Baylor Institute for Immunology Research

Jadavji, N. M., H. Mosnier, E. Kelly, K. Lawrence, S. Cruickshank, S. Stacey, A. McCall, S. Dhatt, E. Arning, T. Bottiglieri and P. D. Smith (2019). “One-carbon metabolism supplementation improves outcome after stroke in aged male MTHFR-deficient mice.” Neurobiol Dis Dec 1. 132:104613.

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The prevalence of stroke increases with age and the ability to absorb all nutrients from our diets decreases with age. Nutrition is a modifiable risk factor for stroke, which is a leading cause of death and disability in world-wide. Deficiencies in onecarbon metabolism, including in methyltetrahydrofolate reductase (MTHFR), have been linked to increased risk of stroke. The Mthfr(+/-) mice mouse model mimic the phenotype of the MTHFR677CT polymorphism, such as elevated levels of homocystine. Using this mouse model, the aim of this study was to investigate the impact of dietary supplementation with 5-methylTHF, vitamin B12, and choline after ischemic stroke. Male Mthfr(+/-) and wildtype littermate control mice were aged (~1.5-year-old) and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr(+/-) and wildtype littermate mice were placed on 5-methylTHF, vitamin B12, and choline supplemented diet (SD). Four weeks after PT and SD motor function was assessed using the accelerating rotarod, forepaw asymmetry, and ladder beam walking tasks. Total homocysteine and cysteine levels were measured in blood. Brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes. After PT and SD, Mthfr(+/-) mice were able to stay on the accelerating rotarod longer and used their impaired forepaw to explore more when compared to CD animals. Furthermore, total homocysteine levels in plasma and lesion volume were reduced in Mthfr(+/+) and Mthfr(+/-) SD mice. Within the damage site, there were reduced levels of apoptotic cell death and increased neuroprotective cellular response in the brains of SD treated Mthfr(+/-) mice. This study reveals a critical role for onecarbon supplementation, with 5-methylTHF, vitamin B12, and choline, in supporting improvement after ischemic stroke damage.

Jadavji, N. M., H. Mosnier, E. Kelly, K. Lawrence, S. Cruickshank, S. Stacey, A. McCall, S. Dhatt, E. Arning, T. Bottiglieri and P. D. Smith (2019). “One-Carbon Metabolism Supplementation Improves Outcome after Stroke in Aged Male Mthfr-Deficient Mice.” Neurobiol Dis Sep 13: 104613. [Epub ahead of print].

Full text of this article.

The prevalence of stroke increases with age and the ability to absorb all nutrients from our diets decreases with age. Nutrition is a modifiable risk factor for stroke, which is a leading cause of death and disability in world-wide. Deficiencies in onecarbon metabolism, including in methyltetrahydrofolate reductase (MTHFR), have been linked to increased risk of stroke. The Mthfr(+/-) mice mouse model mimic the phenotype of the MTHFR677CT polymorphism, such as elevated levels of homocystine. Using this mouse model, the aim of this study was to investigate the impact of dietary supplementation with 5-methylTHF, vitamin B12, and choline after ischemic stroke. Male Mthfr(+/-) and wildtype littermate control mice were aged (~1.5-year-old) and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr(+/-) and wildtype littermate mice were placed on 5-methylTHF, vitamin B12, and choline supplemented diet (SD). Four weeks after PT and SD motor function was assessed using the accelerating rotarod, forepaw asymmetry, and ladder beam walking tasks. Total homocysteine and cysteine levels were measured in blood. Brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes. After PT and SD, Mthfr(+/-) mice were able to stay on the accelerating rotarod longer and used their impaired forepaw to explore more when compared to CD animals. Furthermore, total homocysteine levels in plasma and lesion volume were reduced in Mthfr(+/+) and Mthfr(+/-) SD mice. Within the damage site, there were reduced levels of apoptotic cell death and increased neuroprotective cellular response in the brains of SD treated Mthfr(+/-) mice. This study reveals a critical role for onecarbon supplementation, with 5-methylTHF, vitamin B12, and choline, in supporting improvement after ischemic stroke damage.

Askar, M., A. Madbouly, L. Zhrebker, A. Willis, S. Kennedy, K. Padros, M. B. Rodriguez, C. Bach, B. Spriewald, R. Ameen, S. A. Shemmari, K. Tarassi, A. Tsirogianni, N. Hamdy, G. Mossallam, G. Honger, R. Spinnler, G. Fischer, I. Fae, R. Charlton, A. Dunk, T. A. Vayntrub, M. Halagan, K. Osoegawa and M. Fernandez-Vina (2019). “Hla Haplotypes in 250 Families: The Baylor Laboratory Results and a Perspective on a Core Ngs Testing Model for the 17(Th) International Hla and Immunogenetics Workshop.” Hum Immunol Sep 23. [Epub ahead of print].

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Since their inception, the International HLA & Immunogenetics Workshops (IHIW) served as a collaborative platform for exchange of specimens, reference materials, experiences and best practices. In this report we present a subset of the results of human leukocyte antigen (HLA) haplotypes in families tested by next generation sequencing (NGS) under the 17th IHIW. We characterized 961 haplotypes in 921 subjects belonging to 250 families from 8 countries (Argentina, Austria, Egypt, Jamaica, Germany, Greece, Kuwait, and Switzerland). These samples were tested in a single core laboratory in a high throughput fashion using 6 different reagents/software platforms. Families tested included patients evaluated clinically as transplant recipients (kidney and hematopoietic cell transplant) and their respective family members. We identified 486 HLA alleles at the following loci HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, -DPB1 (77, 115, 68, 69, 10, 6, 4, 44, 31, 20 and 42 alleles, respectively). We also identified nine novel alleles with polymorphisms in coding regions. This approach of testing samples from multiple laboratories across the world in different stages of technology implementation in a single core laboratory may be useful for future international workshops. Although data presented may not be reflective of allele and haplotype frequencies in the countries to which the families belong, they represent an extensive collection of 3rd and 4th field resolution level 11-locus haplotype associations of 486 alleles identified in families from 8 countries.

Fovet, C. M., L. Stimmer, V. Contreras, P. Horellou, A. Hubert, N. Seddiki, C. Chapon, S. Tricot, C. Leroy, J. Flament, J. Massonneau, N. Tchitchek, B. A. t Hart, S. Zurawski, P. Klucar, P. Hantraye, K. Deiva, G. Zurawski, S. Oh, R. Le Grand and C. Serguera (2019). “Intradermal vaccination prevents anti-MOG autoimmune encephalomyelitis in macaques.” EBioMedicine Sep 3. [Epub ahead of print].

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BACKGROUND: Autoimmune demyelinating diseases (ADD) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. A cure for chronic ADD could be obtained by appropriate immunomodulation. METHODS: We implemented a preclinical scheme to foster immune tolerance to myelin oligodendrocyte glycoprotein (MOG), in a cynomolgus-macaque model of experimental autoimmune encephalomyelitis (EAE), in which administration of recombinant human MOG (rhMOG) elicits brain inflammation mediated by MOG-autoreactive CD4(+) lymphocytes and anti-MOG IgG. For immunotherapy, we used a recombinant antibody (Ab) directed against the dendritic cell-asialoglycoprotein receptor (DC-ASGPR) fused either to MOG or a control antigen PSA (prostate-specific antigen). FINDINGS: rhMOG and the anti-DC-ASGPR-MOG were respectively detected in CD1a(+) DCs or CD163(+) cells in the skin of macaques. Intradermal administration of anti-DC-ASGPR-MOG, but not control anti-DC-ASGPR-PSA, was protective against EAE. The treatment prevented the CD4(+) T cell activation and proinflammatory cytokine production observed in controls. Moreover, the administration of anti-DC-ASGPR-MOG induced MOG-specific CD4(+)CD25(+)FOXP3(+)CD39(+) regulatory lymphocytes and favoured an upsurge in systemic TGFbeta and IL-8 upon rhMOG re-administration in vivo. INTERPRETATION: We show that the delivery of an anti-DC-ASGPR-MOG allows antigen-specific adaptive immune modulation to prevent the breach of immune tolerance to MOG. Our findings pave the way for therapeutic vaccines for long-lasting remission to grave encephalomyelitis with identified autoantigens, such as ADD associated with anti-MOG autoantibodies. FUND: Work supported by the French ANR (ANR-11-INBS-0008 and ANR-10-EQPX-02-01), NIH (NIH 1 R01 AI 105066), the Baylor Scott and White Healthcare System funding and Roche Research Collaborative grants.

Brown, M., P. Ashcraft, E. Arning, T. Bottiglieri, J. B. Roullet and K. M. Gibson (2019). “Gamma-Hydroxybutyrate content in dried bloodspots facilitates newborn detection of succinic semialdehyde dehydrogenase deficiency.” Mol Genet Metab Jul 18. [Epub ahead of print].

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Increased gamma-hydroxybutyric acid in urine and blood are metabolic hallmarks of succinic semialdehyde dehydrogenase deficiency, a defect of 4-aminobutyric acid metabolism. Here, we examined the hypothesis that succinic semialdehyde dehydrogenase deficiency could be identified via measurement of gamma-hydroxybutyric acid in newborn and post-newborn dried bloodspots. Quantitation of gamma-hydroxybutyric acid using liquid chromatography-tandem mass spectrometry in twelve archival newborn patient dried bloodspots was 360+/-57muM (mean, standard error; range 111-767), all values exceeding the previously established cutoff for newborn detection of 78 muMu established from 2831 dried bloodspots derived from newborns, neonates and children. Gamma-hydroxybutyric acid in post-newborn dried bloodspots (n=19; ages 0.8-38years) was 191+/-65muM (mean, standard error; range 20-1218), exceeding the aforementioned GHB cutoff for patients approximately 10years of age or younger. Further, gamma-hydroxybutyric acid in post-newborn dried bloodspots displayed a significant (p<.0001) inverse correlation with age. This preliminary study suggests that succinic semialdehyde dehydrogenase deficiency may be identified in newborn and post-newborn dried bloodspots via quantitation of gamma-hydroxybutyric acid, while forming the platform for more extensive studies in affected and unaffected dried bloodspots.