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Investigating the Role of Interleukin-4 and Type 2 Immune Responses in Articular Joint Health and Disease.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Investigating the Role of Interleukin-4 and Type 2 Immune Responses in Articular Joint Health and Disease./
作者:	von Kaeppler, Ericka Priscilla.
面頁冊數:	1 online resource (128 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-03, Section: B.
Contained By:	Dissertations Abstracts International84-03B.
標題:	Pathogens. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29288666click for full text (PQDT)
ISBN:	9798845457622

Investigating the Role of Interleukin-4 and Type 2 Immune Responses in Articular Joint Health and Disease.
von Kaeppler, Ericka Priscilla.

Investigating the Role of Interleukin-4 and Type 2 Immune Responses in Articular Joint Health and Disease. - 1 online resource (128 pages)

Source: Dissertations Abstracts International, Volume: 84-03, Section: B.

Thesis (Ph.D.)--Stanford University, 2022.

Includes bibliographical references

Osteoarthritis (OA), often called degenerative joint disease, is widely accepted as the most common type of joint disease[1], affecting 14% of adults, over 30 million individuals, in the U.S. annually from 2008-2014. Despite the high prevalence, significant economic burden, and debilitating impact on individuals with OA, there currently are no disease modifying treatments available for OA. Current therapeutic strategy is largely palliative and focuses on symptom management. For end-stage disease in patients with severe functional impairment, total joint replacement is considered both clinically-relevant and cost-effective[2]. While the current therapeutic strategies are effective for symptom management, the focus of drug development has shifted to disease-modifying agents, in an effort to more effectively address the larger epidemic of OA.Historically, OA has been thought of as a simple 'wear-and-tear' mechanically-driven disease. In the past decade, improved understanding of OA pathobiology has challenged this view, instead favoring the view of OA as a multifactorial disorder with many significant drivers of disease. Identification and characterization of these additional 'significant drivers' has and will continue to identify new targets for therapeutic intervention. Though OA is not thought of as classical "inflammatory arthritis", chronic, low-grade inflammation is now thought to be one of the significant drivers of disease, playing a central role in pathogenesis[3]. The current understanding of the role of inflammation in OA is that injury (acute, subacute, or chronic) initiates tissue damage that, in turn, triggers an inflammatory response. In the context of other risk factors such as obesity, aging, or other genetic factors, this sequence of events can trigger a vicious cycle of inflammatory response to local tissue damage and failed tissue regeneration, ultimately leading to joint degeneration[3].One inflammatory pathway that has been less commonly studied in OA is that of interleukin-4 (IL-4), an important cytokine in type 2 immunity. Though yet to be understood as a driver of disease, IL-4 pathway components have been linked to OA with genomic analyses identifying associations between IL-4R polymorphisms and hand OA[4], knee OA[5], and hip OA[6]. Additionally, a number of joint-resident cell types are known to be IL-4-responsive, further supporting the hypothesis that IL-4 may play an important role in joint homeostasis. In this thesis, I attempt to demonstrate my overarching hypothesis that, though OA is not a disease of type 2 immunity, components of type 2 immune responses can contribute to maintenance of joint health and protect against OA. In Chapter 2, we investigated the role of IL-4 in OA pathogenesis using in vivo and in vitro models of disease. Mice deficient in various IL-4 pathway components were subjected to destabilization of the medial meniscus to induce OA. Macrophages, osteoclasts, and synovial explants were stimulated with IL-4 in vitro, and their function and expression profiles characterized. We found that mice lacking in IL-4 cytokine, receptors, and signal transducers developed exacerbated cartilage damage and osteophyte formation relative to WT controls. In vitro analyses revealed that IL-4 downregulates osteoarthritis-associated genes, enhances macrophage phagocytosis of cartilage debris, and inhibits osteoclast differentiation and activation via the type I receptor. Taken together, our findings demonstrate that IL-4 protects against osteoarthritis in a myeloid and STAT6-dependent manner.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798845457622Subjects--Topical Terms:

3540520
Pathogens.
Index Terms--Genre/Form:

542853
Electronic books.

Investigating the Role of Interleukin-4 and Type 2 Immune Responses in Articular Joint Health and Disease.
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