• Acute cerebellitis
• Cerebellar ataxia
• Cerebellar atrophy
• GABAB receptor antibodies

• Humans
• Male
• Middle Aged
• Receptors, GABA-B/immunology
• Encephalitis/diagnostic imaging
• Encephalitis/pathology
• Hashimoto Disease/diagnostic imaging
• Hashimoto Disease/complications
• Cerebellar Diseases/diagnostic imaging
• Cerebellar Diseases/pathology
• Magnetic Resonance Imaging

• Immune-mediated cerebellar ataxias
• Opsoclonus myoclonus ataxia syndrome
• Paraneoplastic cerebellar degeneration
• Postinfectious cerebellar ataxia
• Primary autoimmune cerebellar ataxia

• Humans
• Cerebellar Ataxia/etiology
• Cerebellar Ataxia/pathology
• Ataxia/diagnosis
• Ataxia/etiology
• Cerebellum/pathology
• Opsoclonus-Myoclonus Syndrome/pathology

• 2-Deoxy-2-[18F]fluoro-D-glucose
• Cerebellar ataxia
• Fluorodeoxyglucose
• GAD65
• Glutamic acid decarboxylase 65
• Positron emission tomography
• Stiff person syndrome

• Humans
• Fluorodeoxyglucose F18
• Cerebellar Ataxia/diagnostic imaging
• ROC Curve
• Cerebellum
• Glucose
• Positron-Emission Tomography

• T32EB006351 National Institute of Biomedical imaging and Bioengineering of the National Institutes of Health

In immunocompetent animals, numerous factors including the immune system of the host regulate the survival of neuro-glial precursors transplanted into the cerebellum. We transplanted human neuro-glial precursors derived in vitro from partial differentiation of IPS cells into the developing cerebellum of mice and rats before maturation of the host immune system. These approaches should facilitate the development of immune-tolerance for the transplanted cells. However, we found that human cells survived the engraftment and integrated into the host cerebellum and brain stem up to about 1 month postnatally when they were rejected in both species. On the contrary, when we transplanted the same cells in NOD-SCID mice, they survived indefinitely. Our findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts the induction of immune-tolerance to human antigens expressed before completion of the maturation of the immune system. As predicted by our hypothesis, when we engrafted the human neuro-glial precursor cells either in a more mature state or mixed with extracts from adult cerebellum, we prolonged the survival of the graft.

• Animals
• Cerebellum
• Heterografts
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Rats
• Transplantation, Heterologous

• Fondazione Telethon
• Fondazione IRCCS Policlinico San Matteo
• Università degli Studi di Torino
• Ministero dell’Istruzione, dell’Università e della Ricerca

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum.

• ataxias
• cerebellar reserve
• cerebellum
• preataxic
• prodromal

• Immune ataxias
• Primary autoimmune cerebellar ataxia (PACA)

We xeno-transplanted human neural precursor cells derived from induced pluripotent stem cells into the cerebellum and brainstem of mice and rats during prenatal development or the first postnatal week. The transplants survived and started to differentiate up to 1 month after birth when they were rejected by both species. Extended survival and differentiation of the same cells were obtained only when they were transplanted in NOD-SCID mice. Transplants of human neural precursor cells mixed with the same cells after partial in vitro differentiation or with a cellular extract obtained from adult rat cerebellum increased survival of the xeno-graft beyond one month. These findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts induction of immune-tolerance to human antigens expressed before completion of maturation of the immune system. With further maturation the transplanted neural precursors expressed more mature antigens before the graft were rejected. Supplementation of the immature cells suspensions with more mature antigens may help to induce immune-tolerance for those antigens expressed only later by the engrafted cells.

Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.

• Anti-GAD ataxia
• Gluten ataxia
• Immune-mediated cerebellar ataxias
• Opsoclonus myoclonus syndrome
• Paraneoplastic cerebellar degeneration
• Postinfectious cerebellitis

• MGUS
• cerebellar autoantibodies
• immunoglobulin G
• immunoglobulin M
• monoclonal gammopathy of undetermined significance
• plasma exchange
• primary autoimmune cerebellar ataxia

In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.

• anti-GAD 65 antibody
• anti-metabotropic glutamate receptor 1 antibody
• anti-voltage-gated Ca channel antibody
• autoantibodies
• cerebellar ataxias
• immune-mediated cerebellar ataxias

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Autoantibodies/blood
• Autoantibodies/cerebrospinal fluid
• Autoimmune Diseases of the Nervous System/blood
• Autoimmune Diseases of the Nervous System/drug therapy
• Autoimmune Diseases of the Nervous System/physiopathology
• Cerebellar Ataxia/blood
• Cerebellar Ataxia/drug therapy
• Cerebellar Ataxia/physiopathology
• Child
• Child, Preschool
• Epilepsy/blood
• Epilepsy/drug therapy
• Epilepsy/physiopathology
• Female
• Glutamate Decarboxylase/immunology
• Humans
• Immunotherapy
• Limbic Encephalitis/blood
• Limbic Encephalitis/drug therapy
• Limbic Encephalitis/physiopathology
• Male
• Middle Aged
• Outcome Assessment, Health Care
• Retrospective Studies
• Stiff-Person Syndrome/blood
• Stiff-Person Syndrome/drug therapy
• Stiff-Person Syndrome/physiopathology
• Young Adult

• Autophagy
• Cerebellar ataxias
• Cerebellar cognitive affective syndrome
• Cerebellar reserve
• Cerebellum
• Dendritic spines
• Environmental enrichment
• Eye movement
• Neuromodulation therapy
• Predictive control
• Saccade

• Adaptation, Physiological/physiology
• Animals
• Cerebellar Diseases/diagnosis
• Cerebellar Diseases/physiopathology
• Cerebellar Diseases/psychology
• Cerebellum/physiology
• Cerebellum/physiopathology
• Consensus
• Eye Movements/physiology
• Humans

Anti-Sry-like high mobility group box (SOX) 1 antibodies (abs) are partly characterized onconeural autoantibodies (autoabs) due to their correlation with neoplastic diseases. Anti-SOX1 abs are associated with various clinical manifestations, including Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar degeneration (PCD). However, the clinical characteristics of patients with anti-SOX1 abs have not been described in detail. This review systematically explores the reported patients with anti-SOX1 abs and analyzes these cases for demographic characteristics, clinical features, coexisting neuronal autoabs, neuroimaging findings, treatment, and clinical outcomes. In addition, considering that PCD is the most common paraneoplastic neurological syndrome and that the association between PCD and anti-SOX1 abs remains unclear, we focus on the presence of autoabs in relation to PCD and associated tumors. PCD-associated autoabs include various intracellular autoabs (e.g., anti-Hu, anti-Yo, anti-Ri, and anti-SOX1) and cell-surface autoabs (anti-P/Q-type voltage-gated calcium channel). Commonly involved tumors in PCD are small-cell lung cancer (SCLC), gynecological, and breast tumors. LEMS is the most common clinical symptom in patients with anti-SOX1 abs, followed by PCD, and multiple neuronal autoabs coexist in 47.1% of these patients. SCLC is still the predominant tumor in patients with anti-SOX1 abs, while non-SCLC is uncommon. No consistent imaging feature is found in patients with anti-SOX1 abs, and there is no consensus on either the therapy choice or therapeutic efficacy. In conclusion, the presence of anti-SOX1 abs alone is a potential predictor of an uncommon paraneoplastic neurological disorder, usually occurring in the setting of LEMS, PCD, and SCLC. The detection of anti-SOX1 abs contributes to an early diagnosis of underlying tumors, given the diversity of clinical symptoms and the absence of characteristic neuroimaging features.

• SOXB1 transcription factors
• antibodies
• carcinoma
• non-small-cell lung
• paraneoplastic cerebellar degeneration
• small cell lung carcinoma

The bacteria Campylobacter jejuni (C. jejuni) is commonly associated with Guillane-Barré syndrome (GBS) and irritable bowel syndrome (IBS), but studies have also linked it with Miller Fisher syndrome, reactive arthritis and other disorders, some of which are autoimmune. It is possible that C. jejuni and its toxins may be cross-reactive with some human tissues and food antigens, potentially leading to autoimmune responses.

To measure the immune reactivity of C. jejuni and C. jejuni cytolethal distending toxin (Cdt) antibodies with tissue and food antigens to examine their role in autoimmunities.

Using enzyme-linked immunosorbent assay (ELISA) methodology, specific antibodies made against C. jejuni and C. jejuni Cdt were applied to a variety of microwell plates coated with 45 tissues and 180 food antigens. The resulting immunoreactivities were compared to reactions with control wells coated with human serum albumin (HSA) which were used as negative controls and with wells coated with C. jejuni lysate or C. jejuni Cdt which served as positive controls.

At 3 SD above the mean of control wells coated with HSA or 0.41 OD, the mouse monoclonal antibody made against C. jejuni showed moderate to high reactions with zonulin, somatotropin, acetylcholine receptor, β-amyloid and presenilin. This immune reaction was low with an additional 25 tissue antigens including asialoganglioside, and the same antibody did not react at all with another 15 tissue antigens. Examining the reaction between C. jejuni antibody and 180 food antigens, we found insignificant reactions with 163 foods but low to high immune reactions with 17 food antigens. Similarly, we examined the reaction of C. jejuni Cdt with the same tissues and food antigens. The strongest reactions were observed with zonulin, intrinsic factor and somatotropin. The reaction was moderate with 9 different tissue antigens including thyroid peroxidase, and reaction was low with another 10 different antigens, including neuronal antigens. The reaction of C. jejuni Cdt antibody with an additional 23 tissue antigens was insignificant. Regarding the reaction of C. jejuni Cdt antibody with different food antigens, 160 out of 180 foods showed insignificant reactions, while 20 foods showed reactions ranging from low to high.

Our findings indicate that C. jejuni and its Cdt may play a role in inflammation and autoimmunities beyond the gut.

• Campylobacter jejuni
• Cytolethal distending toxin
• Tissue antigens
• Food antigens
• Autoimmune reactivities
• Cross-reactivity

• Antibodies, Bacterial/immunology
• Autoimmune Diseases/immunology
• Autoimmune Diseases/microbiology
• Autoimmunity
• Bacterial Toxins/immunology
• Campylobacter Infections/immunology
• Campylobacter jejuni/immunology
• Cholera Toxin/immunology
• Cross Reactions/immunology
• Dietary Proteins/immunology
• Haptoglobins
• Host Microbial Interactions/immunology
• Human Growth Hormone/immunology
• Humans
• Intrinsic Factor/immunology
• Protein Precursors

• Cerebellar ataxia
• Palliative care
• Pharmacological and non-pharmacological management
• Treatment

• Cerebellar ataxias
• anti-GAD65Ab-associated cerebellar ataxia
• gluten ataxia
• immune-mediated cerebellar ataxias
• immunotherapy
• opsoclonus myoclonus syndrome
• paraneoplastic cerebellar degeneration
• post-infectious cerebellitis
• prognosis
• therapy
• treatment.

• Animals
• Autoimmune Diseases/diagnosis
• Autoimmune Diseases/pathology
• Autoimmune Diseases/therapy
• Cerebellar Ataxia/diagnosis
• Cerebellar Ataxia/immunology
• Cerebellar Ataxia/pathology
• Cerebellar Ataxia/therapy
• Cerebellum/immunology
• Cerebellum/pathology
• Disease Progression
• Humans
• Practice Guidelines as Topic

• R01 DK026190 NIDDK NIH HHS

• Cerebellar Diseases/diagnosis
• Cerebellar Diseases/physiopathology
• Cerebellar Diseases/therapy
• Early Diagnosis
• Humans
• Time-to-Treatment

• R01 DK026190 NIDDK NIH HHS

• cerebellum
• challenges
• children
• elderly
• fetus
• genetics
• neuroimaging
• therapies