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Expression of major histocompatibility complex antigens on mouse brain microvascular endothelial cells in relation to
C Monso-Hinard1, J N Lou, C Behr
1Department of Anaesthesiology, Pharmacology and Surgical Intensive Care, CMU, University of Geneva, Switzerland.
Abstract:
The physiopathology of experimental cerebral malaria (CM), an acute neurological complication of Plasmodium berghei ANKA (PbA) infection, involves interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), two cytokines that are known to modulate major histocompatibility complex (MHC) molecule expression. The aim of this study was to evaluate whether the genetic susceptibility to CM is related to the constitutive or IFN-gamma-induced expression of MHC molecules on brain microvessels. To this end, brain microvascular endothelial cells (B-MVEC) were isolated from CM-susceptible (CM-S, CBA/J) and resistant (CM-R, BALB/c) mice. By flow cytometry, we found that less than 5% of CM-S B-MVEC constitutively expressed MHC class I molecules, in contrast to up to 90% of CM-R B-MVEC. Upon stimulation with IFN-gamma, the percentage of positive cells for MHC class I molecules in CM-S B-MVEC became comparable to CM-R B-MVEC, but a higher fluorescence intensity existed on CM-S B-MVEC compared with CM-R B-MVEC. MHC class II molecules were not constitutively expressed on B-MVEC from either strain. IFN-gamma-induced expression of MHC class II (I-A, I-E) molecules was significantly higher in CM-S than CM-R B-MVEC both in percentage of positive cells and fluorescence intensity. These data demonstrate that absent or low MHC class I and higher inducibility of MHC class II expression on B-MVEC are associated with the genetic susceptibility to CM.
Insights
Genetic susceptibility to experimental cerebral malaria (CM) in mice is linked to low constitutive expression of major histocompatibility complex (MHC) class I and high IFN-gamma-induced MHC class II expression on brain endothelial cells.
Area of Science:
- Neuroimmunology
- Infectious Diseases
- Molecular Biology
Background:
- Experimental cerebral malaria (CM) is a severe neurological complication of Plasmodium berghei ANKA (PbA) infection.
- Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) are key cytokines involved in CM pathogenesis.
- Cytokines modulate major histocompatibility complex (MHC) molecule expression, influencing immune responses.
Purpose of the Study:
- To investigate the relationship between genetic susceptibility to CM and the expression of MHC molecules on brain microvessels.
- To compare constitutive and IFN-gamma-induced MHC molecule expression in CM-susceptible and CM-resistant mice.
Main Methods:
- Isolation of brain microvascular endothelial cells (B-MVEC) from CM-susceptible (CBA/J) and CM-resistant (BALB/c) mice.
- Flow cytometry analysis to quantify MHC class I and class II molecule expression.
- Stimulation of B-MVEC with IFN-gamma to assess inducible expression.
Main Results:
- CM-susceptible B-MVEC showed significantly lower constitutive MHC class I expression compared to CM-resistant B-MVEC.
- IFN-gamma stimulation normalized MHC class I expression percentage but increased intensity in CM-susceptible B-MVEC.
- MHC class II expression, absent constitutively, was significantly higher in IFN-gamma-stimulated CM-susceptible B-MVEC.
Conclusions:
- Low constitutive MHC class I expression on brain microvessels is associated with genetic susceptibility to experimental cerebral malaria.
- Enhanced IFN-gamma-inducible MHC class II expression on brain microvessels contributes to CM susceptibility.
- These findings highlight the role of endothelial MHC molecule regulation in malaria neuropathology.