Potential associations of MS-associated genes with BBB function. The 20 highest ranking genes on DisGeNET were searched for in PubMed with the keywords ‘blood brain barrier’, ‘endothelial’, ‘endothelium’, ‘astrocyte’, ‘pericyte’ and ‘tight junction’. Results were reviewed and the most relevant possible associations are discussed. *Data from UniProt (http://www.uniprot.org/). All references for this table are included in the online supplementary table 1
| Gene | Protein function* | Possible BBB associations |
| IL7R | Interleukin-7 cytokine receptor | Expressed by human microvascular ECs (although not specifically in brain). Exogenous IL-7 stimulates EC proliferation in a dose-dependent manner. Expression of IL7R by non-bone marrow-derived cells contributes to EAE pathogenesis in a mouse model. IL7R is expressed in mouse astrocytes. |
| IL2RA | Interleukin-2 cytokine receptor. A soluble form has also been isolated, thought to result from extracellular proteolysis | IL-2 stimulates angiogenesis in human umbilical vein ECs, indicating that IL2RA is likely expressed. Administration of recombinant IL-2 leads to BBB disruption. Intrathecal levels of soluble IL2R are higher in MS compared with controls, and correlated with BBB damage. |
| HLA-DRB1 | HLA class II molecule | Two polymorphisms in ALCAM, a molecule involved in leucocyte migration across the BBB, modify HLA-DRB1*1501 effect in MS, with a fivefold lower risk of MS in HLA-DRB1*1501 individuals. |
| CLEC16A | Involved in regulation of mitophagy | Strongly induced in astrocytes in inflamed cerebral cortex. |
| CD58 | Also known as LFA-3. Ligand of the CD2 glycoprotein found on T lymphocytes | Constitutively expressed by human brain microvascular ECs (HBMECs). Monoclonal antibodies to LFA-3 block proliferation of activated CD4 T cells that are incubated with HBMECs. |
| HLA-DRA | HLA class II molecule | None found |
| TNFRSF1A | Receptor for TNF-α and lymphotoxin-α, forms DISC complex mediating apoptosis | TNFR1 knockout mice have reduced activation of astrocytes in response to LPS. In humans, TNFR1 is expressed on vasculature of brain metastases and in non-specific brain inflammation, but minimally in normal controls, and was associated with increased BBB permeability on administration of TNF in mice. Expression of TNFR1 found to be higher in brain microvessels than spinal cord microvessels in rats. TNFR1 signalling implicated in the response to hypoxic-ischaemic injury and BBB breakdown in rats. |
| CD6 | Adhesion molecule, involved in regulating T-cell responses, acting as a costimulatory molecule and involved in the response to LPS | Expressed on lymphocytes. Interacts with ALCAM, which is expressed on resting human BBB ECs, to mediate migration of cells across BBB. CD6 blockade suppresses migration of CD4+ T cells. CD6 on T cells required for efficient migration through BBB in EAE. |
| CBLB | Ubiquitin ligase that promotes substrate degradation by the proteasome. Negatively regulates TCR, BCR and FCER1 signalling pathways | Implicated in regulating LFA-1 activity. In vitro, Cbl-b deficient phagocytes displayed increased adhesion to ECs. Also identified as a potential caspase 8 substrate, in a study where caspase 8 inhibition abrogated the ex vivo formation of endothelial progenitor cells, suggesting a role of Cbl-b in neovascularisation. |
| KIF1B | Motor for anterograde transport of mitochondria | None found |
| TNFSF14 | Cytokine also known as LIGHT, that, through binding to LTBR, activates NF-κB and stimulates proliferation of T cells | Induces pro-inflammatory changes in ECs through NF-κB signalling and restores vascular integrity in tumours by inducing pericyte contractility. Platelet-associated LIGHT mediates adhesion to endothelium. |
| APOE | Apolipoprotein found in chylomicron that binds lipoproteins and mediates their catabolism. Main cholesterol carrier in the brain. | Produced by astrocytes. ApoE deficiency has been shown to increase BBB permeability via an effect on MMP-9 in EAE. One isoform, APOE4, increases BBB susceptibility to injury by activating a cyclophilin A-MMP-9 pathway in pericytes. In a mouse model, expression of APOE4 or deficiency of murine ApoE lead to neurodegeneration preceded by vascular effects. ApoE has similarly been implicated in BBB integrity following experimental subarachnoid haemorrhage in mice. Furthermore, ApoE inhibits pericyte mobility, which is needed for cerebrovascular function, through a RhoA-mediated pathway. However, in a study of dementia disorders, increased BBB permeability was not related to ApoE genotype and a more recent GWAS study provided good evidence that the two SNPs in ApoE implicated in MS are in fact not associated with susceptibility to MS. |
| HLA-DQB1 | HLA class II molecule | None found |
| IFNB1 | Cytokine, classically important in the innate immune response to viruses | Exogenous IFN-β is an important treatment in RRMS. Shown to decrease BBB permeability in MRI studies and in vitro. Serum from patients treated with IFN-β-1b causes reduced BBB permeability when applied in vitro. |
| IL1B | Cytokine in interleukin family. Classically described as a pro-inflammatory pyrogen | Increases BBB permeability by several mechanisms including: directly through PKCθ signalling in microvascular endothelium; through production of an inflammatory response causing increased ICAM-1 and decreased TJ ZO-1 expression; and through a chemokine reaction mediated by astrocytes. Others report that IL-1b can cause neurodegeneration independently of a leaky BBB, using an adenovirus model in mice which disrupts the BBB but subsequently repairs; chronic IL-1b exposure can cause BBB disruption without neurodegeneration. |
| HLA-DPB1 | HLA class II molecule | None found |
| PTPRC | Phosphatase involved in TCR signalling | None found |
| EVI5 | Regulator of cell cycle | None found |
| CIITA | Transcriptional coactivator of HLA class II gene | One study looked at CIITA expression in astrocytes and endothelial cells in response to cytokines. CIITA expression was increased in both astrocytes and endothelial cells by IFN-γ, but this effect was inhibited by TNF-α in ECs, leading the authors to conclude that ECs in the BBB are not inducible antigen-presenting cells (APCs) but astrocytes are, and that ECs instead respond to T-cell interactions by making the BBB more permeable. Others speculate that since astrocytes in the white matter of subjects with MS are deficient in β2 adrenergic receptors that deficiency will reduce a suppressive action of CIITA via PKA, enabling astrocytes to function as facultative APCs. Fluoxetine, a PKA agonist, reduced development of focal inflammatory lesions. |
| ICAM-1 | Adhesion molecule found on ECs. Ligand for LFA-1 integrin found on leucocytes; on binding enables transmigration of leucocytes into tissues. | Widely studied in terms of action in transmigration of inflammatory cells across the BBB. One recent study showed that patients with SPMS had autoantibodies against galectin 3, which increased ICAM-1 levels and might contribute to BBB breakdown. |
ALCAM, Activated Leukocyte Cell Adhesion Molecule; BBB, blood-brain barrier; EC, endothelial cell; Gd, gadolinium; GWAS, genome-wide association studies; HLA, Human Leukocyte Antigen; MMP, matrix metalloproteinase; LFA,Lymphocyte Function-Associated Antigen; PKA, Protein Kinase ARRMS, relapsing-remitting MS; TNF, tumour necrosis factor; SPMS, secondary progressive; MS; TJ, tight junction.