Major Histocompatibility Complex and Epilepsy – Autism Implications ?

Differential expression of major histocompatibility complex class I in developmental glioneuronal lesions

http://www.jneuroinflammation.com/content/10/1/12/abstract

Department of (Neuro)Pathology, Academic Medical Center, University of
Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands

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Abstract (provisional)

The expression of the major histocompatibility complex class I (MHC-I) in the brain has received considerable interest not only because of its fundamental role in the immune system, but also for its non-immune functions in the context of activity-dependent brain development and plasticity.

Methods

In the present study we evaluated the expression and cellular pattern of MHC-I in focal glioneuronal lesions associated with intractable epilepsy. MHC-I expression was studied in epilepsy surgery cases with focal cortical dysplasia (FCD I, n = 6; FCD IIa, n = 6 and FCD IIb, n = 15), tuberous sclerosis complex (TSC, cortical tubers; n = 6) or ganglioglioma (GG; n = 15) using immunocytochemistry. Evaluation of T lymphocytes with granzyme-B+ granules and albumin immunoreactivity was also performed.

Results

All lesions were characterized by MHC-I expression in blood vessels.

Expression in both endothelial and microglial cells as well as in neurons (dysmorphic/dysplastic neurons) was observed in FCD II, TSC and GG cases.

We observed perivascular and parenchymal T lymphocytes (CD8+, T-cytotoxic) with granzyme-B+ granules in FCD IIb and TSC specimens. Albumin extravasation, with uptake in astrocytes, was observed in FCD IIb and GG cases.

Conclusions

Our findings indicate a prominent upregulation of MHC-I as part of the immune response occurring in epileptogenic glioneuronal lesions.

In particular, the induction of MHC-I in neuronal cells appears to be a feature of type II FCD, TSC and GG and may represent an important accompanying event of the immune response, associated with blood–brain barrier dysfunction, in these developmental lesions.

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From the discussion section

“Several studies demonstrate that expression of MHC-I can be upregulated in glia and neurons in response to different types of challenges, including injury, infections (chronic and acute), central administration of endotoxins and exposure to different cytokines ([28-33] reviewed in [7]). Cytokines have been show to differentially regulate MHC-I induction in neurons [31,34,35]. Previous studies have demonstrated prominent expression of components of the IL-1R/TLR signaling pathways in neuronal cells in epileptogenic glioneuronal lesions [6,26,27,36]. Signaling through these pathways leads to activation of the transcription factor, nuclear factor-kappa B (NF-κB) [37]. Interestingly, it has been suggested that activation of NF-κB plays a role in induction of MHC-I [38,39]. Thus, NF-κB-dependent mechanisms of regulation may contribute to the more prominent MHC-I expression detected in FCD II (associated with consistent activation of IL-1R/TLR signaling pathways [6]) compared to FCD I.
Endogenous peptides presented by MHC-I molecules (called MHC-I peptides (MIPs) or the immunopeptidome) represent the key to self/non-self-discrimination by cells of the immune system. In this respect, a recent study confirmed previous observations indicating that the immune system is tolerant to MIPs expressed at physiological levels but may promote immune responses towards self MIPs present in excessive amounts [40,41]. This may be important in the context, of the suggestion that neuronal MHC-I expression mediates removal of dysfunctional neurons [30]. The study by Caron et al. also suggests that changes in mTOR signaling can affect the expression of MHC-I and the repertoire of MIPs presented by MHC-I [41]. These observations highlight the complexity of MHC-I regulation and indicate the need for further analysis of the effect of mTOR modulation in lesions (such as FCD II, TSC and GG) in which this pathway is involved. Interestingly, a recent study suggests a novel viral etiology for FCD IIB [42], which could explain the constitutive activation of mTOR, as well as the induction of MHC-I, in this focal malformation of cortical development.

Interestingly, neuronal MHC-I expression has been reported in Rasmussen’s encephalitis and it has been suggested that it plays a critical role in antigen-specific cytotoxicity [8]. MHC-I expression is necessary for antigen-specific cytotoxicity mediated by CD8+ lymphocytes [43]. In this context, we also detected CD8+ T lymphocytes with GrB in FCD IIB and TSC specimens in the vicinity of neurons. The possible contribution of a MHC-I restricted immune response to neuronal injury, occurring in patients with developmental pathologies and intractable epilepsy [18,44], requires further investigation.

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Further Readings of Interest

https://asdresearchinitiative.wordpress.com/?s=major+histocompatibility+complex

The major histocompatibility complex and autism spectrum disorder.

http://www.ncbi.nlm.nih.gov/pubmed/22760919

Center for Neuroscience, UC Davis, Davis, California

Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune-related genes and immune responses to environmental stimuli.

Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function.

Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD.

This entry was posted in Allergy, Asthma, Autism, co-morbid, Environment, Epigenetics, epilepsy, Immune System, Inflammation, Neurology, Physiology, Schizophrenia, Treatment and tagged , , , , , , , , , , , , , , . Bookmark the permalink.

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