An Investigation Into the Role of IgA and Its Fc Receptor (FcαRI) in Activation of Pro-Inflammatory Signaling and Inhibition Thereof
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CitationGetchell, Kristen. 2019. An Investigation Into the Role of IgA and Its Fc Receptor (FcαRI) in Activation of Pro-Inflammatory Signaling and Inhibition Thereof. Master's thesis, Harvard Extension School.
AbstractAutoimmune diseases are defined as conditions in which the immune system mistakenly attacks the person’s tissues or organs. This often leads to inflammation, tissue destruction, and organ damage. In many cases, unknown precursors trigger autoimmune diseases, which presents a difficult therapeutic problem. Although some therapeutics are effective, many are not across all patients highlighting an unmet medical need. Some non-responder patients with autoimmune diseases have increased levels of immunoglobulin A (IgA). IgA’s sole activating Fc receptor, FcαRI, activates the Immunoreceptor Tyrosine Activation Motif (ITAM) which triggers downstream pro-inflammatory pathways. These pathways are only activated by polymeric IgA. Scientists showed that inhibiting FcαRI with a blocking antibody prevents this activation; however, there is limited understanding of how polymeric IgA’s structure influences activation of inflammatory pathways. Furthermore, a crosstalk between IgA and IgG receptors has been reported. These studies sought to develop in vitro methods to facilitate further investigation into IgA’s activating pro-inflammatory mechanisms. A method was designed to create synthetic immune complex memetics of IgA and IgG, which were used to probe the activation of pro-inflammatory pathways in the U937 monocytic cell line. A comprehensive gene panel of pro-inflammatory pathways associated receptors and cytokines was developed and used to measure via qPCR the downstream impact of IgA- and IgG-immune complex mimetics. IgA-immune complexes induced an increase in expression of IL8, FCAR1, CXCL2, TNFA, and IL1B. IgG-immune complexes also induced a pro-inflammatory signal, which had a unique signature in comparison to IgA-immune complex activation. Immune complex activation could be inhibited with a FcαRI receptor blocking antibodies; thus, reversing the pro-inflammatory signal and suggesting this signal is mediated by FcαRI. Therefore, these studies outline a method development process that resulted in a reproducible assay that can be used to analyze IgA- and IgG-immune complex activation and subsequent inhibition with blocking FcαRI antibodies by measuring gene expression changes in U937 cells. These methods can therefore be useful for screening of therapeutic candidates designed to inhibit IgA and IgG mediated pro-inflammatory signals and further understanding of structural properties of immune complexes necessary to induce cellular activation.
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