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Anti-Ro/SAA Antibodies May Be Responsible for Cerebellar Degeneration in Sjogren's Syndrome

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Anti-Ro/SAA Antibodies May Be Responsible for Cerebellar Degeneration in Sjogren's Syndrome Original Article J Clin Med Res. 2021;13(2):113-120 Anti-Ro/SSA Antibodies May Be Responsible for Cerebellar Degeneration in Sjogren’s Syndrome Syuichi Tetsukaa, b, Tomohiro Suzukia, Tomoko Ogawaa, Ritsuo Hashimotoa, Hiroyuki Katoa Abstract eration in patients with SjS and Ro52/TRIM21 expression in the Purkinje cells of murine cerebellar tissue sections. These outcomes Background: Neurological disorders have been identified to be a indicate that anti-Ro/SSA antibodies were likely responsible for cer- common extraglandular manifestation of Sjogren’s syndrome (SjS). ebellar degeneration in patients suffering from SjS. Central nervous system (CNS) symptoms appear in about 5% of pa- Anti-Ro/SSA antibodies; Cerebellar degeneration; tients with SjS. However, so far, only a few incidences of cerebellar Keywords: Purkinje cell; Ro52/TRIM21; Sjogren’s syndrome degeneration have been reported, and the clinical features and path- ological mechanisms associated with SjS remain to be unclear. In- tramedullary production of anti-Ro/anti-SjS-related antigen A (SSA) has been observed in some patients with SjS patients who have CNS involvement, suggesting the involvement of anti- Ro/SSA antibodies Introduction as antineuronal antibodies in previous studies. Sjogren’s syndrome (SjS) has been defined as an autoimmune Methods: We recently treated cerebellar degeneration in a patient with disease in which the exocrine glands, primarily the salivary SjS. We analyzed the serum and cerebrospinal fluid (CSF) in order glands, are damaged. In addition, SjS is known to affect a wide to detect anti-Ro/SSA and anti-La/anti-SjS-related antigen B (SSB) variety of organs, including the skin, joints, nervous system, antibodies. We also searched the literature for previous case reports lungs, kidneys and digestive tract [1]. In particular, peripheral to evaluate the characteristics of cerebellar degeneration in patients and central neurological symptoms can be evident in about with SjS. First, we have studied in mouse brain tissue and examined 15% and 5% of patients with SjS, respectively [2]. In the past whether the Ro/SSA (Ro52/tripartite motif protein (TRIM)21) protein decade, central nervous system (CNS) involvement in SjS has was expressed in the cerebellum of mice using immunohistochemistry. been observed more commonly than initially suspected, with Results: Although all patients that we found in the literature review disorders that include encephalitis, cognitive disorders, men- and our patient 1 were positive for anti-Ro/SSA antibodies, some pa- ingitis, myelitis and cerebellar degeneration. However, only a tients were also negative for anti-La/SSB antibodies. Anti-Ro/SSA few reports of cerebellar degeneration have been described, antibodies were observed in both serum and CSF; however, anti-Ro/ and its clinical features and pathological mechanisms associ- SSA antibodies were negative in the CSF of patients with SjS with- ated with SjS are yet to be determined. out CNS involvement. Cerebellar atrophy was observed, and sequelae Anti-Ro/anti-SjS-related antigen A (SSA) and anti-La/ remained in the majority of patients. Autopsy findings indicated a se- anti-SjS-related antigen B (SSB) antibodies have been identi- lective loss of Purkinje cells. Ro52/TRIM21 expression was also de- fied to be essential for the classification of SjS during diagnos- tected throughout murine brains, including the hippocampus, cerebral tic workups [3]. On the basis of molecular weights, Ro/SSA cortex and cerebellum. High Ro52/TRIM21 expression was observed and La/SSB antibodies target three cellular proteins, namely, in the Purkinje cells. Ro52 (also referred to as tripartite motif protein (TRIM)21), Ro60 and La48 [3]. Intramedullary production of anti-Ro52/ Conclusions: We described the characteristics of cerebellar degen- TRIM21 antibodies has been observed in some patients with SjS who have CNS involvement, suggesting the involvement of anti-Ro52/TRIM21 antibodies as antineuronal antibodies, Manuscript submitted January 16, 2021, accepted January 26, 2021 and it has been reported that cerebrospinal fluid (CSF) anti-Ro/ Published online February 25, 2021 SSA antibodies can serve as a biomarker for SjS-related CNS involvement [4]. However, an understanding on the molecular a Department of Neurology, International University of Health and Welfare and pathological mechanisms behind autoantibodies in CNS Hospital, 537-3, Iguchi, Nasushiobara, Tochigi 329-2763, Japan manifestations of SjS, including cerebellar degeneration, re- bCorresponding Author: Syuichi Tetsuka, Department of Neurology, Interna- tional University of Health and Welfare Hospital, 537-3, Iguchi, Nasushio- mains to be lacking; thus, further investigations are required to bara, Tochigi 329-2763, Japan. Email: [email protected] clarify their associations. We recently treated cerebellar degeneration in a patient doi: https://doi.org/10.14740/jocmr4429 with SjS. We analyzed serum and CSF to determine any pres- Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits 113 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited SSA Antibodies Cause Cerebellar Degeneration J Clin Med Res. 2021;13(2):113-120 ence of anti-Ro/SSA and anti-La/SSB antibodies. We also per- polyradiculoneuropathy (CIDP)) formed a literature review to assess the clinical characteristics, diagnostic methods and therapeutic strategies used for patients A 53-year-old male patient was admitted to our neurology de- with SjS who have cerebellar degeneration. Moreover, we ex- partment with complaints of numbness and weakness in all amined the expression of autoantigens (potential autoantibody limbs, which emerged 3 years earlier and gradually worsened. target sites) in the murine cerebellar tissue sections to elucidate He had a history of hypertension and hyperlipidemia. His cra- the molecular and pathological mechanisms of cerebellar de- nial nerves were intact, and there were no overt symptoms of generation in these patients. cerebellar ataxia by neurological examination. Deep tendon reflexes were not present in the upper and lower extremities, Materials and Methods and there were no pathological reflexes. Muscle atrophy and weakness (Medical Research Center muscle scale, grade: R4-/L4) were noted in the distal muscles of lower extremities. Patients Sensory disturbance (dysesthesia and hypoesthesia) was ob- served along the dermatomes of the left chest, left abdomen, Written informed consent was obtained from the patients in left back and both extremities. A slight decrease in position these case presentations, including for the accompanying im- and vibration sense was observed in both feet. He showed a ages in the figures. wadding gait and inability to walk with a tandem gait. The se- rum anti-Ro/SSA and anti-La/SSB antibody levels were 26.5 and 24.5 U/mL, respectively. The levels of ANA, anti-dsDNA, Patient 1 (SjS with cerebellar degeneration) anti-GM1 and anti-GQ1b were also within the normal limits. He was also negative for serum anti-neutrophil cytoplasmic A 36-year-old male patient with progressive gait imbalance for antibodies (ANCAs) targeting myeloperoxidase (MPO) and 2 weeks was admitted to our neurology department. He had no proteinase 3 (PR3). A lip biopsy showed lymphocyte infiltra- family history of gait disturbance and neurological disorders tion around the salivary gland duct. A series of electromyo- and no history of exposure to toxins or drugs. The neurological graphic examinations showed polyradiculoneuropathy with examination revealed dysarthria, dysmetria in both legs, ataxic demyelination, consistent with the electrodiagnostic criteria gait and inability to walk without assistance due to several of CIDP. CSF specimens showed increased total protein levels cerebellar ataxia affecting all limbs and trunk. His scale for (96 mg/dL), and both anti-Ro/SSA and anti-La/SSB antibod- the assessment and rating of ataxia score, in which ≤ 8 points ies were determined to be absent (< 1.0 U/mL). Brain MRI did indicates the ability to walk unassisted, was 24.5. His muscle not reveal abnormalities, and the patient was diagnosed with strength and sensory examinations were normal, and his deep SjS with CIDP. tendon reflexes were normoactive. He did not have nystagmus We present patient 2 to show the differences between pa- or cognitive impairment. Laboratory evaluation revealed high tients with SjS with peripheral nervous system (PNS) involve- serum anti-Ro/SSA and anti-La/SSB antibody levels (≥ 1,200 ment and those with CNS involvement (patient 1). Anti-Ro/ and 198 U/mL, respectively) and antinuclear antibody (ANA) SSA antibodies were positive in the serum, but negative in the positivity (1:80). He was negative for anti-dsDNA, anti-Sm CSF, in the patient with SjS who had PNS involvement with- and anti-phospholipid (cardiolipin and β2 glycoprotein) anti- out CNS involvement. bodies. Paraneoplastic (anti-Hu, nti-Ri, anti-Yo, anti-Tr, anti- PNMA2 and anti-CV2), anti-GAD and anti-thyroglobulin an- Literature review tibodies were not detected. Both Schirmer’s and fluorescein tests were positive, indicating that the patient also had dry eye. A salivary gland biopsy was then performed, revealing a lym- We conducted a literature review by searching PubMed for ar- phocytic infiltration around the salivary
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