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SYSTEMATIC REVIEW OPEN

Autoantibodies in patients with obsessive-compulsive disorder:

a systematic review
Dominik Denzel1, Kimon Runge 1, Bernd Feige 1, Benjamin Pankratz1, Karoline Pitsch1, Andrea Schlump1, Kathrin Nickel 1
,
✉
Ulrich Voderholzer1,2,3, Ludger Tebartz van Elst1, Katharina Domschke 1, Miriam A. Schiele1,4 and Dominique Endres 1,4

© The Author(s) 2023

Obsessive-compulsive disorder (OCD) is a frequent and debilitating mental illness. Although efficacious treatment options are
available, treatment resistance rates are high. Emerging evidence suggests that biological components, especially autoimmune
processes, may be associated with some cases of OCD and treatment resistance. Therefore, this systematic literature review
summarizing all case reports/case series as well as uncontrolled and controlled cross-sectional studies investigating autoantibodies
in patients with OCD and obsessive-compulsive symptoms (OCS) was performed. The following search strategy was used to search
PubMed: “(OCD OR obsessive-compulsive OR obsessive OR compulsive) AND (antib* OR autoantib* OR auto-antib* OR
immunoglob* OR IgG OR IgM OR IgA)”. Nine case reports with autoantibody-associated OCD/OCS were identified: five patients with
anti-neuronal autoantibodies (against N-methyl-D-aspartate-receptor [NMDA-R], collapsin response mediator protein [CV2],
1234567890();,:

paraneoplastic antigen Ma2 [Ma2], voltage gated potassium channel complex [VGKC], and “anti-brain” structures) and four with
autoantibodies associated with systemic autoimmune diseases (two with Sjögren syndrome, one with neuropsychiatric lupus, and
one with anti-phospholipid autoantibodies). Six patients (67%) benefited from immunotherapy. In addition, eleven cross-sectional
studies (six with healthy controls, three with neurological/psychiatric patient controls, and two uncontrolled) were identified with
inconsistent results, but in six studies an association between autoantibodies and OCD was suggested. In summary, the available
case reports suggest an association between OCD and autoantibodies in rare cases, which has been supported by initial cross-
sectional studies. However, scientific data is still very limited. Thus, further studies on autoantibodies investigated in patients with
OCD compared with healthy controls are needed.

Translational Psychiatry (2023)13:241 ; https://doi.org/10.1038/s41398-023-02545-9

INTRODUCTION alterations were identified [15–17]. Neuroimaging studies point to

Approximately 2% of the population worldwide suffer from an aberration of neuronal pathways involving cortico-striato-
obsessive-compulsive disorder (OCD; [1, 2]), frequently first thalamo-cortical circuits [18, 19]. Electroencephalography (EEG)
presenting in childhood/adolescence or early adulthood [3]. The data suggest abnormalities in frontal areas of the brain and
delayed diagnosis and disease burden results in considerable overstimulation regarding event-related potentials [20]. Further-
economic and psychological impairment [4, 5]. Patients with OCD more, neurochemical investigations indicate an imbalance,
tend to report poorer quality of life than, for example, patients especially in serotonergic, but also dopaminergic and glutama-
with depression or even heroin addiction [6]. Core obsessive- tergic neurotransmission [7, 8, 18, 21].
compulsive symptoms (OCS) are ego-dystonic irrational obsessive An autoimmune hypothesis in some cases was initially
thoughts that lead to time-consuming repetitive behaviors postulated based on an association between OCS in children
(compulsions) to reduce anxiety [7, 8]. Exposure therapy with and their exacerbation after infections with beta-hemolytic
response prevention as a form of cognitive behavioral therapy streptococci [22]. This subgroup of patients has been termed
(CBT) constitutes the first choice in terms of psychotherapeutic “pediatric autoimmune neuropsychiatric disorder associated with
approaches for OCD and serotonin reuptake inhibitors (SSRIs) are streptococcal infection”, or PANDAS. The pathogenic antibodies
mainly used for psychopharmacotherapy [9–12]. Nevertheless, associated with the M-protein of beta-hemolytic streptococci are
treatment resistance rates are high with approximately half of hypothesized to be able to cross the blood–brain barrier and
patients not responding sufficiently to first-line therapy [8]. cross-react with basal ganglia tissue, which may result in OCS
There is increasing evidence that biological components have [22–24]. Other studies corroborated this assumption by identifying
substantial influence on the development of this disorder. A anti-basal ganglia autoantibodies (ABGA) in children with PANDAS
moderate genetic component with heritability estimates ranging [25–28]. In line with this, Pearlman and colleagues [29] conducted
from 27 to 65% has been reported [13, 14]. Besides, epigenetic a meta-analysis on ABGA in OCD patients and detected

1
Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 2Department of Psychiatry
and Psychotherapy, University Hospital, LMU Munich, Munich, Germany. 3Schoen Clinic Roseneck, Prien am Chiemsee, Germany. 4These authors contributed equally: Miriam A.
Schiele, Dominique Endres. ✉email: [email protected]

Received: 31 January 2022 Revised: 29 April 2023 Accepted: 26 June 2023

 D. Denzel et al.
2
significantly elevated ABGA levels. However, several studies also obsessive-compulsive OR obsessive OR compulsive) AND (antib*
suggest that other autoantibodies besides ABGA may be OR autoantib* OR auto-antib* OR immunoglob* OR IgG OR IgM OR
associated with OCD and OCS [30–35]. To date, however, IgA)”. All articles available until 17 February 2021 were searched.
systematic analyses on different autoantibodies in OCD are Titles and abstracts of all articles were screened independently by
missing. Therefore, the aim of this systematic review is to two expert raters (DD and KR). Subsequently, a full text analysis
summarize and analyze the findings on different autoantibodies was conducted for papers that met the eligibility criteria.
in patients with OCD/OCS. Disagreements were resolved by a third reviewer or consensus-
based discussion. Additionally, references of literature reviews or
meta-analyses specific to the immunological topic of the current
MATERIAL AND METHODS literature search were screened for additional eligible references.
Eligibility criteria In total, 13 reviews [30, 31, 33–43], and one meta-analysis [29] on
Original research findings comprising case reports, case series, autoimmunity in OCD were screened. In addition, the references
uncontrolled and controlled cross-sectional studies of patients of the included papers were screened. All publications could be
with OCD or OCS reporting on autoantibodies detected in blood/ accessed and none of the authors had to be asked specifically for
and or cerebrospinal fluid (CSF) were included. Patients of all ages an article.
were analyzed, and no restrictions were placed on the methodol-
ogy of autoantibody testing.
Preliminary results as well as case reports/series and cross- RESULTS
sectional studies reporting findings of patients with OCD and Search results
comorbid Tourette syndrome were excluded. Studies conducted The literature search resulted in a total of 473 reports. After
exclusively in animals or with pathogen-associated antibodies screening, nine case reports [44–52] and eleven cross-sectional
(e.g., streptococcal antibodies) were ruled out. Furthermore, all studies [53–63] were included. Of those, six studies included a
articles that were published in languages other than English or healthy control group [53, 55–57, 61, 63], three included patient
German were excluded. control groups [58–60], and two studies had no control group at
all [54, 62]. The search results are summarized in Fig. 1.
Outcome
The aim was to provide a descriptive presentation of Systematic analysis of case reports
autoantibody-associated case reports of patients with OCD, along In the identified nine case reports, three patients with well-
with the findings from all cross-sectional studies. characterized anti-neuronal autoantibodies (against N-methyl-D-
aspartate-receptor [NMDA-R], collapsin response mediator protein
Literature research [CV2], paraneoplastic antigen Ma2 [Ma2]), two patients with non-
The literature search was performed in PubMed in line with the well-characterized anti-neuronal autoantibodies (against voltage-
PRISMA guidelines using the following search terms: “(OCD OR gated potassium channels [VGKC], “anti-brain” structures), and

Records identified through Additional findings in references of the

Screening and Idenficaon

included papers (N=19), important

PubMed database search immunological review articles or meta-
N = 473 papers were identified analyses*
N = 14 review articles or meta-analyses were
additionally screened

Excluded papers
Excluded

N = 454

Included studies from literature Included papers of references

search N = 0 papers from rev. and meta-analyses
N = 8 case reports N = 1 additional case report paper from the
N = 11 cross-sectional studies (9
Incl. Syst. Rev.

references of a case report

controlled/2 uncontrolled)

Included papers overall: 20

Fig. 1 PRISMA flow diagram for systematic literature search. *Screened reviews and meta-analyses: [29–31, 33–43]. Additional case study
from references of case report [45]: [49]. Included controlled studies into systematic review: [53, 55–61, 63]. Included uncontrolled studies into
systematic review: [54, 62]. Included case reports into systematic review: [44–50, 52]. Incl. Inclusion, Syst. Systematic, Rev. Review.

Translational Psychiatry (2023)13:241

 D. Denzel et al.
3
four with autoantibodies associated with systemic autoimmune Sjögren syndrome: A 40-year-old female patient with xerostomia
diseases (two with Sjögren syndrome, one with neuropsychiatric and xerophthalmia presented with OCS that included washing,
lupus, and one with anti-phospholipid autoantibodies) were checking behavior, and fear of contamination. The patient was
described. The detailed findings are summarized in Table 1. diagnosed with OCD, and treatment with CBT and psychotropic
drugs (fluoxetine/risperidone/aripiprazole) was initiated. Further-
Specific autoantibodies against central nervous structures more, the diagnosis of Sjögren syndrome was ascertained based
NMDA-R: Seven patients in a case series with anti-NMDA-R on increased titers of ANAs with anti-Ro/SS-A and -La/SS-B
encephalitis developed initial cognitive deficits and persisting specificity, a positive Schirmer test, and positive lisamin green
impairment of neuropsychological function (mean follow-up = 35 staining. Ultrasound and scintigraphy showed dysfunction of the
months). One out of these seven patients developed persistent salivary glands. Both her rheumatological symptoms and OCS
OCS [44]. improved significantly after treatment with hydroxychloroquine
and nutrition supplements [45].
CV2: OCS where the patient arranges and frequently rearranges Ong and colleagues (2017) described the case of a 17-year-old
objects in distinct lines, were the first symptoms diagnosed in a woman who initially presented with symptoms of OCD that
69-year-old woman. Four weeks later, she showed initial included contamination fears, hoarding, symmetry, washing,
neurological symptoms (choreatiform movements and unsteady cleaning and checking, and comorbid depression, which was
gait, later followed by a loss of higher cortical functions) that managed with a low dosage of psychotropic drugs (fluoxetine,
steadily deteriorated until her death. Immunological treatment quetiapine, and prazosin) and psychotherapy. Subsequently, she
was unsuccessful. Brain autopsy revealed global cerebral amyloid developed severe neuropsychiatric symptoms (unusual sensa-
with extensive neuronal loss and perivascular/parenchymal tions, visual hallucination, tinnitus, etc.) and was additionally
infiltration of T-lymphocytes limited to the striatum. Anti-CV2 diagnosed with Sjögren syndrome based on the positive titers of
autoantibodies were positive in the serum after her death. A ANAs with anti-Ro/SS-A and anti-La/SS-B specificity. Magnetic
tumor was not found, however, the autopsy was limited to the resonance spectroscopy revealed a reduction in N-acetylaspartate
brain only [48]. in both hippocampi, while brain MRI presented insignificant
findings. The CSF displayed pleocytosis, elevated protein,
Ma2: OCS consisting of checking central heating, light, doors, increased neopterin, immunoglobulin G (IgG) elevation, and a
and so forth were the first signs of paraneoplasia in a 39-year-old significant increase of CSF IgG to albumin ratio and oligoclonal
male who later on started to develop severe neurological bands, while anti-neuronal autoantibodies were negative. OCS
symptoms (memory decline, gustatory sensory auras, headache, completely disappeared with immunotherapy using plasmapher-
etc.). Orchiectomy revealed a differentiated teratoma and esis and intravenous methylprednisolone [49].
seminoma in situ. Thoracic computer tomography (CT) confirmed
metastasis of the teratoma. Magnetic resonance imaging (MRI) of “Anti-phospholipid”: A 5-year-old girl developed rapid-onset
the brain showed a T2 hyperintense signal alteration in the left OCD after an ear infection without evidence of streptococcal
hippocampus. EEG indicated left temporal sharp slow-wave infection, but the patient had elevated anti-phosphatidylethanol-
activity, and laboratory analysis (CSF and serum) identified anti- amine autoantibodies and the antibody levels correlated with
Ma2 autoantibodies. Neither surgical removal of the pulmonary OCS. Immunotherapy was not administered since she improved
metastasis nor chemotherapy (bleomycin/cisplatin/etoposide) with low dose sertraline [51].
yielded clinical improvements in contrast to the antiepileptic
and immunological treatment [50]. Systematic review of cross-sectional studies
The findings are summarized in Table 2.
VGKC: A 64-year-old man without comorbidities presented with
sudden OCS related to his garden (compulsively trimming of the Specific autoantibodies against central nervous structures. In a
lawn, especially the edges, with an extraordinary time investment). sample of mixed mental disorders (N = 48) comprising seven
He additionally developed faciobrachial dystonic seizures. Anti-VGKC patients with OCD and 52 healthy controls, two out of seven
autoantibodies were significantly elevated in the CSF, whereas the patients with OCD were positive for autoantibodies against
other parameters were normal. Metabolic brain imaging with 18F- Purkinje cells, for which all healthy volunteers were negative.
Fluorodeoxyglucose positron-emission tomography (FDG-PET) Overall, Purkinje cell antibodies were identified in 11 of 48
revealed increased symmetrical uptake in the caudate and lentiform patients (22.9%) with mental disorders but in 0% of controls [56].
nuclei while no association between seizures and EEG alterations Another study showed that a significant proportion of patients
were detected. After treatment with cytostatics and prednisolone, with OCD (N = 25) possessed IgG serum autoantibodies against
complete remission of OCS and seizure symptoms was observed, the dopamine D1 receptor, while other anti-CNS autoantibody
along with normalization of anti-VGKC autoantibody levels and findings (dopamine D2 receptor, lysoganglioside GM1, and
reduced FDG uptake in the basal ganglia [46]. tubulin) were detected in comparable rates in healthy controls
(N = 28) [55]. Ten patients with OCD exhibited significantly
“Anti-brain”: Zhu and colleagues [52] described a case of a 23- elevated serum autoantibodies to somatostatin and prodynorphin
year-old man who suffered from OCS three months after the compared with 25 healthy controls and patients with advanced
irradiation of a pineal gland germinoma. “Anti-brain” autoantibo- immunodeficiency virus (HIV), schizophrenia, Alzheimer’s disease,
dies were detected after symptom onset. These resembled and multiple sclerosis [61]. Singer et al. [62] measured the titers of
antinuclear antibodies (ANAs) and showed a fine punctate pattern. anti-neuronal autoantibodies b [“ANAb”] in the sera of patients
with mental disorders (including five patients with OCD) using
Autoantibodies associated with systemic autoimmune diseases different methods. Two out of five patients with OCD showed low
Neuropsychiatric lupus: OCS with psychotic tendencies were titers for ANAb [62]. Serum IgG autoantibodies reacted with
observed in a 22-year-old male patient who had ANAs with anti- lysoganglioside GM1 and GlcNAc (epitope of streptococcus) in
nucleosome specificity detected in his blood and CSF accom- only one out of five OCD-sera (20%), while it reacted in all the
panied by abnormalities in the MRI (multiple inflammatory Sydenham’s chorea-sera (100%), 11 out of 16 PANDAS-sera (69%),
bilateral white matter lesions) and EEG (slowing); improvement 3 out of 10 Tic-sera (30%), and 2 out of 10 ADHD-sera (20%). OCD
was reported by methylprednisolone, methotrexate, and hydro- and other non-PANDAS CSF failed to show reactivity for human
xychloroquine [47]. caudate-putamen tissue compared with patients with PANDAS

Translational Psychiatry (2023)13:241

 Table 1. Case-reports - Autoantibodies associated with obsessive-compulsive disorders (OCD) or obsessive-compulsive symptoms (OCS). 4

Study Antibody Diagnosis Sex, Laboratory Other Diagnostic Findings Treatment

Age Methods Examinations
Well-characterized anti-neuronal autoantibodies
1. Cainelli et al. Anti NMDA-R Ab Anti-NMDAR encephalitis F, 8 Ab identification MMSPE and neuro- CSF: Anti-NMDAR Ab with blood Plasmapheresis and IV
2019 [44] with initial apathy and years in CSF psychological brain barrier dysfunction and no methylprednisolone →
emerging OCS evaluation bacterial or neurotropic viruses improvement in
(controlling) Neuropsychological and neuropsychological tests
memory tests: Impaired (residual symptoms remaining,
performance OCS remaining)
2. Muehlschlegel Anti-CV2 Ab Paraneoplastic F, 69 Ab identification Physical Serum: Anti-CV2 Ab Steroid and cyclophosphamide
et al. 2005 [48] encephalitis with initial years in serum examination MRI: White matter lesions in → no improvement, patient
OCS (order) MRI striatum and globus pallidus, died 5 weeks later
Chest x-ray mild atrophy
Brain biopsy Physical examination:
Autopsy Progressing of severe
neurological deficits
Chest x-ray: Normal
Brain biopsy: Cerebral amyloid;
perivascular infiltration of
T lymphocytes, non-specific
gliosis
Autopsy: “Dusky coloration” of
basal ganglia; reduced caudate
nucleus; extensive neuronal loss
and perivascular and
parenchymal infiltration of
T-lymphocytes limited to the
D. Denzel et al.

striatum, cerebral amyloid

3. Scheid et al. Anti-Ma2 Ab Paraneoplastic M, 39 Ab identification Physical Serum: Anti-Ma2 Ab IV immunoglobulins and
2003 [50] encephalitis with initial years in CSF and serum examination CSF: Anti-Ma2 Ab lamotrigine → improvement of
OCD (checking) MRI EEG: Inconstant left temporal memory function and OCS
EEG sharp slow-wave activity
CSF MRI: T2-hyperintense signal
Thoracic CT change in the left hippocampus
Physical examination:
Progressing of severe
neurological deficits
Histologic examination:
Differentiated teratoma and
seminoma-in-situ
Thoracic CT: Metastasis of
teratoma
Non-well characterized anti-neuronal autoantibodies
4. Celliers et al. 2016 Anti-VGKC Ab VGKC-Ab associated limbic M, 64 Ab identification FDG-PET CSF: Increased VGKC Ab Levetiracetam + IV
[46] encephalitis with OCS and years in CSF EEG FDG-PET: Increased symmetrical methylprednisolone +
faciobrachial seizures uptake in the caudate and mycophenolate mofetil → full
lentiform nuclei remission of seizures and OCS;
EEG: No associated EEG-changes CSF: inconspicuous levels of
with seizures detected VGKC Ab; FDG-PET: follow up
showed significant glucose
uptake reduction in the basal
ganglia bilaterally

Translational Psychiatry (2023)13:241

5. Zhu et al. 2014 [52] IgG “ANAb” Antibody associated OCS M, 23 Ab identification Physical Serum: 43-45kDA, positive Cranial irradiation → OCS and
(checking, washing) after years in serum examination staining with Hep2 epithelial Ab detection in serum (3
pineal germinoma MRI cells month later)
Brain biopsy Physical examination: Severe
neurological symptoms
MRI: Enlarged pineal gland
Brain biopsy: Germinoma
 Table 1. continued
Study Antibody Diagnosis Sex, Laboratory Other Diagnostic Findings Treatment
Age Methods Examinations
Autoantibodies associated with systemic autoimmune diseases
6. Lüngen et al. 2019 ANA with anti- OCS (with psychotic M, 22 Ab identification Physical CSF: ANA pos., pleocytosis, OCBs IV methylprednisolone +
[47] nucleosome features) in the context of years in CSF and serum examination Serum: ANA pos., complement MTX + HCQ → nearly full
specificity neuropsychiatric lupus EEG factor C4 reduced and C3d remission
MRI increased
FDG-PET Physical examination: Normal
EEG: Slowing
MRI: Multiple bilateral white
matter lesions

Translational Psychiatry (2023)13:241

FDG-PET: Normal
7. Carvalho et al., ANA, anti-Ro/SS- OCS (contamination, F, 40 Ab identification Lisamin green Serum: ANA pos., anti-Ro/SS-A, HCQ + vitamin D3 + omega-3
2020 [45] A, anti-La/SS-B checking, washing) in the years in serum staining anti-La/SS-B Ab pos. → Improvement (OCS under
Ab context of Sjögren Break up time Lisamin green staining: Pos. adequate control)
syndrome Schirmer test Schirmer test: Pos., break up
Scintigraphy time: Pos.
Ultrasound Scintigraphy: Dysfunction of
salivary glands
Ultrasound: Gland dysfunction
8. Ong et al. 2017 [49] ANA, anti-Ro/SS- OCS (contamination, F, 17 Ab identification Physical Serum: ANA pos., anti-Ro/SS-A, Plasmapheresis and IV
A, anti-La/SS-B hoarding, symmetry, years in serum examination anti-La/SS-B Ab pos, RF immunoglobulins → complete
Ab washing, cleaning, Electrophoresis Electrophoresis: Increase in remission of OCS, partial
checking) with depression CSF polyclonal gammaglobulins remission of depression
in the context of Sjögren Cerebral single Physical examination: “Fleeting
syndrome photon emission sensation in the upper body”,
CT tinnitus, rare visual
MRI hallucinations
MRS CSF: Pleocytosis, elevated
protein, neopterin positive, CSF
IgG elevation, significant
increase of CSF IgG to albumin
ratio, OCBs, no Ab
MRI and cerebral single photon
emission CT: Insignificant
D. Denzel et al.

finding
MRS: Reduction in
N-acetylaspartate in both
hippocampi
9. Sokol et al. 2006 Anti- OCS (sudden onset after F, 5 Ab identification Physical and Physical and neurological Improvement with low dose
[51] phosphatidyl- an ear infection) years in serum neurological examination: Normal sertraline
ethanol-amine examination Blood: Repeated positive anti-
Ab phosphatidylethanol-amine
levels, these correlated with the
clinical course of OCD; no
evidence of streptococcal
infection
Case reports that did not report OCD and Tourette syndrome separately were excluded as well as case studies reporting PANDAS/PANS. Patients from case series were included. M Male, F Female, OCD Obsessive-
compulsive disorder, PANDAS Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, PANS Pediatric acute-onset neuropsychiatric syndrome, RF Rheumatoid factor, Ab
Autoantibody, ANA Antinuclear antibody, ASO Serum anti-streptolysin O, CV2 Collapsin response mediator protein, VGKC Ab voltage gated potassium channel antibodies, CSF Cerebrospinal fluid, MRI Magnetic
resonance imaging, CT Computed tomography, MRS Magnetic resonance spectroscopy, OCBs Oligoclonal bands, OCS Obsessive-compulsive symptoms, MMSPE Mini-Mental State Pediatric Examination, BVN
Batteria di Valutazione Neuropsicologica per l’Età Evolutiva, IV Intra-venous, IF Immunofluorescence, IgG Immunoglobulin G, kDa Kilodaltons, FDG-PET 18F-Fluorodeoxyglucose positron-emission tomography,
MTX Methotrexate, HCQ Hydroxychloroquine, N.A. (data) not available.
5
 6
Table 2. Cross-sectional studies - Autoantibody findings received through the systematic literature search.
Study Diagnoses Autoantibody- N (OCD Sex Age of Control Group Methods Statistics Significance Special Features
Type Patients Patients and OCD vs.
vs. Controls Controls
Controls)
Anti-CNS autoantibodies
1. Yuwiler et al. OCD Ab against P: 6 n.a. P: 10 HC SS Regression Serum: S Significantly more
1992 [63] TS serotonin C: 12 C: 33 analysis binding inhibition
Schizophrenia in the sera of
MS patients with OCD
ASS compared to HC.
2. Chain et al. OCD Tu, D1R, D2R, P: 25 n.a. n.a HC ELISA Mann- Serum: S OCD-sera
2020 [55] TS GM1, ANA, Anti- C: 28 microtiter Whitney U exhibited elevated
ADHD DNAase B, ASO plate test, Ab against D1R
PANDAS Wilcoxon compared to HC-
SC signed-rank sera. No significant
test, Fisher´s elevation for other
exact test Ab in OCD-Sera
compared to HC.
3. Chiaie et al. OCD PCA, ANA, AMA, P: 7 P: 1 F: P: HC IF ANOVA / Serum: S PCA were more
2012 [56] BD ASMA, APCA C: 52 6M 31.72 ± 12.01 MANOVA prevalent in sera of
Schizophrenia C: 26 F: C: A = 43 OCD patients in
PCD 26 M 5 ± 15.3 comparison to HC.
4. Black et al. OCD PCA, VGCC, P: 13 P: 6 F: P: No controls IP No statistical Serum: NS The only 2 subjects
1998 [54] AChR Bi, striated 7M 39.92 ± 4.13 EI approach with comorbid
muscle Ab, IF cancer (breast
D. Denzel et al.

Amph, ANA, RAI MPA adenocarcinoma /

SMA, AMA, Tg, thyroid carcinoma)
Tp, GAD-65 exhibited elevated
titer for
microsomal
autoantibodies.
5. Roy et al. OCD Ab against P: 10 P: 4 F: P: 31 ± 6 HC ELISA ANCOVA Serum: S Auto-Ab
1994 [61] Schizophrenia somatostatin C: 25 6 M C: C: 40 ± 17 (somatostatin and
AD and dynorphin 15 F: dynorphin) were
MS 10 M significantly
HIV elevated in the
sera of patients
with OCD in
comparison to HC.
6. Singer et al. OCD ABGA and other P: 5 n.a. n.a. No controls IHC ANOVA and Serum: NS No comparison
2005 [62] OCD + ADHD non-specific ELISA post hoc-t- between the
TS-only ANAb test groups. No
TS + ADHD correlation
TS + ADHD + OCD between
ADHD stereotypy scores
of rats correlations
toward infused
ANAb titers.
7. Kirvan et al. OCD ABGA (CSF) and P: 5 n.a. n.a. Psychiatric and IHC ANOVA Serum: NS Low prevalence of
2006 [58] Tics GM1 / GlcNAc Tics: 10 neurological ELISA CSF: NS lysoganglioside
ADHD (serum) ADHD: 10 patients GM1 and GlcNAc

Translational Psychiatry (2023)13:241

PANDAS PANDAS: in OCD-sera. No
SC 16 reactivity for
SC: 6 human-caudate
tissue in the CFS.
 Table 2. continued
Study Diagnoses Autoantibody- N (OCD Sex Age of Control Group Methods Statistics Significance Special Features
Type Patients Patients and OCD vs.
vs. Controls Controls
Controls)
8. Nicholson et OCD ABGA and ASO P: 96 P: 52 F: P: 42.4 ± 13.3 Psychiatric WB Fisher´s Serum: S ABGA were
al. 2012 [60] Depression C: 50 44M C: 45.7 ± 13.1 patients exact test significantly
Schizophrenia C: 32 F: (schizophrenia elevated compared
18 M and depression) to the
heterogeneous
psychiatric group.
No significant
correlation with

Translational Psychiatry (2023)13:241

ABGA-positivity in
OCD and
symptoms or
clinical variables.
9. Gause et al. OCD ABGA and Ab P: 13 P: 5 F: P: HC WB ANOVA, Serum: NS ASO titers did not
2009 [57] OCD+Tics against C: 29 8 M C: 14.1 ± 3.1 C: IHC Tukey´s correlate with
OCD + PANDAS cingulate gyrus, 17 F: 12.4 ± 2.4 ELISA post-hoc- immunoassays and
dorsolateral 12 M test, chi- were similar
prefrontal and square test, among the groups.
orbitofrontal Fisher´s
cortex, ASO exact test
10. OCD ABGA and Ab P: 23 P: 5 F: P: HC WB Chi-square Serum: NS CFS glutamate and
Bhattacharyya against C: 23 18 M C: 24.65 ± 8.95 test/ CSF: S glycine levels were
et al. 2009 [53] Thalamus 5 F: C: 32 ± 12.95 MANCOVA significantly higher
18 M in patients.
Autoantibodies associated with systemic autoimmune diseases
11. Morer et al. OCD (early and late ANA, AMA, P (early P (early P (early Psychiatric IF Mann- Serum: NS No significant
2006 [59] onset) APCA, ASMA, onset): o.): 11 F: onset): patients ELISA Whitney U differences for
psychiatric patients LKM, Tp, Tg, 18 P (late 7M 29.56 ± 8.29 (affective, test, autoimmune
ASO onset): 22 P (late P (late onset): adaptive, Wilcoxon parameters in
C: 14 o.): 9 F: 33.33 ± 9.04 psychotic or signed-rank OCD-sera
13M C: anxiety test, Fisher´s compared to the
D. Denzel et al.

C: 6 F: 34.90 ± 10.60 disorders) exact test patient control

8M group.
Studies that did not report OCD and Tourette syndrome separately were excluded as well as studies reporting PANDAS/PANS. Only studies reporting autoantibody findings are presented. All autoantibodies
were illustrated in the table. Findings with significant group differences are marked in bold. CNS Central nervous system, OCD Obsessive-compulsive disorder, TS Tourette Syndrome, ADHD Attention deficit
hyperactivity disorder, AD Alzheimer´s disease, ASS Autism spectrum disorder, MS Multiple sclerosis, HIV Patients with advanced immunodeficiency virus, PANDAS Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infections, PANS Pediatric acute-onset neuropsychiatric syndrome, BD Bipolar disorder, PCD Paraneoplastic cerebellar degeneration, P Patient (only patients with OCD), C
Control group, HC Healthy controls, Ab Autoantibody, ABGA Anti-basal ganglia autoantibodies, ANAb Anti-neuronal autoantibodies b, Amph Amphiphysin, ANA Antinuclear antibody, AMA Anti-mitochondrial
autoantibody, APCA Anti-gastric parietal cell autoantibody, ASMA Anti-smooth muscle autoantibody, ASO Serum antistreptolysin O, ELISA Enzyme-linked Immunosorbent Assay, AChR Acetylcholine receptor-
binding autoantibodies, D1R/D2R Dopamine receptor autoantibodies, GM1 Lysoganglioside GM1 autoantibody, LKM Anti-liver-kidney microsome autoantibody, PCA Purkinje cell cytoplasmic autoantibodies, SMA
Smooth muscle autoantibody, GAD-65 Glutamic acid decarboxylase-65-kDa isoform autoantibody, Tg Thyroglobulin autoantibody, Tu Tubulin autoantibody, Tp Thyroid microsomal (peroxidase) autoantibody,
VGCC N-type and P/Q-type voltage gated calcium channel autoantibodies, N Number, F Female, M Male, A Mean age, WB Western blotting, IF Immunofluorescence, IHC Immunohistochemistry, IP
Immunoprecipitation assays, EI Enzyme immunoassay (not explained in more detail whether ELISA or other test), RIA Radioimmunoassay, MPA Microtiter particle agglutination test, SS Scintillation spectrometry,
CSF Cerebrospinal fluid, S Significant, NS Not significant, N.A. (data) not available, o. Onset.
7
 D. Denzel et al.
8
[58]. In a larger cohort of 96 patients with OCD, ABGA was had well-characterized anti-neuronal autoantibodies (against NMDA-
significantly elevated in 19 out of 96 participants compared with a R, CV2 and Ma2), and two patients had autoantibodies against non-
heterogeneous psychiatric group (N = 50, schizophrenia and well-characterized neuronal antigens (VGKC and “anti-brain”). The
depression, elevation in 2 out of 50). Most positive OCD-sera patient with anti-NMDA-R autoantibodies was autoantibody positive
displayed anti-enolase autoantibodies (13 out of 19), as measured in CSF and responded well to immunotherapy [44], suggesting a
by immunoblotting [60]. Bhattacharyya and colleagues [53] causal role of these autoantibodies in this patient [64]. In line with
included OCD-only patients and healthy controls when comparing this, Al-Diwani et al. [65] showed that 2% of all patients with anti-
ABGA concentration levels. They did not find significant differ- NMDA-R encephalitis exhibited OCS. The two patients with
ences of ABGA in OCD compared with healthy controls. However, paraneoplastic anti-neuronal autoantibodies against intracellular
Bhattacharyya et al. [53] showed that the binding of CSF antigens (CV2 and Ma2; 48, 50) had severe courses. In both patients,
autoantibodies to the thalamus and basal ganglia was significantly OCS consisted of early symptoms of paraneoplastic encephalitis; this
higher in patients (N = 23) than in controls (N = 23), whereas no suggests that a paraneoplastic cause could be considered in patients
significant difference was found when the autoantibodies were with late onset OCS or additional tumor disease or neurologic
examined in sera. In addition, the concentration of CSF glutamate symptoms. Nevertheless, these results should be interpreted with
and glycine levels was higher in patients compared to controls caution, as this observation is based on a small number of cases.
[53]. Anti-Ma2 autoantibodies were also detected in the CSF, and typical
One study analyzed the correlation between blood serotonin autopsy findings with infiltration of T-lymphocytes to the striatum
concentration in patients with OCD (N = 6) and healthy controls were found in the patient with anti-CV2 autoantibodies. Thus, it
(N = 12) and the presence of IgG autoantibodies inhibiting might be assumed that these three cases were not only associated
serotonin binding to the human frontal cortex was positive but with irrelevant serum autoantibodies [66–69]. Anti-VGKC autoanti-
not significant. However, the serotonin concentration of patients bodies are increasingly considered non-specific, and a determination
with OCD was lower and binding inhibition significantly higher in of anti-leucine-rich, glioma inactivated 1 (anti-LGI1) and contactin-
comparison to healthy volunteers [63]. Another study that associated protein-2 (CASPR2) autoantibodies is suggested [70].
examined the serum of 13 patients with OCD did not find any However, the OCD patient with anti-VGKC autoantibodies showed
specific pattern involving anti-neuronal autoantibodies (against typical findings of limbic encephalitis with anti-VGKC autoantibody
Purkinje cells, N-type and P/Q-type voltage-gated calcium detection in the CSF and additional faciobrachial dystonic seizures
channels, neuronal nuclear epitopes, amphiphysin, and glutamic [46, 70]. Thus, this patient might have had functional autoantibodies
acid decarboxylase) or systemic autoantibodies [54]. Although two as well, which is also supported by the response to immunotherapy.
individuals had elevated titers for anti-microsomal autoantibodies. Another patient showed novel “anti-brain” autoantibodies [52]. These
These were the only participants in this cohort with a cancer “anti-brain” autoantibodies have not yet been investigated in larger
diagnosis (breast adenocarcinoma and thyroid carcinoma) [54]. cross-sectional studies (see Table 2). However, a small previous study
Gause and colleagues [57] included OCD-only patients and identified a more frequent occurrence of autoantibodies against
healthy controls when comparing ABGA concentration levels. Purkinje cell targets [56]. Such immunofluorescence patterns are
Gause and collegues did not find significant differences of ABGA mostly found in patients with paraneoplastic anti-neuronal auto-
in OCD compared with healthy controls. Three methods (ELISA, antibodies [71]. Future studies are necessary to investigate a possible
immunohistochemistry, Western blot) were utilized, but no association of OCD with well-characterized anti-neuronal autoanti-
significant group differences (13 OCD patients and 29 controls) bodies against (paraneoplastic) intracellular or cell surface antigens.
were identified [57]. Previous cross-sectional studies have mostly focused on
autoantibodies associated with dysfunction along the cortico-
Autoantibodies associated with systemic autoimmune diseases. striato-thalamo-cortical circuits and serotonin or dopamine
Serum autoantibodies such as ANAs, anti-mitochondrial autoantibo- receptor pathways, based on established OCD pathophysiology.
dies [AMA], anti-gastric parietal cell autoantibodies [APCA], anti- In this context, several studies investigated ABGA
smooth muscle autoantibodies [ASMA], as well as antibodies against [53, 57, 58, 60, 62], and one study investigated autoantibodies
liver-kidney microsome [LKM]/ thyroid microsomal (peroxidase) [Tp]/ against serotonin [63] while another explored autoantibodies
thyroglobulin [Tg]/ and streptolysin O [ASO]) were screened in a against dopamine receptors [55]. ABGA was first described in
study of 40 OCD patients and compared to 14 patients with other Sydenham’s chorea, a disease associated with streptococcal
mental disorders including mood, adjustment, psychotic, or anxiety infection [72] and later for OCD-related disorders such as Tourette
disorders. Furthermore, OCD patients were divided into two syndrome [73, 74] and PANDAS (25, 26; 27). ABGAs appear to be
subgroups based on disease onset (early- vs. late-onset OCD). No the most studied autoantibodies in trials in patients with OCD, and
significant differences in autoantibody prevalence emerged between several studies indicate a link between ABGAs and OCD [53, 60]. A
OCD subgroups and controls. However, early-onset OCD was meta-analysis by Pearlman and colleagues [29], which included six
associated with higher anti-streptolysin O levels [59]. studies and one meeting abstract, reported significant elevation of
ABGA in patients with OCD compared with controls [29]. However,
Pearlman and colleagues [29] included studies comparing OCD
DISCUSSION patients with heterogeneous groups of psychiatric or neurological
This systematic literature review examined the association controls including comorbid Tourette syndrome. Tourette syn-
between OCD/OCS and different autoantibodies. It includes all drome may be linked with immunological processes and different
articles on this topic published until February 2021 to provide a autoantibodies itself [73, 75, 76], and, ABGA in patients with OCD
comprehensive and broad overview. Patients with PANDAS and and comorbid Tourette syndrome has been strongly correlated
PANS patients were not content of the paper. Nine case reports of with Tourette syndrome [25]. A comparison of patients with OCD
autoantibody-associated OCD have been published, of which six to patients with other mental or neurological disorders may be
patients (67%) benefited from immunotherapy. Six of eleven vulnerable because many studies showed immunological findings
cross-sectional studies have also provided evidence for an in these disorders as well [32, 77–80]. Bhattacharyya and
association between autoantibodies and OCD. colleagues [53] revealed no significant difference in the serum
autoantibodies binding to basal ganglia homogenate, whereas
Anti-CNS autoantibodies from serum and CSF CSF ABGA was significantly elevated in patients with OCD
A total of five patients with OCS described as case reports had anti- compared with healthy controls. The same was true for
CNS autoantibodies [44, 46, 48, 50, 52]; out of those, three patients autoantibodies against the thalamus [53]. This might be related

Translational Psychiatry (2023)13:241

 D. Denzel et al.
9
to intrathecal autoantibody synthesis. Further studies are war- CONCLUSIONS
ranted to analyze CSF autoantibodies in OCD and healthy controls Case reports suggest a possible association of OCS with
to differentiate whether CSF autoantibodies are more specific autoantibodies. Some cross-sectional studies also showed correla-
biomarkers than serum autoantibodies. The studies on autoanti- tions between OCD and different autoantibodies in rare cases, but
bodies preventing serotonin binding as well as on the dopamine were mostly conducted with small sample size or were not
D1 receptor [55, 63] also yielded promising results. Nonetheless, replicated. Therefore, larger studies analyzing different autoanti-
each autoantibody has been investigated in only one study to bodies are needed. The concept of a rare subtype of “autoimmune
date and should be replicated in future studies. OCD” should be further investigated as it may open up novel
avenues for targeted therapeutic approaches in the future.
Systemic autoantibodies from serum and CSF
Four case reports with autoimmune forms of OCD in the context
of systemic autoantibodies were identified [45, 47, 49, 51]. Three DATA AVAILABILITY
patients suffered from connective tissue disorders (one patient All relevant findings are presented descriptively in the paper.
with neuropsychiatric lupus [47], two patients with Sjögren
syndrome [45, 49], and one patient was positive for anti-
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Psychiatry. 2003;74:602–7. https://doi.org/10.1136/jnnp.74.5.602 LTvE: Advisory boards, lectures, or travel grants within the last three years: Roche, Eli
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