Disruption of the blood–brain barrier contributes to neurobehavioral changes observed in rheumatic heart disease

Abstract

Sydenham chorea (SC) is the neurological manifestation associated with acute rheumatic fever (ARF). ARF and rheumatic heart disease (RHD) are autoimmune complications triggered by a group A streptococcal (GAS) infection. In ARF/RHD and SC, tissue cross-reactive antibodies and T-cells generated against GAS antigens have been implicated in the pathogenesis. In SC, antibodies against GAS antigens are known to cross-react with neuronal proteins causing neurological manifestations including choreiform movements and neuropsychiatric symptoms such as irritability, attention deficit, and obsessive-compulsive disorder. Previous studies in a rat autoimmune valvulitis (RAV) model of RHD, have shown that injection of streptococcal M protein could cause both cardiac and neurological symptoms. In this study it was shown that adoptive transfer of serum with anti-GAS M antibodies to naive rats caused carditis but failed to demonstrate neurobehavioral symptoms. However, when the blood–brain barrier (BBB) was disrupted using lipopolysaccharide, all animals that received anti-GAS M protein antibodies, developed neurobehavioral defects in addition to carditis. This highlights that impaired BBB integrity is essential for the development of neurobehavioral symptoms. The use of the RAV model and the disruption of BBB required for the development of neurobehavioral changes provides a platform to further investigate the mechanisms that lead to antibodies binding to basal ganglia structures that cause SC.

Keywords

animal model / blood–brain-barrier / group a streptococcus / rheumatic fever / Sydenham's chorea

References

[1] Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group a streptococcal diseases. Lancet Infect Dis. 2005; 5(11): 685-694.

[2] Karthikeyan G, Guilherme L. Acute rheumatic fever. Lancet. 2018; 392(10142): 161-174.

[3] Carapetis JR, Beaton A, Cunningham MW, et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers. 2016; 2: 15084.

[4] Colony HS, Malamud N. Sydenham's chorea; a clinicopathologic study. Neurology. 1956; 6(9): 672-676.

[5] Marques-Dias MJ, Mercadante MT, Tucker D, Lombroso P. Sydenham's chorea. Psychiatr Clin North Am. 1997; 20(4): 809-820.

[6] Dean SL, Singer HS. Treatment of Sydenham's chorea: a review of the current evidence. Tremor Other Hyperkinet Mov (N Y). 2017; 7: 456.

[7] Carapetis JR, Currie BJ. Rheumatic chorea in northern Australia: a clinical and epidemiological study. Arch Dis Child. 1999; 80(4): 353-358.

[8] Pavone P, Parano E, Rizzo R, Trifiletti RR. Autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS, and PANDAS variants. J Child Neurol. 2006; 21(9): 727-736.

[9] Swedo SE, Leonard HL, Mittleman BB, et al. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry. 1997; 154(1): 110-112.

[10] Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998; 155(2): 264-271.

[11] Brimberg L, Benhar I, Mascaro-Blanco A, et al. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology. 2012; 37(9): 2076-2087.

[12] Cox CJ, Sharma M, Leckman JF, et al. Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: implications in human disease. J Immunol. 2013; 191(11): 5524-5541.

[13] Kirvan CA, Cox CJ, Swedo SE, Cunningham MW. Tubulin is a neuronal target of autoantibodies in Sydenham's chorea. J Immunol. 2007; 178(11): 7412-7421.

[14] Ben-Pazi H, Stoner JA, Cunningham MW. Dopamine receptor autoantibodies correlate with symptoms in Sydenham's chorea. PLoS One. 2013; 8(9): e73516.

[15] Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med. 1976; 144(4): 1094-1110.

[16] Kirvan CA, Swedo SE, Heuser JS, Cunningham MW. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med. 2003; 9(7): 914-920.

[17] Church AJ, Cardoso F, Dale RC, Lees AJ, Thompson EJ, Giovannoni G. Anti-basal ganglia antibodies in acute and persistent Sydenham's chorea. Neurology. 2002; 59(2): 227-231.

[18] Rafeek RA, Hamlin AS, Andronicos NM, et al. Characterization of an experimental model to determine streptococcal M protein-induced autoimmune cardiac and neurobehavioral abnormalities. Immunol Cell Biol. 2022; 100(8): 653-666.

[19] Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020; 17(1): 69.

[20] Rafeek RAM, Lobbe CM, Wilkinson EC, et al. Group a streptococcal antigen exposed rat model to investigate neurobehavioral and cardiac complications associated with post-streptococcal autoimmune sequelae. Anim Model Exp Med. 2021; 4(2): 151-161.

[21] Kolb B, Holmes C. Neonatal motor cortex lesions in the rat: absence of sparing of motor behaviors and impaired spatial learning concurrent with abnormal cerebral morphogenesis. Behav Neurosci. 1983; 97(5): 697-709.

[22] Gorton GB, Olive C, Ketheesan N. B- and T-cell responses in group a streptococcus M-protein- or peptide-induced experimental carditis. Infect Immun. 2009; 77(5): 2177-2183.

[23] Reynolds S, Rafeek RAM, Hamlin A, et al. Streptococcus pyogenes vaccine candidates do not induce autoimmune responses in a rheumatic heart disease model. NPJ Vaccines. 2023; 8(1): 9.

[24] Bonthius DJ, Karacay B. Sydenham's chorea: not gone and not forgotten. Semin Pediatr Neurol. 2003; 10(1): 11-19.

[25] Teixeira AL, Vasconcelos LP, Nunes M, Singer H. Sydenham's chorea: from pathophysiology to therapeutics. Expert Rev Neurother. 2021; 21(8): 913-922.

[26] Kirvan CA, Swedo SE, Kurahara D, Cunningham MW. Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham's chorea. Autoimmunity. 2006; 39(1): 21-29.

[27] Korn-Lubetzki I, Brand A, Steiner I. Recurrence of Sydenham chorea: implications for pathogenesis. Arch Neurol. 2004; 61(8): 1261-1264.

[28] Cutforth T, DeMille MM, Agalliu I, Agalliu D. CNS autoimmune disease after streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors. Future Neurol. 2016; 11(1): 63-76.

[29] Dale RC, Merheb V, Pillai S, et al. Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain. 2012; 135(Pt 11): 3453-3468.

[30] Lotan D, Benhar I, Alvarez K, et al. Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav Immun. 2014; 38: 249-262.

[31] Swedo SE, Rapoport JL, Cheslow DL, et al. High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea. Am J Psychiatry. 1989; 146(2): 246-249.

[32] Gordon N. Sydenham's chorea, and its complications affecting the nervous system. Brain Dev. 2009; 31(1): 11-14.

[33] Peng X, Luo Z, He S, Zhang L, Li Y. Blood-brain barrier disruption by lipopolysaccharide and sepsis-associated encephalopathy. Front Cell Infect Microbiol. 2021; 11: 768108.

[34] Banks WA, Gray AM, Erickson MA, et al. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation. 2015; 12: 223.

[35] Sikder S, Williams NL, Sorenson AE, et al. Group G streptococcus induces an autoimmune carditis mediated by interleukin 17A and interferon gamma in the Lewis rat model of rheumatic heart disease. J Infect Dis. 2018; 218(2): 324-335.

[36] Sikder S, Rush CM, Govan BL, Alim MA, Ketheesan N. Anti-streptococcal antibody and T-cell interactions with vascular endothelial cells initiate the development of rheumatic carditis. J Leukoc Biol. 2020; 107(2): 263-271.

[37] Sikder S, Price G, Alim MA, et al. Group a streptococcal M-protein specific antibodies and T-cells drive the pathology observed in the rat autoimmune valvulitis model. Autoimmunity. 2019; 52(2): 78-87.

[38] Liu YH, Wu PH, Kang CC, et al. Group a streptococcus subcutaneous infection-induced central nervous system inflammation is attenuated by blocking peripheral TNF. Front Microbiol. 2019; 10: 265.

[39] Dileepan T, Smith ED, Knowland D, et al. Group a streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells. J Clin Invest. 2016; 126(1): 303-317.

[40] Dileepan T, Linehan JL, Moon JJ, Pepper M, Jenkins MK, Cleary PP. Robust antigen specific th17 T cell response to group a streptococcus is dependent on IL-6 and intranasal route of infection. PLoS Pathog. 2011; 7(9): e1002252.

[41] Platt MP, Bolding KA, Wayne CR, et al. Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis. Proc Natl Acad Sci USA. 2020; 117(12): 6708-6716.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.