Results of the assessment of immune status in children with ASD: immunodeficiency associated with genetic deficiency of the folate cycle
Keywords:
immunodiagnostics, immunotherapy, neuropsychiatric disorders, children, diagnostics, therapySynopsis
The results of the last 5 meta-analyses of randomized controlled clinical trials indicate an association between genetically determined deficiency of folate cycle enzyme (GDFC) and autism spectrum disorders (ASD) in children, however, the mechanism of this relationship, as well as the association with additional clinical manifestations of a broad disease phenotype, has not yet been fully explained. Since there are frequent reports of the association of ASD with immunodeficiency diseases and signs of immune dysregulation, and immune-dependent mechanisms of CNS damage in children with ASD have been described, including opportunistic infections, cerebral autoimmunity, and intracerebral inflammation, there is reason to assume that impaired immune status is a key link in the pathogenesis of ASD in children with GDFC.
Indeed, there is now accumulating evidence that the immune system plays an important role in brain development, participating in the regulation of neuronal proliferation and synapse formation, as well as influencing neuroplasticity processes, so disruption of its functioning may be important in the formation of encephalopathy in children with ASD.
References
Abe, I., Shirato, K., Hashizume, Y., Mitsuhashi, R., Kobayashi, A., Shiono, C. et al. (2012). Folate-deficiency induced cell-specific changes in the distribution of lymphocytes and granulocytes in rats. Environmental Health and Preventive Medicine, 18 (1), 78–84. https://doi.org/10.1007/s12199-012-0286-6
Ashwood, P., Corbett, B. A., Kantor, A., Schulman, H., Van de Water, J., Amaral, D. G. (2011). In Search of Cellular Immunophenotypes in the Blood of Children with Autism. PLoS ONE, 6 (5), e19299. https://doi.org/10.1371/journal.pone.0019299
Bagheri-Hosseinabadi, Z., Imani, D., Yousefi, H., Abbasifard, M. (2020). MTHFR gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis based on 16 studies. Clinical Rheumatology, 39 (8), 2267–2279. https://doi.org/10.1007/s10067-020-05031-5
Bhatnagar, N., Wechalekar, A., McNamara, C. (2012). Pancytopenia due to severe folate deficiency. Internal Medicine Journal, 42 (9), 1063–1064. Portico. https://doi.org/10.1111/j.1445-5994.2012.02849.x
Binstock, T. (2001). Intra-monocyte pathogens delineate autism subgroups. Medical Hypotheses, 56 (4), 523–531. https://doi.org/10.1054/mehy.2000.1247
Brimberg, L., Sadiq, A., Gregersen, P. K., Diamond, B. (2013). Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Molecular Psychiatry, 18 (11), 1171–1177. https://doi.org/10.1038/mp.2013.101
Chen, F., Wen, T., Lv, Q., Liu, F. (2019). Associations between Folate Metabolism Enzyme Polymorphisms and Lung Cancer: A Meta-Analysis. Nutrition and Cancer, 72 (7), 1211–1218. https://doi.org/10.1080/01635581.2019.1677924
Chen, L., Shi, X.-J., Liu, H., Mao, X., Gui, L.-N., Wang, H., Cheng, Y. (2021). Oxidative stress marker aberrations in children with autism spectrum disorder: a systematic review and meta-analysis of 87 studies (N = 9109). Translational Psychiatry, 11 (1). https://doi.org/10.1038/s41398-020-01135-3
Courtemanche, C., Elson-Schwab, I., Mashiyama, S. T., Kerry, N., Ames, B. N. (2004). Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro. The Journal of Immunology, 173 (5), 3186–3192. https://doi.org/10.4049/jimmunol.173.5.3186
Crawley, J. N., Heyer, W.-D., LaSalle, J. M. (2016). Autism and Cancer Share Risk Genes, Pathways, and Drug Targets. Trends in Genetics, 32 (3), 139–146. https://doi.org/10.1016/j.tig.2016.01.001
de Magistris, L., Picardi, A., Siniscalco, D., Riccio, M. P., Sapone, A., Cariello, R. et al. (2013). Antibodies against Food Antigens in Patients with Autistic Spectrum Disorders. BioMed Research International, 2013, 1–11. https://doi.org/10.1155/2013/729349
Dimitroulas, T., Sandoo, A., Hodson, J., Smith, J., Douglas, K., Kitas, G. (2015). Associations between asymmetric dimethylarginine, homocysteine, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in rheumatoid arthritis. Scandinavian Journal of Rheumatology, 45 (4), 267–273. https://doi.org/10.3109/03009742.2015.1086433
Enstrom, A. M., Lit, L., Onore, C. E., Gregg, J. P., Hansen, R. L., Pessah, I. N. et al. (2009). Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain, Behavior, and Immunity, 23 (1), 124–133. https://doi.org/10.1016/j.bbi.2008.08.001
Frye, R. E., Sequeira, J. M., Quadros, E. V., James, S. J., Rossignol, D. A. (2012). Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry, 18 (3), 369–381. https://doi.org/10.1038/mp.2011.175
Furlano, R. I., Anthony, A., Day, R., Brown, A., McGarvey, L., Thomson, M. A. et al. (2001). Colonic CD8 and γδ T-cell infiltration with epithelial damage in children with autism. The Journal of Pediatrics, 138 (3), 366–372. https://doi.org/10.1067/mpd.2001.111323
Gazit, Y., Mory, A., Etzioni, A., Frydman, M., Scheuerman, O., Gershoni-Baruch, R., Garty, B.-Z. (2010). Leukocyte Adhesion Deficiency Type II: Long-Term Follow-Up and Review of the Literature. Journal of Clinical Immunology, 30 (2), 308–313. https://doi.org/10.1007/s10875-009-9354-0
Grimbacher, B., Dutra, A. S., Holland, S. M., Fischer, R. E., Pao, M., Gallin, J. I., Puck, J. M. (1999). Analphoid marker chromosome in a patient with hyper-IgE syndrome, autism, and mild mental retardation. Genetics in Medicine, 1 (5), 213–218. https://doi.org/10.1097/00125817-199907000-00008
Hayes, B., Stanley, J., Peppers, B. P. (2021). COVID-19 Recurrence Without Seroconversion in a Patient With Mannose-Binding Lectin Deficiency. Allergy & Rhinology, 12. https://doi.org/10.1177/21526567211024140
Heuer, L., Ashwood, P., Schauer, J., Goines, P., Krakowiak, P., Hertz‐Picciotto, I. et al. (2008). Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms. Autism Research, 1 (5), 275–283. https://doi.org/10.1002/aur.42
Hughes, H. K., Ashwood, P. (2018). Anti-Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders. Frontiers in Psychiatry, 9. https://doi.org/10.3389/fpsyt.2018.00627
Hughes, H. K., Mills Ko, E., Rose, D., Ashwood, P. (2018). Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders. Frontiers in Cellular Neuroscience, 12. https://doi.org/10.3389/fncel.2018.00405
Isung, J., Williams, K., Isomura, K., Gromark, C., Hesselmark, E., Lichtenstein, P. et al. (2020). Association of Primary Humoral Immunodeficiencies With Psychiatric Disorders and Suicidal Behavior and the Role of Autoimmune Diseases. JAMA Psychiatry, 77 (11), 1147–1154. https://doi.org/10.1001/jamapsychiatry.2020.1260
Jefferson, T., Price, D., Demicheli, V., Bianco, E. (2003). Unintended events following immunization with MMR: a systematic review. Vaccine, 21 (25-26), 3954–3960. https://doi.org/10.1016/s0264-410x(03)00271-8
Jyonouchi, H., Geng, L., Streck, D. L., Toruner, G. A. (2012). Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study. Journal of Neuroinflammation, 9 (1). https://doi.org/10.1186/1742-2094-9-4
Lau, N. M., Green, P. H. R., Taylor, A. K., Hellberg, D., Ajamian, M., Tan, C. Z. et al. (2013). Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS ONE, 8 (6), e66155. https://doi.org/10.1371/journal.pone.0066155
Li, M., Tang, Y., Zhao, E. Y., Chen, C.-H., Dong, L.-L. et al. (2021). Relationship between MTHFR gene polymorphism and susceptibility to bronchial asthma and glucocorticoid efficacy in children. Zhongguo Dang Dai Er Ke Za Zhi., 23 (8), 802–808. https://doi.org/10.7499/j.issn.1008-8830.2105035
Li, Y., Qiu, S., Shi, J., Guo, Y., Li, Z., Cheng, Y., Liu, Y. (2020). Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis. BMC Pediatrics, 20 (1). https://doi.org/10.1186/s12887-020-02330-3
Liao, P., Soong, T. W. (2009). CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency. Pflügers Archiv – European Journal of Physiology, 460 (2), 353–359. https://doi.org/10.1007/s00424-009-0753-0
Mao, N., Chen, J., Wang, J., Xie, X., Li, F., Liu, Y. et al. (2020). Correlations of Methylenetetrahydrofolate Reductase Gene c and Genomic DNA Hypomethylation Level with Ankylosing Spondylitis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 42 (3), 307–312. https://doi.org/10.3881/j.issn.1000-503X.11516
Matarazzo, E. B. (2002). Treatment of Late Onset Autism as a Consequence of Probable Autommune Processes Related to Chronic Bacterial Infection. The World Journal of Biological Psychiatry, 3 (3), 162–166. https://doi.org/10.3109/15622970209150618
Mead, J., Ashwood, P. (2015). Evidence supporting an altered immune response in ASD. Immunology Letters, 163 (1), 49–55. https://doi.org/10.1016/j.imlet.2014.11.006
Melamed, I. R., Heffron, M., Testori, A., Lipe, K. (2018). A pilot study of high‐dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation. Autism Research, 11 (3), 421–433. https://doi.org/10.1002/aur.1906
Shaik Mohammad, N., Sai Shruti, P., Bharathi, V., Krishna Prasad, C., Hussain, T., Alrokayan, S. A. et al. (2016). Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatric Genetics, 26 (6), 281–286. https://doi.org/10.1097/ypg.0000000000000152
Naghibalhossaini, F., Ehyakonandeh, H., Nikseresht, A., Kamali, E. (2015). Association Between MTHFR Genetic Variants and Multiple Sclerosis in a Southern Iranian Population. International Journal of Molecular and Cellular Medicine, 4 (2), 87–93.
Nauseef, W. M. (2014). Diagnostic Assays for Myeloperoxidase and Myeloperoxidase Deficiency. Neutrophil Methods and Protocols. Totowa: Humana Press, 537–546. https://doi.org/10.1007/978-1-62703-845-4_32
Nayeri, T., Sarvi, S., Moosazadeh, M., Hosseininejad, Z., Sharif, M., Amouei, A., Daryani, A. (2020). Relationship between toxoplasmosis and autism: A systematic review and meta-analysis. Microbial Pathogenesis, 147, 104434. https://doi.org/10.1016/j.micpath.2020.104434
Nicolson, G. L., Gan, R., Nicolson, N. L., Haier, J. (2007). Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus‐6 coinfections in the blood of patients with autistic spectrum disorders. Journal of Neuroscience Research, 85 (5), 1143–1148. https://doi.org/10.1002/jnr.21203
Noriega, D. B., Savelkoul, H. F. J. (2013). Immune dysregulation in autism spectrum disorder. European Journal of Pediatrics, 173 (1), 33–43. https://doi.org/10.1007/s00431-013-2183-4
O’Keeffe, J., Gately, C. M., Counihan, T., Hennessy, M., Leahy, T., Moran, A. P., Hogan, E. L. (2008). T-cells expressing natural killer (NK) receptors are altered in multiple sclerosis and responses to α-galactosylceramide are impaired. Journal of the Neurological Sciences, 275 (1-2), 22–28. https://doi.org/10.1016/j.jns.2008.07.007
Partearroyo, T., Úbeda, N., Montero, A., Achón, M., Varela-Moreiras, G. (2013). Vitamin B12 and Folic Acid Imbalance Modifies NK Cytotoxicity, Lymphocytes B and Lymphoprolipheration in Aged Rats. Nutrients, 5 (12), 4836–4848. https://doi.org/10.3390/nu5124836
Pu, D., Shen, Y., Wu, J. (2013). Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta‐Analysis. Autism Research, 6 (5), 384–392. https://doi.org/10.1002/aur.1300
Puangpetch, A., Suwannarat, P., Chamnanphol, M., Koomdee, N., Ngamsamut, N., Limsila, P., Sukasem, C. (2015). Significant Association ofHLA-BAlleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study. Disease Markers, 2015, 1–7. https://doi.org/10.1155/2015/724935
Rai, V. (2016). Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility. Metabolic Brain Disease, 31 (4), 727–735. https://doi.org/10.1007/s11011-016-9815-0
Reinert, P., Moulias, R., Goust, J. M. (1972). Demonstration of cellular immunity deficiency limited to measles virus in 20 cases of subacute sclerosing leukoencephalitis. Archives Francaises de Pediatrie, 29 (6), 655–665.
Russo, A., Krigsman, A., Jepson, B., Wakefield, A. (2009). Low serum myeloperoxidase in autistic children with gastrointestinal disease. Clinical and Experimental Gastroenterology, 2, 85–94. https://doi.org/10.2147/ceg.s6051
Sadeghiyeh, T., Dastgheib, S. A., Mirzaee-Khoramabadi, K., Morovati-Sharifabad, M., Akbarian-Bafghi, M. J., Poursharif, Z. et al. (2019). Association of MTHFR 677C>T and 1298A>C polymorphisms with susceptibility to autism: A systematic review and meta-analysis. Asian Journal of Psychiatry, 46, 54–61. https://doi.org/10.1016/j.ajp.2019.09.016
Saghazadeh, A., Ataeinia, B., Keynejad, K., Abdolalizadeh, A., Hirbod-Mobarakeh, A., Rezaei, N. (2019). A meta-analysis of pro-inflammatory cytokines in autism spectrum disorders: Effects of age, gender, and latitude. Journal of Psychiatric Research, 115, 90–102. https://doi.org/10.1016/j.jpsychires.2019.05.019
Sakamoto, A., Moriuchi, H., Matsuzaki, J., Motoyama, K., Moriuchi, M. (2015). Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain and Development, 37 (2), 200–205. https://doi.org/10.1016/j.braindev.2014.03.016
Salehi Sadaghiani, M., Aghamohammadi, A., Ashrafi, M. R., Hosseini, F., Abolhassani, H., Rezaei, N. (2013). Autism in a child with common variable immunodeficiency. Iranian Journal of Allergy, Asthma and Immunology, 12 (3), 287–289.
Santaella, M. L., Varela, Y., Linares, N., Disdier, O. M. (2008). Prevalence of autism spectrum disorders in relatives of patients with selective immunoglobulin A deficiency. Puerto Rico Health Sciences Journal, 27 (3), 204–208.
Shin, S., Yu, N., Choi, J. R., Jeong, S., Lee, K.-A. (2015). Routine Chromosomal Microarray Analysis is Necessary in Korean Patients With Unexplained Developmental Delay/Mental Retardation/Autism Spectrum Disorder. Annals of Laboratory Medicine, 35 (5), 510–518. https://doi.org/10.3343/alm.2015.35.5.510
Torres, A. R., Westover, J. B., Gibbons, C., Johnson, R. C., Ward, D. C. (2012). Activating killer-cell immunoglobulin-like receptors (KIR) and their cognate HLA ligands are significantly increased in autism. Brain, Behavior, and Immunity, 26 (7), 1122–1127. https://doi.org/10.1016/j.bbi.2012.07.014
Troen, A. M., Mitchell, B., Sorensen, B., Wener, M. H., Johnston, A., Wood, B. et al. (2006). Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women. The Journal of Nutrition, 136 (1), 189–194. https://doi.org/10.1093/jn/136.1.189
van der Weyden, M. B., Hayman, R. J., Rose, I. S., Brumley, J. (1991). Folate‐deficient human lymphoblasts: Changes in deoxynucleotide metabolism and thymidylate cycle activities. European Journal of Haematology, 47 (2), 109–114. https://doi.org/10.1111/j.1600-0609.1991.tb00131.x
Villanueva, J., Lee, S., Giannini, E. H., Graham, T. B., Passo, M. H., Filipovich, A., Grom, A. A. (2004). Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther, 7 (1). https://doi.org/10.1186/ar1453
Vinck, A., Verhagen, M. M. M., Gerven, M. van, de Groot, I. J. M., Weemaes, C. M. R. et al. (2011). Cognitive and speech-language performance in children with ataxia telangiectasia. Developmental Neurorehabilitation, 14 (5), 315–322. https://doi.org/10.3109/17518423.2011.603368
Vojdani, A., Mumper, E., Granpeesheh, D., Mielke, L., Traver, D., Bock, K. et al. (2008). Low natural killer cell cytotoxic activity in autism: The role of glutathione, IL-2 and IL-15. Journal of Neuroimmunology, 205 (1-2), 148–154. https://doi.org/10.1016/j.jneuroim.2008.09.005
Warren, R. P. (1994). Decreased Plasma Concentrations of the C4B Complement Protein in Autism. Archives of Pediatrics & Adolescent Medicine, 148 (2), 180–183. https://doi.org/10.1001/archpedi.1994.02170020066011
Warren, R. P., Foster, A., Margaretten, N. C. (1987). Reduced Natural Killer Cell Activity in Autism. Journal of the American Academy of Child & Adolescent Psychiatry, 26 (3), 333–335. https://doi.org/10.1097/00004583-198705000-00008
Warren, R. P., Yonk, L. J., Burger, R. A., Cole, P., Odell, J. D., Warren, W. L. et al. (1990). Deficiency of Suppressor-Inducer (Cd4+Cd45ra+) T Cells in Autism. Immunological Investigations, 19 (3), 245–251. https://doi.org/10.3109/08820139009041839
Wasilewska, J., Kaczmarski, M., Stasiak-Barmuta, A., Tobolczyk, J., Kowalewska, E. (2012). Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Archives of Medical Science, 2, 324–331. https://doi.org/10.5114/aoms.2012.28561
Watanabe, N., Gao, S., Wu, Z., Batchu, S., Kajigaya, S., Diamond, C. et al. (2021). Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes. Journal of Leukocyte Biology, 110 (3), 409–424. https://doi.org/10.1002/jlb.3hi0220-119rr
Xu, G., Snetselaar, L. G., Jing, J., Liu, B., Strathearn, L., Bao, W. (2018). Association of Food Allergy and Other Allergic Conditions With Autism Spectrum Disorder in Children. JAMA Network Open, 1 (2), e180279. https://doi.org/10.1001/jamanetworkopen.2018.0279
Yonk, L. J., Warren, R. P., Burger, R. A., Cole, P., Odell, J. D., Warren, W. L. et al. (1990). CD4+ helper T cell depression in autism. Immunology Letters, 25 (4), 341–345. https://doi.org/10.1016/0165-2478(90)90205-5
Downloads
Pages
30-50
Published
May 19, 2025
Categories
Copyright (c) 2025 Dmytro Maltsev
Details about the available publication format: PDF
PDF
ISBN-13 (15)
978-617-8360-21-4
How to Cite
Results of the assessment of immune status in children with ASD: immunodeficiency associated with genetic deficiency of the folate cycle. (2025). In D. Maltsev, IMMUNODIAGNOSTICS AND IMMUNOTHERAPY OF NEUROPSYCHIATRIC DISORDERS IN CHILDREN (pp. 30–50). Kharkiv: TECHNOLOGY CENTER PC. https://doi.org/10.15587/978-617-8360-21-4.ch3
