Cox Carol J, Zuccolo Amir J, Edwards Erica V, Mascaro-Blanco Adita, Alvarez Kathy, Stoner Julie, Chang Kiki, Cunningham Madeleine W
1 Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma.
J Child Adolesc Psychopharmacol. 2015 Feb;25(1):76-85. doi: 10.1089/cap.2014.0048. Epub 2015 Feb 6.
Antineuronal antibodies have been implicated in tic and obsessive compulsive disorders (OCD) associated with group A streptococcal infections. We investigated antineuronal autoantibody levels as well as antibody-mediated neuronal cell signaling activity, as previously reported for Sydenham chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS), to determine immunological profiles for a large cohort of children with tics and/or OCD.
Study participants (n=311; ages 4-27 years, 66% male) were selected from a larger group of individuals with self-reported neuropsychiatric symptoms (n=742) and included only those with accurate knowledge of group A streptococcal infection status, except for four individuals in whom streptococcal infection status was unknown. Healthy control samples (n=16; ages 5-14 years, 81% male), came from the National Institute of Mental Health and Yale University. In addition to serum donations, participants and/or legal guardians provided neuropsychiatric and related medical histories of symptoms that had lasted >1 year. Antineuronal immunoglobulin G (IgG) titers were measured by standard enzyme-linked immunosorbent assay (ELISA) and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was tested in serum.
Of 311 individuals, 222 (71%) had evidence of group A streptococcal infection, which was associated with tics and/or OCD status (p=0.0087). Sera from individuals with tics and/or OCD (n=261) had evidence of elevated serum IgG antibodies against human D1R (p<0.0001) and lysoganglioside (p=0.0001), and higher serum activation of CaMKII activity (p<0.0001) in a human neuronal cell line compared with healthy controls (n=16). Furthermore, patients with tics and OCD had significantly increased activation of CaMKII activity compared with patients with only tics or only OCD (p<0.033 for each).
Our study suggested a significant correlation of streptococcal-associated tics and OCD with elevated anti-D1R and antilysoganglioside antineuronal antibodies in serum concomitant with higher activation of CaMKII in human neuronal cells. Youth and young adults with chronic tics and OCD may have underlying infectious/immunologic etiology.
抗神经元抗体与A组链球菌感染相关的抽动症和强迫症（OCD）有关。我们研究了抗神经元自身抗体水平以及抗体介导的神经元细胞信号传导活性，如先前针对 Sydenham 舞蹈症和与链球菌相关的儿童自身免疫性神经精神疾病（PANDAS）所报道的那样，以确定一大群抽动症和/或强迫症儿童的免疫特征。
研究参与者（n = 311；年龄4 - 27岁，66%为男性）从一大群自我报告有神经精神症状的个体（n = 742）中选取，仅包括那些对A组链球菌感染状况有准确了解的个体，但有4人链球菌感染状况未知。健康对照样本（n = 16；年龄5 - 14岁，81%为男性）来自美国国立精神卫生研究所和耶鲁大学。除了捐献血清外，参与者和/或法定监护人提供了持续时间超过1年的神经精神及相关病史症状。通过标准酶联免疫吸附测定（ELISA）测量抗神经元免疫球蛋白G（IgG）滴度，并与正常年龄匹配血清针对溶血型神经节苷脂、微管蛋白和多巴胺受体（D1R和D2R）的平均滴度进行比较。在血清中测试了人神经元细胞系（SK - N - SH）中抗体介导的钙调蛋白依赖性蛋白激酶II（CaMKII）活性信号传导。
在311名个体中，222名（71%）有A组链球菌感染的证据，这与抽动症和/或强迫症状态相关（p = 0.0087）。与健康对照（n = 16）相比，抽动症和/或强迫症个体（n = 261）的血清有证据表明抗人D1R（p < 0.0001）和溶血型神经节苷脂（p = 0.0001）的血清IgG抗体升高，以及人神经元细胞系中CaMKII活性的血清激活更高（p < 0.0001）。此外，与仅患有抽动症或仅患有强迫症的患者相比，患有抽动症和强迫症的患者CaMKII活性的激活显著增加（每项p < 0.033）。
我们的研究表明，与链球菌相关的抽动症和强迫症与血清中抗D1R和抗溶血型神经节苷脂抗神经元抗体升高以及人神经元细胞中CaMKII的更高激活显著相关。患有慢性抽动症和强迫症的青少年和年轻人可能有潜在的感染/免疫病因。
