Hypersensitivity pneumonitis (HP) is a pulmonary disease caused by repetitive exposure to some components of bioaerosols. HP is characterized by neutrophil recruitment in the airways, B cell-enriched tertiary lymphoid tissue formation in the lung and antigen-specific antibody accumulation that can lead to pulmonary fibrosis. HP diagnosis is challenging since causal agent cannot be identified in 30% of cases and there is no distinct clinical sign for the disease. Given the late diagnosis and the inability of current treatment to restore normal lung function in chronic HP, there is no effective treatment for chronic HP. The objective of this thesis was to improve the knowledge on persistent inflammation mechanisms in HP and to identify new therapeutic targets. Sphingosine-1-phosphate receptor 1 (S1P₁) modulators control lymphocyte migration between lymphoid organs and are currently used or under investigation to treat some inflammatory diseases. The objective of the first study was to determine the impact of S1P₁ modulators on experimental HP progression. Mice were exposed three consecutive days a week for three weeks to the immunogen archaea Methanosphaera stadtmanae (MSS) and treated with an S1P₁ agonist, RP001. In experimental HP, RP001 prevents neutrophil recruitment, TLT reactivation and antigen-specific antibody accumulation induced by MSS rechallenge. Because HP is caused by environmental agents, patients are exposed to both T-dependent and T-independent antigens. Thereby, in a second study, the objective was to evaluate the impact of T-independent antigen on experimental HP. In MSS-sensitized mice, lipopolysaccharide (LPS) challenge induces an increase in neutrophilic inflammation, activates pulmonary lymphocytes and induces MSS-specific IgG1 accumulation in the bronchoalveolar lavage. Since we showed that S1P₁ ligands interfere with antigen-specific antibody accumulation, the second objective of this study was to determine the impact of S1P₁ ligands on T-independent antigen-induced B cell activation and functions. An S1P₁ agonist inhibits LPS-induced cytokine release and co-stimulatory molecule increase leading to a decrease in their ability to activate T cells. Even though it is assumed that B cells and their production of soluble mediators are central to HP pathogenesis, few studies were interested in their regulation in this disease. In a third study, the objectives were to characterize circulatory lymphocyte sub-populations in HP and to determine the impact of S1P₁ ligands on human B cell activation induced by T-independent antigens. Venous blood of ten chronic HP patients and ten control subjects paired for age, sex and smoking status were analyzed. The proportion of circulating memory B cells are reduced, and B cell-related soluble mediators are increased in chronic HP patients compared to control subjects, while T cell populations were similar between the two groups. Furthermore, an S1P₁ ligand prevents co-stimulatory molecule increase and cytokine release (TNF, IL-6), which is insensitive to dexamethasone. In conclusion, we unravel circulating B cell alterations in chronic HP patients. We also identify two potential actors implicated in HP pathogenesis, the T-independent response and the S1P₁ modulators. We showed that an S1P₁ agonist prevents the reactivation of experimental HP and inhibits T-independent antigen induced B cell functions. Thus, this thesis improves the knowledge regarding persistent inflammation in HP and identifies the S1P₁ receptor as a potential target to interfere with HP-related B cell functions.
| Identifer | oai:union.ndltd.org:LAVAL/oai:corpus.ulaval.ca:20.500.11794/67064 |
| Date | 02 February 2024 |
| Creators | Huppé, Carole-Ann |
| Contributors | Marsolais, David, Morissette, Mathieu |
| Source Sets | Université Laval |
| Language | French |
| Detected Language | English |
| Type | thèse de doctorat, COAR1_1::Texte::Thèse::Thèse de doctorat |
| Format | 1 ressource en ligne (xvii, 139 pages), application/pdf |
| Rights | http://purl.org/coar/access_right/c_abf2 |
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