Identification of a Specific Self-Reactive IgM Antibody That Initiates Intestinal Ischemia/Reperfusion Injury

Reperfusion injury of ischemic tissue represents an acute inflammatory response that can cause significant morbidity and mortality. The mechanism of injury is not fully elucidated, but recent studies indicate an important role for natural antibody and the classical pathway of complement. To test the...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-03, Vol.101 (11), p.3886-3891
Main Authors: Zhang, Ming, Austen, Jr, William G, Chiu, Isaac, Alicot, Elisabeth M, Hung, Rachel, Ma, Minghe, Verna, Nicola, Xu, Min, Hechtman, Herbert B, Moore, Jr, Francis D, Carroll, Michael C
Format: Article
Language:English
Subjects:
Animals
Antibodies
B lymphocytes
B-1 cells
B-Lymphocytes - immunology
Biological Sciences
Cell cycle
complement component C3
complement component C4
Endothelial cells
Germ cells
Homeodomain Proteins - genetics
Hybridomas
Hybridomas - immunology
Hypoxia
Immunoglobulin M - immunology
Immunology
Intestines - immunology
Mice
Mice, Knockout
Molecular Sequence Data
Muscular system
Pathology
Physical trauma
Reperfusion injury
Reperfusion Injury - immunology
Villi
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Summary:Reperfusion injury of ischemic tissue represents an acute inflammatory response that can cause significant morbidity and mortality. The mechanism of injury is not fully elucidated, but recent studies indicate an important role for natural antibody and the classical pathway of complement. To test the hypothesis that injury is initiated by specific IgM, we have screened a panel of IgM-producing hybridomas prepared from peritoneal cells enriched in B-1 cells. One clone, CM22, was identified that could restore pathogenic injury in RAG-1-/-mice in an intestinal model of ischemia/reperfusion (I/R). In situ activation of the classical pathway of complement was evident by deposition of IgM, complement C4, and C3 in damaged tissue after passive transfer of CM22 IgM. Sequence analysis of CM22 Ig heavy and light chains showed germ-line configurations with high homology to a VHsequence from the B-1 repertoire and a VKof a known polyreactive natural IgM. These data provide definitive evidence that I/R injury can be initiated by clonally specific natural IgM that activates the classical pathway of complement. This finding opens an avenue for identification of I/R-specific self-antigen(s) and early prevention of injury.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0400347101