and patient samples were taken at time of ICU admission and retrospectively linked to patient clinical outcomes through statistical approaches. These analyses resulted in the definition of a new measure of patient clinical outcome: patients who will recover after short ICU stays (< 6 days) and those who will subsequently die or recover after long ICU stays (≥6 days). Based on these clinical outcome categories, we identified blood prognostic biomarkers that, at time of ICU admission, prospectively distinguish, with 91% sensitivity and 91% specificity (positive likelihood ratio 10.1), patients in the two clinical outcome groups. This is achieved through a tiered evaluation of serum IL-10 and targeted immunophenotyping of monocyte subsets, specifically, CD11clow classical monocytes. Both immune biomarkers were consistently elevated ( ≥15 pg/ml and ≥2.7 x107 /L for serum IL-10 and CD11clow classical monocytes, respectively) in those patients who will subsequently die or recover after long ICU stays. This highly sensitive and specific prognostic test could prove useful in guiding clinical resource allocation.Applied Science, Faculty ofHealth and Social Development, Faculty of (Okanagan)Medicine, Faculty ofNon UBCAnesthesiology, Pharmacology and Therapeutics, Department ofBiomedical Engineering, School ofCellular and Physiological Sciences, Department ofHealth and Exercise Sciences, School of (Okanagan)Medicine, Department ofPathology and Laboratory Medicine, Department ofRespiratory Medicine, Division ofReviewedFacultyResearcherPostdoctora