Andres Villa

The neuroprotective role of inflammation in nervous system injuries.

The contribution of inflammation to the pathogenesis of several nervous system disorders has long been established. Other observations, however, indicate that both inflammatory cells and mediators may also have beneficial functions, assisting in repair and recovery processes. There is compelling evidence to indicate that in the injured nervous system, as in other tissues, macrophages are needed at an early stage after injury in order for healing to take place. Likewise, activated T cells of a particular specificity can reduce the spread of damage. This neuroprotective effect of T cells may be caused, at least in part, by the production of neurotrophic factors such as neurotrophin-3 or brain-derived neurotrophic factor. Interestingly, recent findings indicate that immune cells are able to produce a variety of neurotrophic factors which promote neuronal survival and may also mediate anti-inflammatory effects. Numerous cytokines are induced after nervous system injuries. Some cytokines, such as TNF-α, IL-1 and IFN-γ, are well known for their promotion of inflammatory responses. However, these cytokines also have immunosuppressive functions and their subsequent expression also assists in repair or recovery processes, suggesting a dual role for some pro-inflammatory cytokines. This should be clarified, as it may be crucial in the design of therapeutic strategies to target specific cytokine(s). Finally, there is a growing body of evidence to show that autoreactive IgM antibodies may constitute an endogenous system of tissue repair, and therefore prove of value as a therapeutic strategy. Available evidence would appear to indicate that the inflammatory response observed in several neurological conditions is more complex than previously thought. Therefore, the design of more effective therapies depends on a clear delineation of the beneficial and detrimental effects of inflammation.

Cellular Elements of the Blood-Brain Barrier

The Blood-brain-barrier (BBB) provides both anatomical and physiological protection for the central nervous system (CNS), shielding the brain for toxic substances in the blood, supplying brain tissues with nutrients and filtering harmful compounds from the brain back to the bloodstream. The BBB is composed of four main cellular elements: endothelial cells (ECs), astrocyte end-feet, microglial cells, and perycites. Transport across the BBB is limited by both physical and metabolic barriers (enzymes, and different transport systems). Tight junctions (TJs) present between ECs form an important barrier against diffusion, excluding most blood-borne substances for entering the brain.

Isolation and characterization of CD8+ regulatory T cells in multiple sclerosis

To investigate CD8+ regulatory T cell influence on multiple sclerosis development, peripheral blood and cerebrospinal fluid (CSF) CD8+ T cell clones (TCCs) recognizing MBP(83-102) and MOG(63-87)-specific CD4+ T cells were isolated from 20 patients during acute exacerbations, 15 in remission and 15 controls. Blood and CSF CD8+ regulatory TCC cloning frequency decreased more during exacerbations than remissions or controls. Target cell pre-activation significantly enhanced CD8+ T granule-mediated cell killing of CD4+ targets, and was restricted by HLA-E. During exacerbations, killer-inhibitory receptor CD94/NKG2A expression was significantly higher in CD8+ TCCs, limiting their cytotoxic activity. Moreover, IL-15 and IFN-gamma significantly increased CD94 and NKG2A expression. These data provide evidence that CD94/NKG2A receptors play an important role in regulating T cell activity during the course of MS.

Epidemiological characteristics of pregnancy, delivery, and birth outcome in women with multiple sclerosis in Argentina (EMEMAR study)

Background The influence of pregnancy on Multiple Sclerosis (MS) has been extensively studied but such influence on Latin American women with MS has not been characterized. Our objective was to describe the course of pregnancy and birth outcome in Argentinean MS patients and the evolution of MS during pregnancy and after delivery. Method We used a retrospective design in eight MS centers in Argentina and administered a survey to women with definite MS (Mc Donald) with pregnancies during or after MS onset. We contacted 355 women of which 81 met inclusion criteria. We recorded 141 pregnancies. Results Involuntary abortion was observed in 16% of pregnancies (95% CI = 10–23). Thirty five women received immunomodulatory therapy (IMT) before 42 pregnancies. Twenty three (55%) out of 42 pregnancies were exposed to IMT. The mean time of IMT discontinuation before conception in 19 (45.2%) pregnancies without exposure, was 104 days (95% CI = 61.0–147.0). There were 103 deliveries: 79% full term. Birth defects were detected in 19% of pregnancies exposed to IMT (95% CI = 4–46) and in 2% of non-exposed (95% CI = 0.3–8.0). The mean relapse rate was: pre-pregnancy year: 0.22 (95% CI = 0.12–0.32); pregnancy: 0.31 in 1st (95% CI = 0.10–0.52), 0.19 (95% CI = 0.03–0.36) in 2nd, and 0.04 in 3rd trimester (95% CI = –0.04–0.12); 1st trimester post delivery: 0.82 (95% CI = 0.42–1.22). Conclusion We observed a higher rate of birth defects among infants exposed to immunomodulators in utero than those not exposed. The reduction in MS relapses during 2nd and 3rd trimester of pregnancy and its increase during postpartum is consistent with previous reports.

Neuromyelitis Optica Immunoglobulin G present in sera from neuromyelitis optica patients affects aquaporin-4 expression and water permeability of the astrocyte plasma membrane

NMO‐IgG autoantibody selectively binds to aquaporin‐4 (AQP4), the most abundant water channel in the central nervous system and is now considered a useful serum biomarker of neuromyelitis optica (NMO). A series of clinical and pathological observations suggests that NMO‐IgG may play a central role in NMO physiopathology. The current study evaluated, in well‐differentiated astrocytes cultures, the consequences of NMO‐IgG binding on the expression pattern of AQP4 and on plasma membrane water permeability. To avoid or to facilitate AQP4 down‐regulation, cells were exposed to inactivated sera in two different situations (1 hr at 4°C or 12 hr at 37°C). AQP4 expression was detected by immunofluorescence studies using a polyclonal anti‐AQP4 or a human anti‐IgG antibody, and the water permeability coefficient was evaluated by a videomicroscopy technique. Our results showed that, at low temperatures, cell exposure to either control or NMO‐IgG sera does not affect either AQP4 expression or plasma membrane water permeability, indicating that the simple binding of NMO‐IgG does not affect the water channels activity. However, at 37°C, long‐term exposure to NMO‐IgG induced a loss of human IgG signal from the plasma membrane along with M1‐AQP4 isoform removal and a significant reduction of water permeability. These results suggest that binding of NMO‐IgG to cell membranes expressing AQP4 is a specific mechanism that may account for at least part of the pathogenic process.

Variable patterns of anti-GM1 IgM-antibody populations defined by affinity and fine specificity in patients with motor syndromes: evidence for their random origin

Elevated titers of serum antibodies against GM(1)-ganglioside are associated with a variety of autoimmune neuropathies. Although much evidence indicates that these autoantibodies play a primary role in the disease processes, the mechanism of their appearance is unclear. Low-affinity anti-GM(1) antibodies of the IgM isotype are part of the normal human immunological repertoire. In patients with motor syndromes, we found that in addition to the usual anti-GM(1) antibodies, the sera contain IgM-antibodies that recognize GM(1) with higher affinity and/or different specificity. This latter type of antibodies was not detected in other autoimmune diseases. We studied the fine specificity of both normal and motor disease-associated antibodies using HPTLC-immunostaining of GM(1) and structurally related glycolipids, soluble antigen binding inhibition, and GM(1) affinity columns. Normal low-affinity anti-GM(1) antibodies cross-react with GA(1) and/or GD(1b). In the motor syndrome patients, different populations of antibodies characterized by their affinity and cross-reactivity were detected. Although one population is relatively common (low affinity, not cross-reacting with GA(1) and GD(1b)), there are remarkably few sera having the same set of populations. These results suggest that the appearance of the new antibody populations is a random process. When the different antibody populations were analyzed in relation to the three-dimensional structure of GM(1), a restricted area of the GM(1) oligosaccharide (the terminal Galbeta1-3GalNAc) was found to be involved in binding of normal anti-GM(1) antibodies. Patient antibodies recognize slightly different areas, including additional regions of the GM(1) molecule such as the NeuNAc residue. We hypothesize that disease-associated antibodies may originate by spontaneous mutation of normal occurring antibodies.

TNFSFR1A R92Q mutation, autoinflammatory symptoms and multiple sclerosis in a cohort from Argentina

Systemic autoinflammatory diseases are genetic disorders characterized by seemingly unprovoked inflammation, without major involvement of the adaptive immune system. Among them it is recognized the TNF receptor associated periodic syndrome (TRAPS) caused by mutations in the TNFRSF1A gene and characterized by symptoms such as recurrent high fevers, rash, abdominal pain, arthralgia and myalgia. Recent studies have recognized the potential role of TNFRSF1A mutations in Multiple Sclerosis (MS). Our aim was to investigate the role of TNFRSF1A R92Q gene mutation in a cohort of 90 Argentinean MS patients, where we determined the frequency of the TNFRSF1A R92Q mutation. We also compared autoinflammatory symptoms, MS clinical characteristics and treatment response and tolerability in R92Q carriers and non-carriers. Also, we used a case–control study design to obtain the genotypes of 78 healthy controls and assess the role of this mutation as a risk factor for MS. We found that five patients (5.5%) carried the R92Q mutation, four reported autoinflammatory symptoms previous to MS onset. We found no differences in MS clinical features, treatment response and tolerability between carriers and non-carriers. R92Q mutation was more frequent in MS patients as compared to controls. This increases the risk to develop MS in about 4.5 times. The TNFRSF1A R92Q mutation is a common finding in Argentinean MS patients. This genetic variant might be a risk factor for MS.

Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica

UNLABELLED Tonic spasms have been most commonly associated with multiple sclerosis. To date, few reports of series of patients with neuromyelitis optica and tonic spasms have been published. METHODS We analyzed the characteristics and frequency of tonic spasms in 19 subjects with neuromyelitis optica. Data was collected using a semi-structured questionnaire for tonic spasms, by both retrospectively reviewing medical records and performing clinical assessment. RESULTS All patients except one developed this symptom. The main triggering factors were sudden movements and emotional factors. Spasms were commonly associated to sensory disturbances and worsened during the acute phases of the disease. Carbamazepine was most commonly used to treat the symptom and patients showed good response to the drug. CONCLUSIONS Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica.

Neurocisticercosis en un hospital de la ciudad de Buenos Aires: estudio de once casos

Eleven patients with diagnosis of possible neurocistycercosis were studied in our Department since 1986. All of them were adults. Eight were Bolivian citizens. The commonest neurological clinical manifestation were seizures and/or headache. Brain CT scans showed cystic lesions and calcifications in 5 patients, only calcifications in 3, enlarged ventricles in 2 and an isolated frontal cystic lesion in 1. Six out of 7 patients who were submitted to spinal fluid ELISA test showed positive response for cysticercosis. Patients were put on praziquantel (50mg/Kg/d) or albendazol (15mg/Kg/d) with good outcome for all them. Surgery was carried on for treatment of enlarged ventricles (2 patients) and for a like-expansive lesion (1 patient). The aim of this work is to underscore the fact that in Buenos Aires city, which previously was not within the endemic latinamerican area for cysticercosis, is now possible to find patients with the neurological manifestations of this parasitosis, most probably due to migration of people coming from the north provinces or from countries situated at its border where the disease is endemic.Eleven patients with diagnosis of possible neurocistycercosis were studied in our Department since 1986. All of them were adults. Eight were Bolivian citizens. The commonest neurological clinical manifestation were seizures and/or headache. Brain CT scans showed cystic lesions and calcifications in 5 patients, only calcifications in 3, enlarged ventricles in 2 and an isolated frontal cystic lesion in 1. Six out of 7 patients who were submitted to spinal fluid ELISA test showed positive response for cysticercosis. Patients were put on praziquantel (50 mg/Kg/d) or albendazol (15 mg/Kg/d) with good outcome for all them. Surgery was carried on for treatment of enlarged ventricles (2 patients) and for a like-expansive lesion (1 patient). The aim of this work is to underscore the fact that in Buenos Aires city, which previously was not within the endemic latin american area for cysticercosis, is now possible to find patients with the neurological manifestations of this parasitosis, most probably due to migration of people coming from the north provinces or from countries situated at its border where the disease is endemic.

Normatization of the Symbol Digit Modalities Test-Oral Version in a Latin American Country

The aim of this study was to standardize the Symbol Digit Modalities Test (SDMT)-Oral version in a healthy population living in Argentina and to analyze the influence that age, gender, and education have on the SDMT. Secondarily, it is intended to analyze the performance of patients with multiple sclerosis (MS) on this test. Two hundred ninety-seven healthy participants were evaluated; they had an average age of 39.28 years and 13.87 years of schooling; 77.8% were women. The sample was segmented according to age in three groups: younger than 35 years old, 36 to 50 years old, and 51 to 70 years old. The sample was also segmented according to years of schooling in three groups: 11 years or less, 12 to 16 years, and more than 16 years. All participants were evaluated with the oral version of the SDMT. A clinical sample of 111 patients with MS was also assessed. The mean on the SDMT for the total sample was 51.34 (SD = 12.76). The differences were significant between all groups, p < .05, according to age. The participants with a higher level of education performed better than did those with moderate education and those with less schooling, p < .05. There was a significant difference between patients with MS and healthy controls, p < .01. The SDMT is influenced by age as well as by schooling, although not by gender. The norms displayed here will be useful to accurately evaluate the yield of the patients in the neuropsychological clinic when comparing them with their group of reference. It was also demonstrated that the SDMT can discriminate between patients with MS and healthy people.