Results of the assessment of immune status in children with ASD: immunodeficiency associated with genetic deficiency of the folate cycle

Автори

1 Research Institute of Experimental and Clinical Medicine; 2 Bogomolets National Medical University , Україна
https://orcid.org/0000-0002-6615-3072

Ключові слова:

імунодіагностика, імунотерапія, невропсихіатричні розлади, діти, діагностика, терапія

Короткий опис

Результати останніх 5 мета–аналізів рандомізованих контрольованих клінічних досліджень вказують на асоціацію генетично детермінованого дефіциту ферментів фолатного циклу (ГДФЦ) і розладів спектру аутизму (РАС) у дітей, проте механізм зазначеного зв'язку, так само як і асоціація з додатковими клінічними проявами широкого фенотипу хвороби, досі не знайшли вичерпного пояснення. Оскільки існують непоодинокі повідомлення про зв’язок РАС з імунодефіцитними хворобами та ознаками імунної дизрегуляції, а також описані імунозалежні механізми ураження ЦНС у дітей з РАС, включаючи опортуністичні інфекції, мозковий автоімунітет та інтрацеребральне запалення, є підстави припускати, що порушення імунного статусу є ключовою ланкою патогенезу РАС у дітей з ГДФЦ.

Справді, сьогодні накопичені докази, що імунна система відіграє важливу роль у розвитку головного мозку, беручи участь у регуляції проліферації нейронів та формуванні синапсів, а також впливаючи на процеси нейропластичності, тому порушення її функціонування може мати важливе значення у формуванні енцефалопатії у дітей з РАС.

Посилання

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

##submission.downloads##

Сторінки

30-50

Опубліковано

травня 19, 2025

Категорії

Ліцензія

Creative Commons License

Ця робота ліцензується відповідно до Creative Commons Attribution 4.0 International License.

Деталі щодо доступних видів видань: PDF

PDF

ISBN-13 (15)

978-617-8360-21-4

Як цитувати

Results of the assessment of immune status in children with ASD: immunodeficiency associated with genetic deficiency of the folate cycle. (2025). в D. Maltsev, IMMUNODIAGNOSTICS AND IMMUNOTHERAPY OF NEUROPSYCHIATRIC DISORDERS IN CHILDREN (с. 30–50). Kharkiv: ПП "ТЕХНОЛОГІЧНИЙ ЦЕНТР". https://doi.org/10.15587/978-617-8360-21-4.ch3