John Greenlee - Academia.edu (original) (raw)

Papers by John Greenlee

F1000 - Post-publication peer review of the biomedical literature, 2010

Current Treatment Options in Neurology, 2003

Opinion statementSubdural empyema represents loculated infection between the outermost layer of t... more Opinion statementSubdural empyema represents loculated infection between the outermost layer of the meninges, the dura, and the arachnoid. The empyema may develop intracranially or in the spinal canal. Intracranial subdural empyema is most frequently a complication of sinusitis or, less frequently, otitis or neurosurgical procedures. Spinal subdural empyema is rare and may result from hematogenous infection or spread of infection from osteomyelitis. The most common organisms in intracranial subdural empyema are anaerobic and microaerophilic streptococci, in particular those of the Streptococcus milleri group (S. milleri and Streptococcus anginosus). Staphylococcus aureus is present in a minority of cases, and multiple additional organisms, including Gramnegative organisms, such as Escherichia coli, and anaerobic organisms, such as Bacteroides, may be present. Pseudomonas aeruginosa or Staphylococcus epidermidis may be present in cases related to neurosurgical procedures, and Salmonella species have been detected in patients with advanced AIDS; multiple organisms may be present simultaneously. Spinal subdural empyemas are almost invariably caused by streptococci or by S. aureus. Subdural empyema—whether it occurs in the skull or the spinal canal—may cause rapid compression of the brain or spinal cord, and represents an extreme medical and neurosurgical emergency. The diagnostic procedure of choice for intracranial and spinal subdural empyema is MRI with gadolinium enhancement. Computed tomography scan may miss intracranial subdural empyemas detectable by MRI. Conversely, occasion spinal subdural empyemas may be detected by CT myelography where MRI is negative. Treatment in virtually all cases of intracranial or spinal subdural empyema requires prompt surgical drainage and antibiotic therapy. Pus from the empyema should always be sent for anaerobic, as well as aerobic, culture. Because intracranial subdural empyemas may contain multiple organisms, provisional antibiotic therapy of intracranial subdural empyema, where the organism is unknown, should be directed against S. aureus, microaerophilic and anaerobic streptococci, and Gram-negative organisms. Antibiotics should include 1) nafcillin, oxacillin, or vancomycin; plus 2) a third generation cephalosporin; plus 3) metronidazole. Provisional antibiotic therapy of spinal subdural empyemas should be directed against S. aureus and streptococci, and should include nafcillin, oxacillin, or vancomycin. Morbidity and mortality in intracranial and spinal subdural empyema relate directly to the delay in institution of therapy. Both conditions should, thus, be treated with great urgency.

Neurology

ObjectiveTo describe the characteristics and outcomes in adult and pediatric patients diagnosed w... more ObjectiveTo describe the characteristics and outcomes in adult and pediatric patients diagnosed with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at the two major referral centers in the Mountain West of the United States, a geographic area encompassing roughly 15% of the land mass of the continental US.BackgroundSince the development of commercial assays, MOGAD has become increasingly recognized as an etiologic diagnosis for several CNS demyelinating phenotypes, yet the epidemiological characteristics, relapse rates and outcomes of large populations are not well-describedDesign/MethodsA retrospective chart review for patients within the health systems at the University of Utah and the University of Colorado, and affiliated children's hospitals, was conducted. To identify MOGAD patients, we queried the ICD10 codes corresponding to demyelinating disease of CNS, neuromyelitis optic spectrum disease, optic neuritis, transverse myelitis, and acute dissemin...

F1000 - Post-publication peer review of the biomedical literature, 2018

Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encep... more Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encephalitis in which serum and cerebrospinal fluid contain antibodies targeting LGI1, a protein of the voltage gated potassium channel (VGKC) complex. Recently, we showed that a feline model of limbic encephalitis with LGI1 antibodies, called feline complex partial seizures with orofacial involvement (FEPSO), is highly comparable to human LGI1 encephalitis. In human LGI1 encephalitis, neuropathological investigations are difficult because very little material is available. Taking advantage of this natural animal model to study pathological mechanisms will, therefore, contribute to a better understanding of its human counterpart. Here, we present a brain-wide histopathological analysis of FEPSO. We discovered that blood-brain barrier (BBB) leakage was present not only in all regions of the hippocampus but also in other limbic structures such as the subiculum, amygdale, and piriform lobe. However, in other regions, such as the cerebellum, no leakage was observed. In addition, this brain-region-specific immunoglobulin leakage was associated with the breakdown of endothelial tight junctions. Brain areas affected by BBB dysfunction also revealed immunoglobulin and complement deposition as well as neuronal cell death. These neuropathological findings were supported by magnetic resonance imaging showing signal and volume increase in the amygdala and the piriform lobe. Importantly, we could show that BBB disturbance in LGI1 encephalitis does not depend on T cell infiltrates, which were present brain-wide. This finding points toward another, so far unknown, mechanism of opening the BBB. The limbic predilection sites of immunoglobulin antibody leakage into the brain may explain why most patients with LGI1 antibodies have a limbic phenotype even though LGI1, the target protein, is ubiquitously distributed across the central nervous system.

Neurology

ObjectiveTo investigate the mechanisms by which neurons take up paraneoplastic and other antibodi... more ObjectiveTo investigate the mechanisms by which neurons take up paraneoplastic and other antibodies.BackgroundOur laboratory has previously demonstrated that neurons can take up both normal and paraneoplastic IgGs and that paraneoplastic autoantibodies such as anti-Yo and anti-Hu can bind to their intracellular target antigens to produce neuronal death. In this study we investigated how neuronal antibody uptake occurs.Design/MethodsWe first compared neuronal uptake of normal and paraneoplastic Fab fragments with that of normal IgG Fc fragments or whole paraneoplastic IgGs. To determine whether neurons expressed receptors capable of binding the Fc portion of the IgG molecule, paraformaldehyde-fixed mouse and rat brains sections were probed with antibodies for the three major types of Fc receptors: FcγRI (CD64), FcγRII, (CD32) and FcγRIII (CD16). Neuronal uptake of antineuronal IgGs was compared between wild type mice and knockout mice lacking the FcγRI receptor. We also investigated ...

<p>The per cent of Purkinje cells which contained IgG and stained with SYTOX green was coun... more <p>The per cent of Purkinje cells which contained IgG and stained with SYTOX green was counted from eight fields similar to that seen in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123446#pone.0123446.g001&quot; target="_blank">Fig 1</a>. Adsorption with the 62 kDa Yo expression protein effectively abolished Purkinje cell death compared to untreated serum or sham-adsorbed serum circulated through a nickel column with bound vector lacking Yo antigen.</p

<p>In this figure the upper row shows merged images demonstrating both IgG accumulation (re... more <p>In this figure the upper row shows merged images demonstrating both IgG accumulation (red) and entry of SYTOX dyes indicative of cell death (green; yellow indicates colocalization of IgG and SYTOX); the bottom row shows staining with SYTOX death markers only. Rat cerebellar slice cultures were incubated with either 1) patient serum containing anti-Yo antibodies (Native serum); 2) the same serum passed over a nickel column bound with lysates from bacteria containing a control vector which lacked the His-tag Yo antigen (Sham adsorbed); or 3) a nickel column with bound His-tagged 62 kDa Yo expression protein (Anti-Yo adsorbed). Cultures were evaluated at intervals through 72 hours for IgG accumulation within Purkinje cells and for Purkinje cell death. Incubation of cultures with untreated (Native) anti-Yo antibodies for 72 hours resulted in antibody accumulation within virtually all Purkinje cells (red) and in Purkinje cell death as indicated by intracellular penetration of SYTOX green (green; co-labeling appears yellow). Antibody uptake and killing were essentially identical in cultures incubated with native anti-Yo serum and sham adsorbed serum (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123446#pone.0123446.g002&quot; target="_blank">Fig 2</a>). In contrast, adsorption of sera with the 62 kDa Yo expression protein essentially abolished both antibody accumulation and cell death, indicating that Purkinje cell antibody accumulation and death are due specifically to interaction of anti-Yo antibodies with the 62 kDa cytoplasmic Purkinje cell protein. Scale bar = 20μ.</p

Current treatment options in neurology, 2013

Paraneoplastic cerebellar degeneration is an uncommon autoimmune disorder characterized clinicall... more Paraneoplastic cerebellar degeneration is an uncommon autoimmune disorder characterized clinically by progressive, ultimately incapacitating ataxia and pathologically by destruction of cerebellar Purkinje cells, with variable loss of other cell populations. The disorder is most commonly associated with gynecological and breast carcinomas, small cell carcinoma of the lung, and Hodgkin's disease and in most cases comes on prior to identification of the underlying neoplasm. The hallmark of paraneoplastic cerebellar degeneration is the presence of an immune response reactive with intracellular proteins of Purkinje or other neurons or, less commonly, against neuronal surface antigens. Evidence-based treatment strategies for paraneoplastic cerebellar degeneration do not exist; and approaches to therapy are thus speculative. Diagnosis and treatment of the underlying neoplasm is critical, and characterization of the antibody response involved may assist in tumor diagnosis. Most investig...

Monographs on Pathology of Laboratory Animals, 1985

Frontiers in Neurology

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devast... more Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, ...

Annals of Neurology, 2020

We read with great interest the article by the group of Kråkenes et al, “CDR2L Is the Major Antib... more We read with great interest the article by the group of Kråkenes et al, “CDR2L Is the Major Antibody Target in Paraneoplastic Cerebellar Degeneration.” We have previously demonstrated, as has that same group, that anti-Yo antibodies are taken up by cerebellar Purkinje cells in rodent slice cultures and are able to cause neuronal death, possibly by interference with calcium signaling The observations by Kråkenes et al correlate well with recent work demonstrating that ovarian tumors from anti-Yo–positive patients show high rates of genetic alterations in CDR2 and, to a greater extent, CDR2L Yo antigens, suggesting that tumor expression of one or both of these proteins may be a key event in breaking immunological tolerance and initiating Purkinje cell destruction. We have two observations concerning Kråkenes et al’s article. First, the work, although of high importance, does not actually demonstrate whether anti-CDR2L antibodies or anti-CDR2 antibodies are capable of causing Purkinje cell death. This could be readily tested using rodent cerebellar slice cultures and methods in use by the authors and other investigators. Such studies would be important in establishing the roles of these two proteins in disease pathogenesis. Second, we would note that the authors, in their work investigating CDR2 immunoreactivity, relied heavily on a commercial polyclonal rabbit antibody raised by immunization with a peptide that contains only 123 of the 454 amino acids of the complete protein. It is not clear whether antibody raised against this peptide fragment duplicates the immunoreactivity that might have been seen using antibody generated against the entire CDR2 protein. We make this observation because, in our own studies, adsorption of anti-Yo IgG with intact CDR2 protein completely abolished both nuclear and cytoplasmic staining of Purkinje cells in slice culture and prevented antibody-mediated cytotoxicity, suggesting that CDR2 may be an important antigenic target as well. The authors’ work comparing reactivity of anti-Yo antibodies with a commercial antibody to CDR2L represents an important finding. However, it may be premature to dismiss CDR2 as a potential autoantigen at this point. We would submit that the roles of the CDR2 and CDR2L proteins in antibody-mediated Purkinje cell death have not been definitively established, and that further analyses will be needed to elucidate the role of antibody to each antigen in disease pathogenesis.

Neurology - Neuroimmunology Neuroinflammation, 2020

ObjectiveTo characterize patients with neurosarcoidosis within the University of Utah healthcare ... more ObjectiveTo characterize patients with neurosarcoidosis within the University of Utah healthcare system, including demographics, clinical characteristics, treatment, and long-term outcomes.MethodsWe describe the clinical features and outcomes of patients with neurosarcoidosis within the University of Utah healthcare system (a large referral center for 10% of the continental United States by land mass). Patients were selected who met the following criteria: (1) at least one International Classification of Diseases Clinical Modification, 9th revision code 135 or International Classification of Diseases Clinical Modification, 10th revision code D86* (sarcoidosis) and (2) at least one outpatient visit with a University of Utah clinician in the Neurology Department within the University of Utah electronic health record.ResultsWe identified 56 patients meeting the study criteria. Thirty-five patients (63%) were women, and most patients (84%) were white. Twelve patients (22%) met the crite...

F1000Research, 2020

Paraneoplastic neurological syndromes are nonmetastatic complications of malignancy secondary to ... more Paraneoplastic neurological syndromes are nonmetastatic complications of malignancy secondary to immune-mediated neuronal dysfunction or death. Pathogenesis may occur from cell surface binding of antineuronal antibodies leading to dysfunction of the target protein, or from antibodies binding against intracellular antigens which ultimately leads to cell death. There are several classical neurological paraneoplastic phenotypes including subacute cerebellar degeneration, limbic encephalitis, encephalomyelitis, and dorsal sensory neuropathy. The patient’s clinical presentations may be suggestive to the treating clinician as to the specific underlying paraneoplastic antibody. Specific antibodies often correlate with the specific underlying tumor type, and malignancy screening is essential in all patients with paraneoplastic neurological disease. Prompt initiation of immunotherapy is essential in the treatment of patients with paraneoplastic neurological disease, often more effective in c...

F1000 - Post-publication peer review of the biomedical literature, 2020

F1000 - Post-publication peer review of the biomedical literature, 2020

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

F1000 - Post-publication peer review of the biomedical literature, 2020

F1000 - Post-publication peer review of the biomedical literature, 2010

Current Treatment Options in Neurology, 2003

Opinion statementSubdural empyema represents loculated infection between the outermost layer of t... more Opinion statementSubdural empyema represents loculated infection between the outermost layer of the meninges, the dura, and the arachnoid. The empyema may develop intracranially or in the spinal canal. Intracranial subdural empyema is most frequently a complication of sinusitis or, less frequently, otitis or neurosurgical procedures. Spinal subdural empyema is rare and may result from hematogenous infection or spread of infection from osteomyelitis. The most common organisms in intracranial subdural empyema are anaerobic and microaerophilic streptococci, in particular those of the Streptococcus milleri group (S. milleri and Streptococcus anginosus). Staphylococcus aureus is present in a minority of cases, and multiple additional organisms, including Gramnegative organisms, such as Escherichia coli, and anaerobic organisms, such as Bacteroides, may be present. Pseudomonas aeruginosa or Staphylococcus epidermidis may be present in cases related to neurosurgical procedures, and Salmonella species have been detected in patients with advanced AIDS; multiple organisms may be present simultaneously. Spinal subdural empyemas are almost invariably caused by streptococci or by S. aureus. Subdural empyema—whether it occurs in the skull or the spinal canal—may cause rapid compression of the brain or spinal cord, and represents an extreme medical and neurosurgical emergency. The diagnostic procedure of choice for intracranial and spinal subdural empyema is MRI with gadolinium enhancement. Computed tomography scan may miss intracranial subdural empyemas detectable by MRI. Conversely, occasion spinal subdural empyemas may be detected by CT myelography where MRI is negative. Treatment in virtually all cases of intracranial or spinal subdural empyema requires prompt surgical drainage and antibiotic therapy. Pus from the empyema should always be sent for anaerobic, as well as aerobic, culture. Because intracranial subdural empyemas may contain multiple organisms, provisional antibiotic therapy of intracranial subdural empyema, where the organism is unknown, should be directed against S. aureus, microaerophilic and anaerobic streptococci, and Gram-negative organisms. Antibiotics should include 1) nafcillin, oxacillin, or vancomycin; plus 2) a third generation cephalosporin; plus 3) metronidazole. Provisional antibiotic therapy of spinal subdural empyemas should be directed against S. aureus and streptococci, and should include nafcillin, oxacillin, or vancomycin. Morbidity and mortality in intracranial and spinal subdural empyema relate directly to the delay in institution of therapy. Both conditions should, thus, be treated with great urgency.

Neurology

ObjectiveTo describe the characteristics and outcomes in adult and pediatric patients diagnosed w... more ObjectiveTo describe the characteristics and outcomes in adult and pediatric patients diagnosed with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at the two major referral centers in the Mountain West of the United States, a geographic area encompassing roughly 15% of the land mass of the continental US.BackgroundSince the development of commercial assays, MOGAD has become increasingly recognized as an etiologic diagnosis for several CNS demyelinating phenotypes, yet the epidemiological characteristics, relapse rates and outcomes of large populations are not well-describedDesign/MethodsA retrospective chart review for patients within the health systems at the University of Utah and the University of Colorado, and affiliated children's hospitals, was conducted. To identify MOGAD patients, we queried the ICD10 codes corresponding to demyelinating disease of CNS, neuromyelitis optic spectrum disease, optic neuritis, transverse myelitis, and acute dissemin...

F1000 - Post-publication peer review of the biomedical literature, 2018

Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encep... more Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encephalitis in which serum and cerebrospinal fluid contain antibodies targeting LGI1, a protein of the voltage gated potassium channel (VGKC) complex. Recently, we showed that a feline model of limbic encephalitis with LGI1 antibodies, called feline complex partial seizures with orofacial involvement (FEPSO), is highly comparable to human LGI1 encephalitis. In human LGI1 encephalitis, neuropathological investigations are difficult because very little material is available. Taking advantage of this natural animal model to study pathological mechanisms will, therefore, contribute to a better understanding of its human counterpart. Here, we present a brain-wide histopathological analysis of FEPSO. We discovered that blood-brain barrier (BBB) leakage was present not only in all regions of the hippocampus but also in other limbic structures such as the subiculum, amygdale, and piriform lobe. However, in other regions, such as the cerebellum, no leakage was observed. In addition, this brain-region-specific immunoglobulin leakage was associated with the breakdown of endothelial tight junctions. Brain areas affected by BBB dysfunction also revealed immunoglobulin and complement deposition as well as neuronal cell death. These neuropathological findings were supported by magnetic resonance imaging showing signal and volume increase in the amygdala and the piriform lobe. Importantly, we could show that BBB disturbance in LGI1 encephalitis does not depend on T cell infiltrates, which were present brain-wide. This finding points toward another, so far unknown, mechanism of opening the BBB. The limbic predilection sites of immunoglobulin antibody leakage into the brain may explain why most patients with LGI1 antibodies have a limbic phenotype even though LGI1, the target protein, is ubiquitously distributed across the central nervous system.

Neurology

ObjectiveTo investigate the mechanisms by which neurons take up paraneoplastic and other antibodi... more ObjectiveTo investigate the mechanisms by which neurons take up paraneoplastic and other antibodies.BackgroundOur laboratory has previously demonstrated that neurons can take up both normal and paraneoplastic IgGs and that paraneoplastic autoantibodies such as anti-Yo and anti-Hu can bind to their intracellular target antigens to produce neuronal death. In this study we investigated how neuronal antibody uptake occurs.Design/MethodsWe first compared neuronal uptake of normal and paraneoplastic Fab fragments with that of normal IgG Fc fragments or whole paraneoplastic IgGs. To determine whether neurons expressed receptors capable of binding the Fc portion of the IgG molecule, paraformaldehyde-fixed mouse and rat brains sections were probed with antibodies for the three major types of Fc receptors: FcγRI (CD64), FcγRII, (CD32) and FcγRIII (CD16). Neuronal uptake of antineuronal IgGs was compared between wild type mice and knockout mice lacking the FcγRI receptor. We also investigated ...

<p>The per cent of Purkinje cells which contained IgG and stained with SYTOX green was coun... more <p>The per cent of Purkinje cells which contained IgG and stained with SYTOX green was counted from eight fields similar to that seen in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123446#pone.0123446.g001&quot; target="_blank">Fig 1</a>. Adsorption with the 62 kDa Yo expression protein effectively abolished Purkinje cell death compared to untreated serum or sham-adsorbed serum circulated through a nickel column with bound vector lacking Yo antigen.</p

<p>In this figure the upper row shows merged images demonstrating both IgG accumulation (re... more <p>In this figure the upper row shows merged images demonstrating both IgG accumulation (red) and entry of SYTOX dyes indicative of cell death (green; yellow indicates colocalization of IgG and SYTOX); the bottom row shows staining with SYTOX death markers only. Rat cerebellar slice cultures were incubated with either 1) patient serum containing anti-Yo antibodies (Native serum); 2) the same serum passed over a nickel column bound with lysates from bacteria containing a control vector which lacked the His-tag Yo antigen (Sham adsorbed); or 3) a nickel column with bound His-tagged 62 kDa Yo expression protein (Anti-Yo adsorbed). Cultures were evaluated at intervals through 72 hours for IgG accumulation within Purkinje cells and for Purkinje cell death. Incubation of cultures with untreated (Native) anti-Yo antibodies for 72 hours resulted in antibody accumulation within virtually all Purkinje cells (red) and in Purkinje cell death as indicated by intracellular penetration of SYTOX green (green; co-labeling appears yellow). Antibody uptake and killing were essentially identical in cultures incubated with native anti-Yo serum and sham adsorbed serum (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123446#pone.0123446.g002&quot; target="_blank">Fig 2</a>). In contrast, adsorption of sera with the 62 kDa Yo expression protein essentially abolished both antibody accumulation and cell death, indicating that Purkinje cell antibody accumulation and death are due specifically to interaction of anti-Yo antibodies with the 62 kDa cytoplasmic Purkinje cell protein. Scale bar = 20μ.</p

Current treatment options in neurology, 2013

Paraneoplastic cerebellar degeneration is an uncommon autoimmune disorder characterized clinicall... more Paraneoplastic cerebellar degeneration is an uncommon autoimmune disorder characterized clinically by progressive, ultimately incapacitating ataxia and pathologically by destruction of cerebellar Purkinje cells, with variable loss of other cell populations. The disorder is most commonly associated with gynecological and breast carcinomas, small cell carcinoma of the lung, and Hodgkin's disease and in most cases comes on prior to identification of the underlying neoplasm. The hallmark of paraneoplastic cerebellar degeneration is the presence of an immune response reactive with intracellular proteins of Purkinje or other neurons or, less commonly, against neuronal surface antigens. Evidence-based treatment strategies for paraneoplastic cerebellar degeneration do not exist; and approaches to therapy are thus speculative. Diagnosis and treatment of the underlying neoplasm is critical, and characterization of the antibody response involved may assist in tumor diagnosis. Most investig...

Monographs on Pathology of Laboratory Animals, 1985

Frontiers in Neurology

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devast... more Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, ...

Annals of Neurology, 2020

We read with great interest the article by the group of Kråkenes et al, “CDR2L Is the Major Antib... more We read with great interest the article by the group of Kråkenes et al, “CDR2L Is the Major Antibody Target in Paraneoplastic Cerebellar Degeneration.” We have previously demonstrated, as has that same group, that anti-Yo antibodies are taken up by cerebellar Purkinje cells in rodent slice cultures and are able to cause neuronal death, possibly by interference with calcium signaling The observations by Kråkenes et al correlate well with recent work demonstrating that ovarian tumors from anti-Yo–positive patients show high rates of genetic alterations in CDR2 and, to a greater extent, CDR2L Yo antigens, suggesting that tumor expression of one or both of these proteins may be a key event in breaking immunological tolerance and initiating Purkinje cell destruction. We have two observations concerning Kråkenes et al’s article. First, the work, although of high importance, does not actually demonstrate whether anti-CDR2L antibodies or anti-CDR2 antibodies are capable of causing Purkinje cell death. This could be readily tested using rodent cerebellar slice cultures and methods in use by the authors and other investigators. Such studies would be important in establishing the roles of these two proteins in disease pathogenesis. Second, we would note that the authors, in their work investigating CDR2 immunoreactivity, relied heavily on a commercial polyclonal rabbit antibody raised by immunization with a peptide that contains only 123 of the 454 amino acids of the complete protein. It is not clear whether antibody raised against this peptide fragment duplicates the immunoreactivity that might have been seen using antibody generated against the entire CDR2 protein. We make this observation because, in our own studies, adsorption of anti-Yo IgG with intact CDR2 protein completely abolished both nuclear and cytoplasmic staining of Purkinje cells in slice culture and prevented antibody-mediated cytotoxicity, suggesting that CDR2 may be an important antigenic target as well. The authors’ work comparing reactivity of anti-Yo antibodies with a commercial antibody to CDR2L represents an important finding. However, it may be premature to dismiss CDR2 as a potential autoantigen at this point. We would submit that the roles of the CDR2 and CDR2L proteins in antibody-mediated Purkinje cell death have not been definitively established, and that further analyses will be needed to elucidate the role of antibody to each antigen in disease pathogenesis.

Neurology - Neuroimmunology Neuroinflammation, 2020

ObjectiveTo characterize patients with neurosarcoidosis within the University of Utah healthcare ... more ObjectiveTo characterize patients with neurosarcoidosis within the University of Utah healthcare system, including demographics, clinical characteristics, treatment, and long-term outcomes.MethodsWe describe the clinical features and outcomes of patients with neurosarcoidosis within the University of Utah healthcare system (a large referral center for 10% of the continental United States by land mass). Patients were selected who met the following criteria: (1) at least one International Classification of Diseases Clinical Modification, 9th revision code 135 or International Classification of Diseases Clinical Modification, 10th revision code D86* (sarcoidosis) and (2) at least one outpatient visit with a University of Utah clinician in the Neurology Department within the University of Utah electronic health record.ResultsWe identified 56 patients meeting the study criteria. Thirty-five patients (63%) were women, and most patients (84%) were white. Twelve patients (22%) met the crite...

F1000Research, 2020

Paraneoplastic neurological syndromes are nonmetastatic complications of malignancy secondary to ... more Paraneoplastic neurological syndromes are nonmetastatic complications of malignancy secondary to immune-mediated neuronal dysfunction or death. Pathogenesis may occur from cell surface binding of antineuronal antibodies leading to dysfunction of the target protein, or from antibodies binding against intracellular antigens which ultimately leads to cell death. There are several classical neurological paraneoplastic phenotypes including subacute cerebellar degeneration, limbic encephalitis, encephalomyelitis, and dorsal sensory neuropathy. The patient’s clinical presentations may be suggestive to the treating clinician as to the specific underlying paraneoplastic antibody. Specific antibodies often correlate with the specific underlying tumor type, and malignancy screening is essential in all patients with paraneoplastic neurological disease. Prompt initiation of immunotherapy is essential in the treatment of patients with paraneoplastic neurological disease, often more effective in c...

F1000 - Post-publication peer review of the biomedical literature, 2020

F1000 - Post-publication peer review of the biomedical literature, 2020

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

F1000 - Post-publication peer review of the biomedical literature, 2020