en
Doctoral thesis
English

Time-of-day effect on adaptive immune responses and central nervous system autoimmunity

ContributorsBarnoud, Colineorcid
Number of pages230 p.
Imprimatur date2023
Defense date2023
Abstract

Circadian rhythms are present in virtually all organisms and are evolutionarily conserved time-keeping mechanisms describing biological processes that oscillate in approximately 24-hour patterns. These rhythms are kept in synchrony by environmental cues and participate in the proper function of several physiological processes, among which are the innate and the adaptive immune system. Circadian rhythms are beneficial as they allow organisms to anticipate recurring events and to tune their behavioral response accordingly. With respect to immunity, these rhythms help the host to modulate its reactivity to times at which the probability of pathogen encounters may be highest. In addition, time-of-day-dependent activation of the immune system must be tightly controlled to trigger an efficient immune response without inducing side effects such as autoimmunity.

It is now widely accepted that time-of-day-dependent mechanisms can govern an acute immune response. However, we still do not understand why adaptive immune responses remain oscillatory over long periods of time. In the first part of this thesis, I demonstrate that the initial time of the challenge is key to shape the adaptive immune response for the ensuing several weeks. In particular, the time-of-day-dependent migration of dendritic cells generates oscillations in lymph node cellularity, which persists for weeks after the initial challenge and results in an increased likelihood of functional encounters between antigen-presenting dendritic cells and antigen-recognizing T cells. This is especially important in the context of immune responses to vaccination. Additionally, I show that rhythmic migration, activation, and function of different immune cells are required to create and maintain an efficient immune response over time.

However, immune responses are not always beneficial as is the case for an immune response directed against self, which can lead to autoimmunity. The second part of the thesis aims to decipher to what extent circadian rhythms are contributing to the development of experimental autoimmune encephalomyelitis (EAE), the most common mouse model of multiple sclerosis (MS). Using this model, I show a time-of-day dependent infiltration of immune cells into the central nervous system (CNS) during EAE development that is independent of disease severity. Interestingly, I observe a substantial increase in blood circulating CD11b+Ly6G+ cells before the appearance of symptoms associated with a switch in their phenotype. Altogether, these data suggest a potential contribution of CD11b+Ly6G+ leukocytes to early disease. Analysis of the mRNA levels in the spinal cord of EAE animals reveal a time-of-day dependent expression of both Cxcl1 and Cxcl2 chemokines responsible for the migration of monocytes and neutrophils, respectively. This study suggests the importance of circadian oscillations in cell infiltration in the central nervous system, as well as the importance of CD11b+Ly6G+ leukocytes in EAE development and identifies these cells as potential early biomarkers for diagnosis purposes and new therapeutic targets in MS patients.

eng
Keywords
  • Circadian rhythms
  • Adaptive immunity
  • Autoimmunity
  • Vaccination
  • EAE
Citation (ISO format)
BARNOUD, Coline. Time-of-day effect on adaptive immune responses and central nervous system autoimmunity. 2023. doi: 10.13097/archive-ouverte/unige:168397
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Thesis
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