Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

Song, SungWon; Miranda, Carlos J.; Braun, Lyndsey; Meyer, Kathrin; Frakes, Ashley E.; Ferraiuolo, Laura; Likhite, Shibi; Bevan, Adam K.; Foust, Kevin D.; McConnell, Michael J.; Walker, Christopher M.; Kaspar, Brian K.

doi:10.1038/nm.4052

Cited by 121 publications

(116 citation statements)

References 71 publications

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“…Interestingly, they also proved that the OCs of HLA-F and MHC-I are ligands of KIR. Furthermore, research has shown that the OC of HLA-F may be associated with certain diseases, suggesting that a greater understanding of the OCs of HLA-I molecules is needed (44). Consistent with previous results, our data showed that HLA-A11svE4 alone, or in combination with HLA-I OCs, recognizes and combines with KIR to inhibit NK activity, and participates in the Ag-presentation pathway.…”

Section: Discussionsupporting

confidence: 91%

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

Zhang

Lian

Dai

et al. 2017

The Journal of Immunology

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Alternative splicing occurs frequently in many genes, especially those involved in immunity. Unfortunately, the functions of many alternatively spliced molecules from immunologically relevant genes remain unknown. Classical HLA-I molecules are expressed on almost all nucleated cells and play a pivotal role in both innate and adaptive immunity. Although splice variants of HLA-I genes have been reported, the details of their functions have not been reported. In the current study, we determined the characteristics, expression, and function of a novel splice variant of HLA-A11 named HLA-A11svE4. HLA-A11svE4 is located on the cell surface without b2-microglobulin (b2m). Additionally, HLA-A11svE4 forms homodimers as well as heterodimers with HLA-A open conformers, instead of combining with b2m. Moreover, HLA-A11svE4 inhibits the activation of NK cells to protect target cells. Compared with b2m and HLA-A11, the heterodimer of HLA-A11svE4 and HLA-A11 protected target cells from lysis by NK cells more effectively. Furthermore, HLA-AsvE4 expression was upregulated by HIV-1 in vivo and by HSV, CMV, and hepatitis B virus in vitro. In addition, our findings indicated that HLA-A11svE4 molecules were functional in activating CD8 + T cells through Ag presentation. Taken together, these results suggested that HLA-A11svE4 can homodimerize and form a novel heterodimeric complex with HLA-A11 open conformers. Furthermore, the data are consistent with HLA-A11svE4 playing a role in the immune escape of HIV-1.

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Section: Discussionsupporting

confidence: 91%

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

Zhang

Lian

Dai

et al. 2017

The Journal of Immunology

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“…Similarly to astrocytes (15,19,(32)(33)(34), however, we report that oligodendrocytes affect MNs through two distinct mechanisms of action: soluble factors and cell-to-cell contact, with the latter being more aggressive. Addition of lactate to the cocultures, in fact, does not rescue MNs.…”

Section: Discussionmentioning

confidence: 72%

Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism

Ferraiuolo

Meyer

Sherwood

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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150

142

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Oligodendrocytes have recently been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods. All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture. CM-mediated MN death was associated with decreased lactate production and release, whereas toxicity in coculture was lactate-independent, demonstrating that MN survival is mediated not only by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in MN rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, whereas it was ineffective in differentiated oligodendrocytes. In fact, early SOD1 knockdown rescued lactate impairment and cell toxicity in all lines tested, with the exclusion of samples carrying chromosome 9 ORF 72 (C9orf72) repeat expansions. These did not respond to SOD1 knockdown nor did they show lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type, some damage might be irreversible. In addition, we demonstrate that patients with C9ORF72 represent an independent patient group that might not respond to the same treatment.oligodendrocytes | amyotrophic lateral sclerosis | SOD1 | C9orf72 | lactate

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“…The molecules encoded by the major histocompatibility complex (MHC) regions regulate the innate and adaptive arms of human immune response through antigen presentation, inflammation regulation and the complement system and the impact of this region in various immune-mediated conditions, including neurological diseases, has long been recognized. [4][5][6][7][8][9] The human MHC gene family maps to chromosome 6. With a size of nearly 5 Mbp it encodes approximately 165 protein-coding genes, many of them immune-related, 10 and comprises approximately 0Á13% of the human genome.…”

Section: The Human Major Histocompatibility Complex Region and Neurolmentioning

confidence: 99%

“…119 Overexpression of HLA-F mediated protection of human motor neurons from ALS astrocyte mediated toxicity. 7 Human metabolites binds with P4 pockets of MS susceptible DRB1*15:01 haplotype in most populations. 233 Fine mapping of the HLA locus suggest DRB1*15 haplotype as a factor for AD.…”

Section: Hla and Multiple Sclerosismentioning

confidence: 99%

The immunogenetics of neurological disease

2017

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Summary Genes encoding antigen‐presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin‐like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non‐coding variation in immunogenetic loci using high‐throughput high‐resolution next‐generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.

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Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

Cited by 121 publications

References 71 publications

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism

The immunogenetics of neurological disease

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