NeuroImmunology

Although the brain is now known to actively interact with the immune system under non-inflammatory conditions, the site of cell-cell interactions between brain parenchymal cells and immune cells has been an open question until recently. Studies by our and other groups have indicated that brain structures such as the leptomeninges, choroid plexus stroma and epithelium, attachments of choroid plexus, vascular endothelial cells, cells of the perivascular space, circumventricular organs, and astrocytic endfeet construct the histological architecture that provides a location for intercellular interactions between bone marrow-derived myeloid lineage cells and brain parenchymal cells under non-inflammatory conditions. This architecture also functions as the interface between the brain and the immune system, through which systemic inflammation-induced molecular events can be relayed to the brain parenchyma at early stages of systemic inflammation during which the blood-brain barrier is relatively preserved. Although brain microglia are well known to be activated by systemic inflammation, the mechanism by which systemic inflammatory challenge and microglial activation are connected has not been well documented. Perturbed brain-immune interaction underlies a wide variety of neurological and psychiatric disorders including ischemic brain injury, status epilepticus, repeated social defeat, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Proinflammatory status associated with cytokine imbalance is involved in autism spectrum disorders, schizophrenia and depression. In this article, we propose a mechanism connecting systemic inflammation, brain-immune interface cells, and brain parenchymal cells, and discuss the relevance of basic studies of the mechanism to neurological disorders with a special emphasis on sepsis-associated encephalopathy and preterm brain injury.

Rasmussen encephalitis (RE) is a rare pediatric neuroinflammatory disease characterized by intractable seizures and unilateral brain atrophy. T cell infiltrates in affected brain tissue, and the presence of circulating autoantibodies in some RE patients has indicated that RE may be an autoimmune disease. The strongest genetic links to autoimmunity reside in the MHC locus, therefore we determined the HLA class I and class II alleles carried by a cohort of 24 RE surgery cases by targeted in-depth genomic sequencing. Compared with a reference population the allelic frequency of three alleles, DQA1*04:01:01, DQB1*04:02:01 and HLA-C*07:02:01:01 indicated that they might confer susceptibility to the disease. It has been reported that HLA-C*07:02, is a risk factor for Graves disease. Further, eight patients in the study cohort carried HLA-A*03:01:01:01, which has been linked to susceptibility to multiple sclerosis. Four patients carried a combination of three HLA class II alleles that has been linked to type 1 diabetes (DQA1*05:01:01:01~DQB1*02:01:01~DRB1*03:01:01:01), and five patients carried a combination of HLA class II alleles that has been linked to the risk of contracting multiple sclerosis (DQA1*01:02:01:01~DQB1*06:02:01~DRB1*15:01:01:01). We also analyzed the diversity of T cells in brain and blood specimens from 14 of these RE surgery cases by sequencing the third complementarity regions (CDR3s) of rearranged T cell receptor  genes. A total of 31 unique CDR3 sequences accounted for the top 5% of all CDR3 sequences in the 14 brain specimens. Thirteen of these sequences were found in sequencing data from healthy blood donors; the remaining 18 sequences were patient-specific. These observations provide evidence for the clonal expansion of public and private T cells in the brain, which might be influenced by the RE patient’s HLA haplotype.

There is increasing evidence that natural killer (NK) cells exhibit regulatory features. Among them, CD56bright natural killer cells have been suggested to play a major role in controlling T-cell responses and maintaining homeostasis. Dysfunction in NK cell-mediated regulatory features has been recently described in untreated multiple sclerosis (MS), suggesting a contribution to MS pathogenesis. Moreover, biological disease-modifying treatments effective in MS apparently enhance the frequencies and/or regulatory function of NK cells, further pointing toward an immuno-protective role of NK cells in MS. Here we summarize the current knowledge on the regulatory functions of NK cells, based on their interactions with other cells belonging to the innate compartment, as well as with adaptive effector cells. We review the more recent data reporting disruption of NK-cell/T-cell interactions in MS, and discuss how disease-modifying treatments for MS affect NK cells.