Malondialdehyde-acetaldehyde-haptenated protein induces cell death by induction of necrosis and apoptosis in immune cells

Monte S. Willis, Lynell Warren Klassen, Dean J. Tuma, Geoffrey Milton Thiele

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23 Citations (Scopus)

Abstract

Recent studies have demonstrated that circulating antibodies against malondialdehyde-acetaldehyde (MAA)-haptenated proteins are significantly increased in patients with alcohol-induced cirrhosis and hepatitis and correlate with the severity of liver damage. Additionally, when proteins are haptenated with MAA, they become highly immunogenic in vivo in the absence of adjuvants. However, the mechanism(s) of this immunogenicity are currently unknown. Initial in vitro studies on the effects of MAA-modified proteins on cells demonstrated an increase in cell death at concentrations that were cell type specific and time-dependent. Since immunogenicity due to cell death has been described, we investigated the mechanism(s) by which cell death was occurring. Assessment of cell death in splenocytes after 1 h found significant levels of apoptosis as compared to controls. After 5 h, a significant and dose-dependent necrosis occurred in which cells were exposed to > 62.5 μg/ml (43.1 mM) MAA-haptenated protein. After 24 h, exposure to >31.3 μg/ml (21.6 mM) MAA-haptenated protein resulted in significant levels of necrosis, although DNA laddering studies found apoptosis was occurring as well. Morphological changes in the cells were observed by light microscopy that correlated with a "low" forward scatter population by flow cytometry. Since necrosis has been implicated in enhancing both primary and secondary immune responses, and necrosis was predominantly occurring in response to MAA-haptenated proteins, a possible mechanism by which the immunogenicity of MAA modification of proteins in vivo may occur is suggested. Specifically, MAA modification of self proteins may result in the death of various cell types, most likely those in the liver. These necrotic materials may induce anti-MAA antibodies and other auto antibodies, whose levels may then correlate with the severity of ALD.

Original languageEnglish (US)
Pages (from-to)519-535
Number of pages17
JournalInternational Immunopharmacology
Volume2
Issue number4
DOIs
StatePublished - Mar 5 2002

Fingerprint

Acetaldehyde
Malondialdehyde
Cell Death
Necrosis
Apoptosis
Proteins
Antibodies
Liver
Hepatitis
Microscopy
Flow Cytometry
Fibrosis
Alcohols
Light
DNA

Keywords

  • Aldehydes
  • Apoptosis
  • Cell death
  • Immune system
  • Necrosis
  • Protein adducts

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

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title = "Malondialdehyde-acetaldehyde-haptenated protein induces cell death by induction of necrosis and apoptosis in immune cells",
abstract = "Recent studies have demonstrated that circulating antibodies against malondialdehyde-acetaldehyde (MAA)-haptenated proteins are significantly increased in patients with alcohol-induced cirrhosis and hepatitis and correlate with the severity of liver damage. Additionally, when proteins are haptenated with MAA, they become highly immunogenic in vivo in the absence of adjuvants. However, the mechanism(s) of this immunogenicity are currently unknown. Initial in vitro studies on the effects of MAA-modified proteins on cells demonstrated an increase in cell death at concentrations that were cell type specific and time-dependent. Since immunogenicity due to cell death has been described, we investigated the mechanism(s) by which cell death was occurring. Assessment of cell death in splenocytes after 1 h found significant levels of apoptosis as compared to controls. After 5 h, a significant and dose-dependent necrosis occurred in which cells were exposed to > 62.5 μg/ml (43.1 mM) MAA-haptenated protein. After 24 h, exposure to >31.3 μg/ml (21.6 mM) MAA-haptenated protein resulted in significant levels of necrosis, although DNA laddering studies found apoptosis was occurring as well. Morphological changes in the cells were observed by light microscopy that correlated with a {"}low{"} forward scatter population by flow cytometry. Since necrosis has been implicated in enhancing both primary and secondary immune responses, and necrosis was predominantly occurring in response to MAA-haptenated proteins, a possible mechanism by which the immunogenicity of MAA modification of proteins in vivo may occur is suggested. Specifically, MAA modification of self proteins may result in the death of various cell types, most likely those in the liver. These necrotic materials may induce anti-MAA antibodies and other auto antibodies, whose levels may then correlate with the severity of ALD.",
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T1 - Malondialdehyde-acetaldehyde-haptenated protein induces cell death by induction of necrosis and apoptosis in immune cells

AU - Willis, Monte S.

AU - Klassen, Lynell Warren

AU - Tuma, Dean J.

AU - Thiele, Geoffrey Milton

PY - 2002/3/5

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KW - Necrosis

KW - Protein adducts

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