Infectious Diseases and Their Role in Neuroimmune Disease

Main Article Content

Isaac Melamed, MD


Recent findings suggest a relationship between a post-infectious immune response and neurologic changes. These changes, manifesting as various neurological symptoms, including memory issues and cognitive alterations, may be linked to a form of post-infectious autoimmunity. We have coined the term “Alzheimer’s of the Immune System,” or AIS, to describe this syndrome and various immune partners that may play a role in this immune dysfunction have been identified. Here, we will discuss several clinical presentations that feed into the hypothesis of infectious-immune axis and its mechanism of action. We propose that these disorders fall under the umbrella of AIS and discuss the role of immuno therapy in their management.

First, we consider pediatric acute-onset neuropsychiatric syndrome (PANS), a broad diagnostic criterion created to describe children with severe, sudden onset of neuropsychiatric changes. Research exploring the link between immune dysregulation in PANS and its amelioration with intravenous immunoglobulin treatment strongly suggests the association of PANS with a pro-inflammatory state. Next, we delve into autism spectrum disorder (ASD), characterizing it as a neuroimmune disorder. ASD marked by communication and social skill deficits, as well as repetitive and stereotypical behaviors, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both the mother’s and child’s immune systems, and their potential role in diagnosis and treatment. Lastly, we discuss post-viral fatigue syndrome in patients who have recovered from SARS-CoV-2 infection as another example of neuroimmune condition recently added to the growing list.

Further research is needed to validate our hypothesis of AIS, including large scale randomized control trials of different immuno therapies. By unravelling the infectious-immune axis and its mechanism of action, we equip physicians with valuable tools for identifying optimal forms of treatment and management for these conditions.

Article Details

How to Cite
MELAMED, Isaac. Infectious Diseases and Their Role in Neuroimmune Disease. Medical Research Archives, [S.l.], v. 12, n. 6, june 2024. ISSN 2375-1924. Available at: <>. Date accessed: 22 july 2024. doi:


Levine KS, Leonard HL, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S, et al. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. 2023;111(7):1086-93 e2.
2. Wainberg M, Luquez T, Koelle DM, Readhead B, Johnston C, Darvas M, Funk CC. The viral hypothesis: How herpesviruses may contribute to Alzheimer's disease. Mol Psychiatry. 2021;26(10):5476-80.
3. Gagliano A, Carta A, Tanca MG, Sotgiu S. Pediatric Acute-onset Neuropsychiatric Syndrome: Current perspectives. Neuropsychiatr Dis Treat. 2023;19:1221-50.
4. Schwenkenbecher P, Pul R, Wurster U, Conzen J, Pars K, Hartmann H, et al. Common and uncommon neurological manifestations of neuroborreliosis leading to hospitalization. BMC Infect Dis. 2017;17(1):90.
5. Rowley AH. Is Kawasaki disease an infectious disorder? Int J Rheum Dis. 2018;21(1):20-5.
6. Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: Clinical description of the first 50 cases. Am J Psychiatry. 1998;155(2):264-71.
7. Al-Beltagi M, Saeed NK, Elbeltagi R, Bediwy AS, Aftab SAS, Alhawamdeh R. Viruses and autism: A bi-mutual cause and effect. World J Virol. 2023;12(3):172-92.
8. Achar A, Ghosh C. COVID-19-associated neurological disorders: The potential route of CNS invasion and blood-brain barrier relevance. Cells. 2020;9(11):2360.
9. Gupta S, Samra D, Agrawal S. Adaptive and Innate Immune Responses in Autism: Rationale for Therapeutic Use of Intravenous Immunoglobulin. J Clin Immunol. 2010;30(1):90-6.
10. Melamed I. Alzheimer’s disease of the immune system: A new variant of immune deficiency. Immunother: Open Acc. 2016;2:2.
11. Swedo SE, Leckman JF, Rose NR. From research subgroup to clinical syndrome: Modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediat Ther. 2012;2:1-8.
12. Chang K, Frankovich J, Cooperstock M, Cunningham MW, Latimer ME, Murphy TK, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2015;25(1):3-13.
13. Williams KA, Swedo SE. Post-infectious autoimmune disorders: Sydenham's chorea, PANDAS and beyond. Brain Res. 2015;1617:144-54.
14. Cunningham MW. Molecular mimicry, autoimmunity, and infection: The cross-reactive antigens of Group A Streptococci and their sequelae. Microbiol Spectr. 2019;7(4):10.
15. Xu J, Liu RJ, Fahey S, Frick L, Leckman J, Vaccarino F, et al. Antibodies from children with PANDAS bind specifically to striatal cholinergic interneurons and alter their activity. Am J Psychiatry. 2021;178(1):48-64.
16. Cooperstock MS, Swedo SE, Pasternack MS, Murphy TK. Clinical management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part III-Treatment and prevention of infections. J Child Adolesc Psychopharmacol. 2017;27(7):594-606.
17. Frankovich J, Swedo S, Murphy T, Dale RC, Agalliu D, Williams K, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: Part II-Use of immunomodulatory therapies. J Child Adolesc Psychopharmacol. 2017;27(7):574-93.
18. Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, Swedo SE. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;354(9185):1153-8.
19. Melamed I, Kobayashi RH, O'Connor M, Kobayashi AL, Schechterman A, Heffron M, et al. Evaluation of Intravenous Immunoglobulin in Pediatric Acute-Onset Neuropsychiatric Syndrome. J Child Adolesc Psychopharmacol. 2021;31(2):118-28.
20. Melamed I, Rahman S, Pein H, Frankovich J, Kreuwel H, Mellins E. A multi-disciplinary approach to post-infectious autoimmunity: The efficacy of IVIg in Patients with Pediatric Acute-Onset Neuropsychiatric Syndrome. Poster presented at IgNS 2023 National Conference, Denver, CO
21. Piras C, Pintus R, Pruna D, Dessì A, Atzori L, Fanos V. Pediatric Acute-onset Neuropsychiatric Syndrome and Mycoplasma pneumoniae infection: A case report analysis with a metabolomics approach. Curr Pediatr Rev. 2020;16(3):183-93.
22. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383(9920):896-910.
23. Pugsley K, Scherer SW, Bellgrove MA, Hawi Z. Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands. Mol Psychiatry. 2022;27(1):710-30.
24. Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J. Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol. 1996;370(2):247-61.
25. Ahlsén G, Rosengren L, Belfrage M, Palm A, Haglid K, Hamberger A, Gillberg C. Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. Biol Psychiatry. 1993;33(10):734-43.
26. Singh VK, Warren RP, Odell JD, Warren WL, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun. 1993;7(1):97-103.
27. Weizman A, Weizman R, Szekely GA, Wijsenbeek H, Livni E. Abnormal immune response to brain tissue antigen in the syndrome of autism. Am J Psychiatry. 1982;139(11):1462-5.
28. Vojdani A, Campbell AW, Anyanwu E, Kashanian A, Bock K, Vojdani E. Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol. 2002;129(1-2):168-77.
29. Mazón-Cabrera R, Vandormael P, Somers V. Antigenic targets of patient and maternal autoantibodies in autism spectrum disorder. Front Immunol. 2019;10:1474.
30. Kovacevic M, Grant P, Swedo SE. Use of intravenous immunoglobulin in the treatment of twelve youths with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Child Adolesc Psychopharmacol. 2015;25(1):65-9.
31. Williams KA, Swedo SE, Farmer CA, Grantz H, Grant PJ, D’Souza P, et al. Randomized, controlled trial of intravenous immunoglobulin for pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections. J Am Acad Child Adolesc Psychiatry. 2016;55(10):860-7.e2.
32. Melamed IR, Heffron M, Testori A, Lipe K. A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation. Autism Res. 2018;11(3):421-33.
33. Rossignol DA, Frye RE. A systematic review and meta-analysis of immunoglobulin G abnormalities and the therapeutic use of intravenous immunoglobulins (IVIG) in autism spectrum disorder. J Pers Med. 2021;11(6) :488.
34. Dixit NM, Churchill A, Nsair A, Hsu JJ. Post-Acute COVID-19 Syndrome and the cardiovascular system: What is known? Am Heart J Plus. 2021;5:100025.
35. Chiappelli F, Fotovat L. Post acute CoViD-19 syndrome (PACS) - Long CoViD. Bioinformation. 2022;18(10):908-11.
36. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-15.
37. Saikarthik J, Saraswathi I, Alarifi A, Al-Atram AA, Mickeymaray S, Paramasivam A, et al. Role of neuroinflammation mediated potential alterations in adult neurogenesis as a factor for neuropsychiatric symptoms in Post-Acute COVID-19 syndrome-A narrative review. PeerJ. 2022;10:e14227.
38. Bell ML, Catalfamo CJ, Farland LV, Ernst KC, Jacobs ET, Klimentidis YC, et al. Post-acute sequelae of COVID-19 in a non-hospitalized cohort: Results from the Arizona CoVHORT. PLoS One. 2021;16(8):e0254347.
39. Yao T, Foo C, Zheng G, Huang R, Li Q, Shen J, Wang Z. Insight into the mechanisms of coronaviruses evading host innate immunity. Biochim Biophys Acta Mol Basis Dis. 2023;1869(5):166671.
40. Heydenreich N, Nolte MW, Gob E, Langhauser F, Hofmeister M, Kraft P, et al. C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms. Stroke. 2012;43(9):2457-67.
41. Gesuete R, Storini C, Fantin A, Stravalaci M, Zanier ER, Orsini F, et al. Recombinant C1 inhibitor in brain ischemic injury. Ann Neurol. 2009;66(3):332-42.
42. Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20(1):34-50.
43. Reboul A, Arlaud GJ, Sim RB, Colomb MG. A simplified procedure for the purification of C1-inactivator from human plasma. Interaction with complement subcomponents C1r and C1s. FEBS Lett. 1977;79(1):45-50.
44. Parej K, Dobo J, Zavodszky P, Gal P. The control of the complement lectin pathway activation revisited: both C1-inhibitor and antithrombin are likely physiological inhibitors, while alpha2-macroglobulin is not. Mol Immunol. 2013;54(3-4):415-22.
45. Bergin DA, Hurley K, McElvaney NG, Reeves EP. Alpha-1 antitrypsin: A potent anti-inflammatory and potential novel therapeutic agent. Arch Immunol Ther Exp. 2012;60(2):81-97.