Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity.
HLA-G is a non-classical major histocompatibility complex (MHC) class I antigen with highly limited tissue distribution under non-pathological conditions. Although capable of acting as a peptide-presenting molecule, its strong immune-inhibitory properties identify HLA-G as a mediator of immune tolerance with specific relevance at immune-privileged sites such as trophoblast or thymus. To assess the role of HLA-G in CNS immunity, we investigated its expression in brain specimens from patients with multiple sclerosis (n = 11), meningitis (n = 2) and Alzheimer's disease (n = 2) and non-pathological CNS controls (n = 6). Furthermore, cultured human microglial cells and CSF of patients with multiple sclerosis and controls were assessed. Furthermore, CSF from MS patients and controls, as well as cultured human microglial cells were assessed. Using several HLA-G specific mAb and immunohistochemistry, HLA-G protein was found strongly expressed in brain specimens from patients with multiple sclerosis while it was rarely detectable in the non-pathological control specimens. In multiple sclerosis brain specimens, HLA-G immunoreactivity was observed in acute plaques, in chronic active plaques, in perilesional areas as well as in normal appearing white matter. In all areas microglial cells, macrophages, and in part endothelial cells were identified as the primary cellular source of expression. HLA-G was also found in other disease entities (meningitis, Alzheimer's specimens) where expression correlated to activation and MHC class II expression on microglial cells. Importantly, ILT2, a receptor for HLA-G, was also found in multiple sclerosis brain specimens thus emphasizing the relevance of this inhibitory pathway in vivo. HLA-G mRNA and protein expression and regulation could also be corroborated on cultured human microglial cells in vitro. Further, expression of HLA-G in the CSF of multiple sclerosis patients and controls was analysed by flow cytometry and ELISA. Monocytes represented the main source of cellular HLA-G expression in the CSF. Corresponding to the observations with the tissue specimens, CSF mean levels of soluble HLA-G were significantly higher in multiple sclerosis than in non-inflammatory controls (171 +/- 31 versus 39 +/- 10 U/ml; P = 0.0001). The demonstration of HLA-G and its receptor ILT2 on CNS cells and in areas of microglia activation implicate HLA-G as a contributor to the fundamental mechanisms regulating immune reactivity in the CNS. This pathway may act as an inhibitory feedback aimed to downregulate the deleterious effects of T-cell infiltration in neuroinflammation.
Wiendl
Heinz
H
Department of General Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. heinz.wiendl@klinik.uni-wuerzburg.de
Feger
Ute
U
Mittelbronn
Michel
M
Jack
Carolyn
C
Schreiner
Bettina
B
Stadelmann
Christine
C
Antel
Jack
J
Brueck
Wolfgang
W
Meyermann
Richard
R
Bar-Or
Amit
A
Kieseier
Bernd C
BC
Weller
Michael
M
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006680:HLA Antigens / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008264:Macrophages / Q000276:immunology; D008297:Male; D008581:Meningitis / Q000276:immunology; D017628:Microglia / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism; D012995:Solubility; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D012333:RNA, Messenger; D011971:Receptors, Immunologic