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Unique features of nucleolar autoant...

Ulanet, Danielle Beth.

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Unique features of nucleolar autoantigens in disease-relevant microenvironments: Insights into the etiology of the specific autoimmune response in scleroderma and cancer.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Unique features of nucleolar autoantigens in disease-relevant microenvironments: Insights into the etiology of the specific autoimmune response in scleroderma and cancer./
Author:	Ulanet, Danielle Beth.
Description:	103 p.
Notes:	Adviser: Antony Rosen.
Contained By:	Dissertation Abstracts International63-03B.
Subject:	Health Sciences, Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3046569
ISBN:	0493607595

Unique features of nucleolar autoantigens in disease-relevant microenvironments: Insights into the etiology of the specific autoimmune response in scleroderma and cancer.
Ulanet, Danielle Beth.

Unique features of nucleolar autoantigens in disease-relevant microenvironments: Insights into the etiology of the specific autoimmune response in scleroderma and cancer. - 103 p.

Adviser: Antony Rosen.

Thesis (Ph.D.)--The Johns Hopkins University, 2002.

Autoantigens are a diverse group of proteins that are targeted by the immune response in numerous different diseases. In autoimmune disorders, such a self-directed immune response is detrimental and can lead to the destruction of healthy tissue. In contrast, an autoimmune response in cancer may be beneficial and promote tumor destruction. The identification of autoantigens and the features that render these self-proteins immunogenic will greatly aid in understanding the etiology of the autoimmune response in these diseases and potentially in precluding or bolstering such responses, where appropriate. We have found that the majority of autoantigens targeted across the spectrum of systemic autoimmune diseases, as well as several cancer autoantigens, are efficiently cleaved by the cytotoxic lymphocyte granule serine protease, granzyme B, to generate unique fragments. No non-autoantigens have been identified that share such features. These findings provide a link between cytotoxic lymphocyte granule-mediated cell death and the selection of autoantigens by the autoimmune response. Since autoimmunity is a rare event compared to the routine occurrence of cytotoxic lymphocyte-induced apoptosis, we have hypothesized that granzyme B-mediated proteolysis of autoantigens may be regulated. By examining the susceptibility of a variety of nucleolar scleroderma and hepatocellular carcinoma autoantigens to cleavage by granzyme B both <italic>in vitro</italic> and in intact cells undergoing cytotoxic lymphocyte granule-induced cell death, we have addressed whether these autoantigens may exhibit differential susceptibility to granzyme B proteolysis in these various systems. We found that while two such autoantigens, B23 and fibrillarin, are efficiently cleaved by granzyme B using <italic>in vitro</italic> translated protein as substrate, they are highly resistant to cleavage by granzyme B in most other more physiological systems tested. An exception was the very efficient cleavage of these molecules by granzyme B in differentiated smooth muscle cells, which interestingly are a scleroderma-relevant cell type. Similarly, B23 was efficiently cleaved by granzyme B in liver tumor extracts, though resistant to cleavage in normal liver extracts. We propose that the selective cleavage of these nucleolar autoantigens by granzyme B in the disease-relevant microenvironment may explain the association of autoantiodies against these molecules with a specific disease phenotype.

ISBN: 0493607595Subjects--Topical Terms:

1017716
Health Sciences, Immunology.

Unique features of nucleolar autoantigens in disease-relevant microenvironments: Insights into the etiology of the specific autoimmune response in scleroderma and cancer.
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245 1 0 $a Unique features of nucleolar autoantigens in disease-relevant microenvironments: Insights into the etiology of the specific autoimmune response in scleroderma and cancer.
300 $a 103 p.
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500 $a Source: Dissertation Abstracts International, Volume: 63-03, Section: B, page: 1253.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2002.
520 $a Autoantigens are a diverse group of proteins that are targeted by the immune response in numerous different diseases. In autoimmune disorders, such a self-directed immune response is detrimental and can lead to the destruction of healthy tissue. In contrast, an autoimmune response in cancer may be beneficial and promote tumor destruction. The identification of autoantigens and the features that render these self-proteins immunogenic will greatly aid in understanding the etiology of the autoimmune response in these diseases and potentially in precluding or bolstering such responses, where appropriate. We have found that the majority of autoantigens targeted across the spectrum of systemic autoimmune diseases, as well as several cancer autoantigens, are efficiently cleaved by the cytotoxic lymphocyte granule serine protease, granzyme B, to generate unique fragments. No non-autoantigens have been identified that share such features. These findings provide a link between cytotoxic lymphocyte granule-mediated cell death and the selection of autoantigens by the autoimmune response. Since autoimmunity is a rare event compared to the routine occurrence of cytotoxic lymphocyte-induced apoptosis, we have hypothesized that granzyme B-mediated proteolysis of autoantigens may be regulated. By examining the susceptibility of a variety of nucleolar scleroderma and hepatocellular carcinoma autoantigens to cleavage by granzyme B both <italic>in vitro</italic> and in intact cells undergoing cytotoxic lymphocyte granule-induced cell death, we have addressed whether these autoantigens may exhibit differential susceptibility to granzyme B proteolysis in these various systems. We found that while two such autoantigens, B23 and fibrillarin, are efficiently cleaved by granzyme B using <italic>in vitro</italic> translated protein as substrate, they are highly resistant to cleavage by granzyme B in most other more physiological systems tested. An exception was the very efficient cleavage of these molecules by granzyme B in differentiated smooth muscle cells, which interestingly are a scleroderma-relevant cell type. Similarly, B23 was efficiently cleaved by granzyme B in liver tumor extracts, though resistant to cleavage in normal liver extracts. We propose that the selective cleavage of these nucleolar autoantigens by granzyme B in the disease-relevant microenvironment may explain the association of autoantiodies against these molecules with a specific disease phenotype.
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