Search

Recent animal studies have found neuronal expression of major histocompatibility complex (MHC) class I in the central nervous system (CNS). However, the developmental expression profiles of MHC class I in human CNS remain unclear. Here, we systemically evaluate the expression and subcellular localization of MHC class I molecules during human CNS development using immunohistochemistry and immunofluorescence. Between the age of 20-33 gestational weeks (GW), MHC class I expression was relatively absent in the cerebral cortex with the exception of a few neurons; however, expression increased rapidly in the cochlear nuclei and in the cerebellar cortical Purkinje cells while increasing slowly in the substantia nigra. Expression was also detected in some nuclei and nerve fibers of the brain stem including the ambiguus nucleus, the locus coeruleus and the solitary tract as early as 20 GW and persisted through 33 GW. These early-stage neural cells with MHC class I protein expression later developed neuronal morphology. 30-33 GW is an important period of MHC class I expression in neurons, and during this period, MHC class I molecules were found to be enriched not only in neuronal cell bodies and neurites but also in nerve fibers and in the surrounding stroma. No expression was detected in the adult brain with exception of the cerebrovascular endothelium. MHC class I molecules displayed greater postsynaptic colocalization in cerebellar Purkinje cells, in the lateral geniculate nucleus and in the cochlear nuclei. These results demonstrate diverse spatiotemporal expression patterns for MHC class I molecules in the prenatal human CNS and strongly support the notion that MHC class I molecules play important roles in both CNS development and plasticity.

The major histocompatibility complex (MHC) class I molecules are considered to be important in the immune system. However, the results reported in the past decade indicate that they also play important roles in the central nervous system. Here we examined the expression of MHC I and β2-microglobulin (β2m) in human and mouse cerebellar cortex. The results show that MHC I molecules are expressed both in human and mouse cerebellar cortex during brain development. The expression of H-2K(b)/D(b) is gradually increased with the development of mouse cerebellar cortex, but finally decreased to a very low level. Similarly, the expression of HLA-B/C genes is increased in developing human cerebellar cortex, but decreased after birth. The spatial and temporal expression of β2m overlaps mostly with that of HLA-B/C molecules, and they are co-expressed in Purkinje cells. Our findings provide a fundamental basis to reveal the functions of neuronal MHC class I molecules in the development of human cerebellum.

In the immune system, the major histocompatibility complex (MHC) class I molecules mediate both the innate and adaptive immune responses in vertebrates. There has been a dogma that the central nervous system (CNS) is immune privileged and healthy neurons do not express MHC class I molecules. However, recent studies have indicated that the expression and non-immunobiologic roles of MHC class I in mammalian CNS. But data referring to humans are scarce. In this study we report the expression and cellular localization of MHC class I in the human fetal, early postnatal and adult hippocampal formation. The expression of MHC class I was very low in the hippocampus at 20 (gestational weeks) GW and slowly increased at 27–33 GW. The gradually increased expression in the somata of some granular cells in dentate gyrus (DG) was observed at 30–33 GW. Whereas, a rapid increase in MHC class I molecules expression was found in the subiculum and it reached high levels at 31–33 GW and maintained at postnatal 55 days. No expression of MHC class I was found in hippocampal formation in adult. MHC class I heavy chain and β2 microglobulin (β2M) showed similar expression in some cells of the hippocampal formation at 30–33 GW. Moreover, MHC class I molecules were mainly expressed in neurons and most MHC class I-expressing neurons were glutamatergic. The temporal and spatial patterns of MHC class I expression appeared to follow gradients of pyramidal neurons maturation in the subiculum at prenatal stages and suggested that MHC class I molecules are likely to regulate neuron maturation. This article is part of a Special Issue entitled Priority to Publish.

Recent studies clearly demonstrate major histocompatibility complex (MHC) class I expression in the brain plays an important functional role in neural development and plasticity. A previous study from our laboratory demonstrated the temporal and spatial expression patterns of classical MHC class I molecules in the brain of C57 mice. Studies regarding non-classical MHC class I molecules remain limited. Here we examine the expression of non-classical MHC class I molecules in mouse central nervous system (CNS) during embryonic and postnatal developmental stages using in situ hybridization and immunofluorescence. We find non-classical MHC class I molecules, M3/T22/Q1, are expressed in the cerebral cortex, neuroepithelium of the lateral ventricle, neuroepithelium of aquaeductus and developing cerebellum during embryonic developmental stages. During the postnatal period from P0 to adult, non-classical MHC class I mRNAs are detected in olfactory bulb, hippocampus, cerebellum and some nerve nuclei. Overall, the expression patterns of non-classical MHC class I molecules are similar to those of classical MHC class I molecules in the developing mouse brain. In addition, non-classical MHC class I molecules are present in the H2-K(b) and H2-D(b) double knock-out mice where their expression levels are greatly increased within the same locations as compared to wild type mice. The elucidation and discovery of the expression profile of MHC class I molecules during development is important for supporting an enhanced understanding of their physiological and potential pathological roles within the CNS.

MHC class I (MHC-I) molecules are important components of the immune system. Recently MHC-I have been reported to also play important roles in brain development and synaptic plasticity. In this study, we examine the molecular mechanism(s) underlying activity-dependent MHC-I expression using hippocampal neurons. Here we report that neuronal expression level of MHC-I is dynamically regulated during hippocampal development after birth in vivo. Kainic acid (KA) treatment significantly increases the expression of MHC-I in cultured hippocampal neurons in vitro, suggesting that MHC-I expression is regulated by neuronal activity. In addition, KA stimulation decreased the expression of pre- and post-synaptic proteins. This down-regulation is prevented by addition of an MHC-I antibody to KA treated neurons. Further studies demonstrate that calcium-dependent protein kinase C (PKC) is important in relaying KA simulation activation signals to up-regulated MHC-I expression. This signaling cascade relies on activation of the MAPK pathway, which leads to increased phosphorylation of CREB and NF-κB p65 while also enhancing the expression of IRF-1. Together, these results suggest that expression of MHC-I in hippocampal neurons is driven by Ca2+ regulated activation of the MAPK signaling transduction cascade.

It has been considered that healthy neurons in central nervous system (CNS) do not express major histocompatibility complex (MHC) class I molecules. However, recent studies clearly demonstrated the expression of functional MHC class I in the mammalian embryonic, neonatal and adult brain. Until now, it is still unknown whether MHC I molecules are expressed in the development of human brain. We collected nine human brain tissues from fetuses aged from 21 to 31 gestational weeks (GW), one newborn of postnatal 55 days and one adult. The expression of MHC class I molecules was detected during the development of visual system in human brain by immunohistochemistry and immunofluorescence. MHC class I proteins were located at lateral geniculate nucleus (LGN) and the expression was gradually increased from 21 GW to 31 GW and reached high levels at 30–31 GW when fine-scale refinement phase was mediated by neural electric activity. However, there was no expression of MHC class I molecules in the visual cortical cortex during all the developmental stages examined. We also concluded that MHC class I molecules were mainly expressed in neurons but not in astrocytes at LGN. In the developing visual system, the expression of β2M protein on neurons was not found in our study.

Classical major histocompatibility complex (MHC) class I, first identified in the immune system, is also expressed in the developing and adult central nervous system (CNS). Although the MHC class I molecules have been found to be expressed in the CNS of different species, a necessary step to elucidate the temporal and spatial expression patterns of MHC class I molecules in the brain development has never been taken. Frozen sections were made from the brains of embryonic and postnatal C57BL/6 J mice, and the expression of H-2D(b) mRNA was examined by in situ hybridization. Immunofluorescence was also performed to define the cell types that express H2-D(b) in P15 mice. At E10.5, the earliest stage we examined, H2-D(b) was expressed in neuroepithelium of the brain vesicles. From E12.5 to P0, H2-D(b) expression was mainly located at cerebral cortex, neuroepithelium of the lateral ventricle, neuroepithelium of aquaeductus and developing cerebellum. From P4 to adult, H2-D(b) mRNA was detected at olfactory bulb, hippocampus, cerebellum and some nerve nuclei. The major cell types expressing H-2D(b) in P15 hippocampus, cerebral cortex and olfactory bulb were neuron. H2-K(b) signal paralleled that of H2-D(b) and the expression levels of the two molecules were comparable throughout the brain. The investigation of the expression pattern of H-2D(b) at both embryonic and postnatal stages is important for further understanding the physiological and pathological roles of H2-D(b) in the developing CNS.