Phagosomal Redox Sensitive Cysteine Cathepsins Modify MHC-II Mediated Adaptive Immune Responses During EAE in Mice
Date
2015-06-18
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Abstract
This dissertation characterizes redox-sensitive cysteine cathepsins during MHC-II- restricted MOG antigen processing, and MOG- induced experimental autoimmune encephalomyelitis (EAE). The phagosomal redox environment can modify the activity of multiple cysteine cathepsins and these proteases can, in turn, perturb antigen processing and presentation, particularly of MOG. Initially, we explored the effects of NADPH oxidase 2 (NOX2) on patterns of antigen processing in antigen presenting cells (APCs). We discovered that NOX2 influences the pattern, and abundance, of model- peptide antigens that are produced during the phagosomal processing of these proteins in a cell-, and antigen- specific manner. Specifically, the immunodominant peptide of MOG (MOG35-55 in C57/Bl6 mice) is likely destroyed by excessive cathepsin S and L activity in NOX2-deficeint macrophages. Mice deficient in NOX2 exhibit protection from EAE, which is likely due to inefficient MOG- antigen processing and presentation. Secondly, we characterized EAE and MOG antigen presentation in cathepsin B-, S-, and L- deficient mice. These redox-sensitive cysteine cathepsins are redundant for the processing and presentation of MOG antigens and EAE, but mice simultaneously deficient in cathepsin B and S are protected from EAE, and have a MHC-II processing deficiency. Cumulatively, these findings indicate that MOG antigen presentation can be modulated by both excessive (by eliminating NOX2-induced cathepsin inhibition) or limited cysteine cathepsin activity in the phagosome of APCs. Lastly, we investigated the role of cathepsin Z during MOG processing, presentation, and EAE. Like the other cysteine cathepsins, cathepsin Z is redundant for MOG processing and presentation; but mice deficient in cathepsin Z are protected from EAE, and exhibit unexpected Th17 and IL-1β deficiencies during EAE. Further exploration revealed that CD4+ T cells deficient in cathepsin Z have a reduced propensity for Th17 polarization when in the presence of cathepsin Z deficient- APCs. Correlatively, we found a novel IL-1β/18 production deficiency in cathepsin Z deficient- APCs. Collectively, the work presented in this dissertation provides novel evidence that phagosomal redox-sensitive cysteine cathepsins have intricate roles in antigen processing and autoimmunity, with particular relevance to MHC-II-restricted adaptive immune responses during MOG- induced EAE.
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Immunology
Citation
Allan, E. (2015). Phagosomal Redox Sensitive Cysteine Cathepsins Modify MHC-II Mediated Adaptive Immune Responses During EAE in Mice (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27323