Camptocormia: pathogenesis, classification, and response to therapy

Originally considered a psychogenic disorder, camptocormia, an abnormal posture with marked flexion of thoracolumbar spine that abates in the recumbent position, is becoming an increasingly recognized feature of parkinsonian and dystonic disorders. Prior reports were limited by sample size, short follow-up, and paucity of data on response to therapy. The authors reviewed 16 patients evaluated in their PD Center and Movement Disorders Clinic diagnosed with camptocormia. In addition to detailed neurologic assessment all patients were videotaped. The mean age was 64.9 +/- 17.4 years, mean age at onset of neurologic symptoms was 51.5 +/- 19.9 years, duration from onset of neurologic symptoms to development of camptocormia was 6.7 +/- 7.6 years, and the mean duration of camptocormia was 4.5 +/- 3.9 years. Of the 16 patients, 11 (68.8%) had Parkinson disease (PD); others had dystonia (n = 4) and Tourette syndrome (n = 1). Twelve patients received levodopa, with minimal or no improvement in the camptocormia. Nine patients received botulinum toxin type A injections into the rectus abdominus, with notable improvement in their camptocormia in four. One patient underwent bilateral subthalamic nucleus deep brain stimulation for PD, but there was no improvement in camptocormia. Based on this series and a thorough review of the literature of camptocormia, head drop, and bent spine syndrome, the authors propose etiologic classification of camptocormia and conclude that this heterogeneous disorder has multiple etiologies and variable response to systemic and local therapies.     

Cellular immune response against acetylcholine receptor in myasthenia gravis: I. Relevance to clinical course and pathogenesis

The cellular immune response to acetylcholine receptor from Torpedo electric organ was studied in 100 myasthenic patients and 41 healthy subjects. The mean stimulation index (SI) was 2 +/- 0.15 for the patients, and 1.06 +/- 0.08 for the controls. Stimulation was significantly greater when the test medium contained autologous serum rather than a standard universal serum (AB serum). Young patients were generally good responders (SI, 2.39 +/- 0.26), but older patients usually did not respond (mean SI, 1.18 +/- 0.13). Among the younger patients, men had higher responses than women (mean SI, 3.13 +/- 0.63 and 2.05 +/- 0.23, respectively). There was no correlation between degree of lymphocytic reactivity and duration or severity of symptoms.     

Lamin A/C mediates microglial activation by modulating cell proliferation and immune response

Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain inflammation, promoting aging and brain disease. In this study, we investigated the role of Lamin A/C in microglial activation and its impact on progeria using Lmna^−/− mice, primary microglia, Lmna knockout (Lmna-KO) and Lmna-knockdown (Lmna-KD) BV2 cell lines. We found that the microglial activation signatures, including cell proliferation, morphology changes, and proinflammatory cytokine secretion (IL-1β, IL-6, and TNF-α), were significantly suppressed in all Lamin A/C-deficient models when stimulated with LPS. TMT-based quantitative proteomic and bioinformatic analysis were further applied to explore the mechanism of Lamin A/C-regulated microglia activation from the proteome level. The results revealed that immune response and phagocytosis were impaired in Lmna^−/− microglia. Stat1 was identified as the hub protein in the mechanism by which Lamin A/C regulates microglial activation. Additionally, DNA replication, chromatin organization, and mRNA processing were also altered by Lamin A/C, with Ki67 fulfilling the main hub function. Lamin A/C is a mechanosensitive protein and, the immune- and proliferation-related biological processes are also regulated by mechanotransduction. We speculate that Lamin A/C-mediated mechanotransduction is required for microglial activation. Our study proposes a novel mechanism for microglial activation mediated by Lamin A/C.     

Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis

OBJECTIVE: To evaluate the ability of mesenchymal stem cells (MSCs), a subset of adult stem cells from bone marrow, to cure experimental autoimmune encephalomyelitis. METHODS: The outcome of the injection of MSCs, in mice immunized with the peptide 139-151 of the proteolipid protein (PLP), was studied analyzing clinical and histological scores of treated mice. The fate of MSCs labeled with the green fluorescent protein was tracked in vivo by a photon emission imaging system and postmortem by immunofluorescence. The modulation of the immune response against PLP was studied through the analysis of in vivo T- and B-cell responses and by the adoptive transfer of MSC-treated encephalitogenic cells. RESULTS: MSC-treated mice showed a significantly milder disease and fewer relapses compared with control mice, with decreased number of inflammatory infiltrates, reduced demyelination, and axonal loss. In contrast, no evidence of green fluorescent protein-labeled neural cells was detected inside the brain parenchyma, thus not supporting the hypothesis of MSCs transdifferentiation. In vivo, PLP-specific T-cell response and antibody titers were significantly lower in MSC-treated mice. When adoptively transferred, encephalitogenic T cells activated against PLP(139-151) in the presence of MSCs induced a milder disease compared with that induced by untreated encephalitogenic T cells. These cells showed decreased production of interferon-gamma and tumor necrosis factor-alpha and did not proliferate on antigen recall, and thus were considered anergic. INTERPRETATION: Overall, these findings suggest that the beneficial effect of MSCs in experimental autoimmune encephalomyelitis is mainly the result of an interference with the pathogenic autoimmune response.     

The innate immune response to adjuvants dictates the adaptive immune response to autoantigens

To elucidate the role of innate immunity in susceptibility to the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we induced EAE by immunization with spinal cord homogenate (SCH) plus complete Freund adjuvant or carbonyl iron in 3 inbred rat strains. Lewis are considered "susceptible," PVG/c-Rt7a (PVG) as "semisusceptible," and Brown Norway (BN) as "resistant" to EAE. Immunization with SCH-carbonyl iron resulted in clinical disease in all 3 strains, but the pathologic features of EAE in the resistant BN and the semisusceptible PVG rats differed from those in the Lewis and PVG model of EAE induced with SCH-complete Freund adjuvant. In BN and PVG rats, there were numerous inflammatory lesions with prominent involvement of microglia and, to a lesser extent, perivascular macrophages. These data suggest that different levels of activation of the innate immune system by different adjuvants determine whether EAE will or will not develop. Accordingly, the widely accepted scale of susceptibility to EAE development (Lewis > PVG > BN) should be revised because it does not take into account the important contribution of the composition of the adjuvant to the quality and quantity of the innate immune response and, consequently, to the generation and extent of the pathogenic T-cell-mediated, that is, adaptive, autoimmune disease.     

Gender differences in experimental autoimmune encephalomyelitis develop during the induction of the immune response to encephalitogenic peptides

Multiple sclerosis (MS) strikes women more often than men. Gender differences in experimental autoimmune encephalomyelitis (EAE) parallel those seen in MS. We utilized the adoptive transfer model of EAE to determine the role of gender on the induction and effector phases of disease. PLP 139–151-sensitized spleen cells from female SJL mice were more effective at transferring disease than male cells. However, there were no gender differences in the frequency of PLP 139–151-specific T cells. PLP 139–151-specific female T cell lines induced more severe disease than male T cell lines. Disease severity was more strongly linked to the sex of the donor T cells, indicating that gender influences the immune response primarily during the induction phase. J. Neurosci. Res. 52:420–426, 1998. © 1998 Wiley-Liss, Inc.     

Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system (CNS). EAE pathogenesis involves various cell types, cytokines, chemokines, and adhesion molecules. Given the complexity of the inflammatory response in EAE, it is likely that many immune mediators still remain to be discovered. To identify novel immune mediators of EAE pathogenesis, we performed an Affymetrix gene array screen on the spinal cords of mice at the onset stage of disease. This screening identified the gene encoding lipocalin 2 (Lcn2) as being significantly upregulated. Lcn2 is a multi-functional protein that plays a role in glial activation, matrix metalloproteinase (MMP) stabilization, and cellular iron flux. As many of these processes have been implicated in EAE, we characterized the expression and role of Lcn2 in this disease in C57BL/6 mice. We show that Lcn2 is significantly upregulated in the spinal cord throughout EAE and is expressed predominantly by monocytes and reactive astrocytes. The Lcn2 receptor, 24p3R, is also expressed on monocytes, macrophages/microglia, and astrocytes in EAE. In addition, we show that EAE severity is increased in Lcn2(-/-) mice as compared with wild-type controls. Finally, we demonstrate that elevated levels of Lcn2 are detected in the plasma and cerebrospinal fluid (CSF) in MS and in immune cells in CNS lesions in MS tissue sections. These data indicate that Lcn2 is a modulator of EAE pathogenesis and suggest that it may also play a role in MS.     

Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease

BACKGROUND: The amyloid-beta (Abeta) peptide has a central role in the neurodegeneration of Alzheimer disease (AD). Immunization of AD transgenic mice with Abeta(1-42) (Abeta(42)) peptide reduces both the spatial memory impairments and AD-like neuropathologic changes in these mice. Therapeutic immunization with Abeta in patients with AD was shown to be effective in reducing Abeta deposition, but studies were discontinued owing to the development of an autoimmune, cell-mediated meningoencephalitis. We hypothesized that gene vaccination could be used to generate an immune response to Abeta(42) that produced antibody response but avoided an adverse cell-mediated immune effect. OBJECTIVE: To develop an effective genetic immunization approach for treatment and prevention of AD without causing an autoimmune, cell-mediated meningoencephalitis. METHODS: Mice were vaccinated with a plasmid that encodes Abeta(42), administered by gene gun. The immune response of the mice to Abeta(42) was monitored by measurement of (1) antibody levels by enzyme-linked immunosorbent assay (ELISA) and Western blot and (2) Abeta(42)-specific T-cell response as measured by interferon-gamma enzyme-linked immunospot (ELISPOT) assay. RESULTS: Gene-gun delivery of the mouse Abeta(42) dimer gene induced significant humoral immune responses in BALB/c wild-type mice after 3 vaccinations in 10-day intervals. All 3 mice in the treated group showed significant humoral immune responses. The ELISPOT assay for interferon-gamma release with mouse Abeta(42) peptide and Abeta(9-18) showed no evident cytotoxic T-lymphocyte response. We further tested the responses of wild-type BALB/c mice to the monomer Abeta(42) gene vaccine. Western blot evaluation showed both human and mouse Abeta monomer gene vaccine elicited detectable humoral immune responses. We also introduced the human Abeta(42) monomer gene vaccine into AD double transgenic mice APPswe/PSEN1(A246E). Mice were vaccinated with plasmids that encode Abeta(1-42) and Abeta(1-16), or with plasmid without the Abeta gene. Treated mice showed significant humoral immune responses as demonstrated by ELISA and by Western blot. These mice also showed no significant cellular immune response as tested by ELISPOT. One of the treated mice was killed at 7 months of age for histological observations, and scattered amyloid plaques were noted in all layers of the cerebral cortex and in the hippocampus in both Abeta(42)- and control-vaccinated mice. No definite difference was discerned between the experimental and control animals. CONCLUSIONS: Gene-gun-administered genetic immunization with the Abeta(42) gene in wild-type BALB/c and AD transgenic mice can effectively elicit humoral immune responses without a significant T-cell-mediated immune response to the Abeta peptide. This immunotherapeutic approach could provide an alternative active immunization method for therapy and prevention of AD.     

Mechanisms of CNS response to systemic immune challenge: the febrile response

The acute-phase reaction is the multisystem response to acute inflammation.  The central nervous system (CNS) mediates a coordinated set of autonomic, endocrine and behavioral responses that constitute the cerebral component of the acute-phase reaction. However, the mechanisms of immune signaling of the CNS remain controversial. Emerging evidence indicates that different parts of the acute-phase reaction are initiated by distinct mechanisms and in different brain regions. Cytokines produced as a result of local infections (for example, in the abdominal or thoracic cavities) might activate vagal sensory fibers, resulting in sickness behavior and fevers.  Additionally, circulating immune stimuli might activate meningeal macrophages and perivascular microglia along the borders of the brain, eliciting the local production of prostaglandins and responses such as fever, anorexia, sleepiness, and activation of the hypothalamo–pituitary–adrenal (HPA) axis.  The biological importance of these responses might favor the existence of multiple parallel CNS pathways that are engaged by cytokines.     

Essential myoclonus: response to anticholinergic therapy

Benztropine mesylate (Cogentin) in total daily dosages of 4 to 9 mg markedly suppressed the involuntary jerking movements in three patients (a brother and sister and a third apparently sporadic case) with essential myoclonus.     

Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis

Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabolism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders frequently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incomplete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies.