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CAREER
[ top ] RESEARCH PhD
thesis:
Experimental models of autoimmune thrombocytopenia in
the mouse
PhD Thesis Summary: Many reports in the literature
indicate that self recognition by the immune system has a physiological role. However, when
dysregulated, this normal type of immune responses can lead to autoimmune diseases. Among
factors that drive autoimmune response to autoimmune pathology, environmental
factors, and especially viruses, play one of the most important roles. Many clinical
reports have indeed associated viruses with autoimmune disease progression.
However, few experimental models have addressed the question of the modulation of
pre-existing autoimmune pathology by viruses.
The main objectives of this work were
to develop a mouse model of human idiopathic autoimmune thrombocytopenic purpura
(AITP) and to study the effector mechanisms of viral modulation exemplified by
lactate dehydrogenase-elevating virus (LDV).
A mouse ITP model was developed by
repetitive active immunizations of mice with rat platelets. Anti-mouse platelet
autoantibody responses were analyzed by ELISA, Western blots and flow cytometry. Immunized
CBA/Ht mice showed a transient thrombocytopenia. Platelets were opsonized by
cross-reactive autoantibodies to both rat and mouse normal platelets. In contrast, BALB/C mice
similarly immunized with rat platelets did not develop thrombocytopenia. The
specificity of the antibody response elicited in these two mouse strains differed markedly,
with a 145-155 kDa mouse platelet antigen, corresponding to platelet glycoprotein
Ib (CD42b) recognized in CBA/Ht, but not in BALB/C animals. In
clodronate-depleting experiments, macrophages were shown to be the effector cells responsible for
antibody-coated platelet destruction.
LDV infection alone was shown to
induce a transient thrombocytopenia in the first 6 days after infection. Platelets are
destroyed by macrophages that are not resident in the spleen. In contrast to IFN-gamma,
M-CSF was shown to be involved in LDV-induced transient thrombocytopenia since
LDV-infected mice treated with anti-M-CSF antibodies showed significantly higher platelet
counts than their untreated counterparts.
In order to study the modulation
effects of LDV on experimentally-induced AITP more simplified mouse experimental models
of human ITP were established. In these models, the autoimmune pathology is mimicked
by a passive transfer of monoclonal autoantibodies, derived from NZBxBXSB
F1 mice as well as by a passive transfer of either polyclonal (obtained from an
immunized rabbit) or monoclonal (commercial antibody derived from the rat)
antibodies.
It was shown in experimental models of
AITP, that a viral infection may enhance the pathogenicity of pre-existing
autoimmune responses. The virus was found to largely increase the platelet destruction
induced by anti-platelet autoantibody, leading to the development of measurable thrombopenia
and of clinical symptoms (petechiae). The viral infection triggered an enhancement of
phagocytosis of autoantibody-coated target cells (platelets). The pathogenicity of the
autoantibodies required the presence of their Fc portion, suggesting that macrophage Fc
and/or complement receptor expression is involved. Macrophages and IFN-gamma
secretion played also a pivotal role in this virally-induced destruction of
autoantibody-coated thrombocytes.
[ top ] LINKS Immunology &
Virology
Lectures on line
Weill Medical College of Cornell University Tamuk.edu micro.msb.le.ac.uk - Virology Lecture Notes www.uct.ac.za - Clinical Virology urmc.rochester.edu - General Virology: For Graduate and Undergraduate Students athena.bioc.uvic.ca - Virus Ultrastructure tulane.edu - Lecture Notes tulane.edu - Infection and Immunity Immunology & Virology Links RESSOURCES DU WEB POUR L'ENSEIGNEMENT DE L'IMMUNOLOGIE et l'apprentissage de l'IMMUNOLOGIE Worldwide Immunology Resources Mik.ki.se - Immunologic Diseases Knockmice database wiley.co.uk ALL THE VIROLOGY ON THE WWW The International Committee on Taxonomy of Viruses VIROLOGY (General, HIV) and Related links umontreal.ca - Ressources d'Internet en microbiologie Immunology forums Biowww Immunology Forum Protocol-on-line Forum |
