Anti-ribosomal-phosphoprotein autoantibodies penetrate to neuronal cells via neuronal growth associated protein, affecting neuronal cells in vitro.

OBJECTIVE: Anti-ribosomal-phosphoprotein antibodies (anti-Ribos.P Abs) are detected in 10-45% of NPSLE patients. Intracerebroventricular administration of anti-ribosomal-P Abs induces depression-like behaviour in mice. We aimed to discern the mechanism by which anti-Ribos.P Abs induce behavioural changes in mice. METHODS: Anti-Ribos.P Abs were exposed to human and rat neuronal cell cultures, as well as to human umbilical vein endothelial cell cultures for a control. The cellular localization of anti-Ribo.P Abs was found by an immunofluorescent technique using a confocal microscope. Identification of the target molecules was undertaken using a cDNA library. Immunohistochemistry and an inhibition assay were carried out to confirm the identity of the target molecules. Neuronal cell proliferation was measured by bromodeoxyuridine, and Akt and Erk expression by immunoblot. RESULTS: Human anti-Ribos.P Abs penetrated into human neuronal cells and rat hippocampal cell cultures in vitro, but not to endothelial cells as examined. Screening a high-content human cDNA-library with anti-Ribos.P Abs identified neuronal growth-associated protein (GAP43) as a target for anti-Ribos.P Abs. Ex vivo anti-Ribos.P Abs bind to mouse brain sections of hippocampus, dentate and amygdala. Anti-Ribos.P Abs brain-binding was prevented by GAP43 protein. Interestingly, GAP43 inhibited in a dose-dependent manner the anti-Ribos.P Abs binding to recombinant-ribosomal-P0, indicating mimicry between the ribosomal-P0 protein and GAP43. Furthermore, anti-Ribos.P Abs reduced neuronal cell proliferation activity in vitro (P < 0.001), whereas GAP43 decreased this inhibitory activity by a factor of 7.6. The last was related to Akt and Erk dephosphorylation. CONCLUSION: Anti-Ribos.P Abs penetrate neuronal cells in vitro by targeting GAP43. Anti -Ribos.P Abs inhibit neuronal-cell proliferation via inhibition of Akt and Erk. Our data contribute to deciphering the mechanism for anti-Ribos.P Abs' pathogenic activity in NPSLE.

Is narcolepsy a classical autoimmune disease?

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness. It is caused by the loss of orexin producing neurons in the lateral hypothalamus. Current evidences suggest an autoimmune mediated process causing the specific loss of orexin neurons. The high association of the disease with the HLA DQB1*06:02, as well as the link with environmental factors and are important clues supporting this theory. Recently, the association between the occurrence of the disease and vaccination campaign after the 2009 H1N1 pandemic highlighted the importance to increase the knowledge in the Pandora box of the vaccines. This review discusses the last finding regarding the pathogenesis of the disease and its relationship with the H1N1 vaccines.

Infection and autoimmunity in Sjogren's syndrome: a clinical study and comprehensive review.

Sjögren's syndrome (SS) is an autoimmune disease characterized primarily by lymphocytic infiltration of the exocrine glands, and autoantibody production. Multiple environmental factors affecting an individual with a genetic susceptibility may trigger the development of SS. Herein, we aimed to evaluate links between the different pebbles in the mosaic of SS. Demographic, clinical data and blood samples were gathered from 82 consecutive patients with SS, and 139 healthy controls. Samples were analyzed for infectious serology and auto-antibodies as well as for relevant genetic mutations (TAP genes) and cytokines levels. An immune response (IgG) against Epstein-Barr virus (EBV) early antigen (EA) was positively associated with SS (OR 4; 95% CI: 1.82-8.83, p = 0.001) while a protective effect of IgG anti-cytomegalovirus (CMV) was observed (OR 0.3; 95%CI: 0.16-0.74, p = 0.009). Anti-Ro/SSA, anti-LA/SSB, anti-nuclear, anti-gliadin, anti-TTG-IgG and anti-RNP antibodies were statistically more prevalent among SS patients than controls. Notably, the presence of anti-Ro/SSA and anti La/SSB correlated with anti-EBVEA IgG (OR 3.1; 95%CI: 1.08-8.74) and (OR 3.9; 95%CI: 1.37-10.96) respectively. Autoantibodies, cytokines and several genetic markers correlated with clinical manifestation of SS. Our data suggest that infectious agents may play both a causative and protective role in the pathogenesis of SS. Moreover certain autoantibodies, cytokines and specific TAP alleles correlate with clinical manifestations of SS, and may enable better prediction and/or directed therapy once confirmed in future studies.

Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model.

Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated liver diseases. However, concerns regarding its safety, particularly among patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the aluminum adjuvant in HBVv was related to immune mediated adverse events. Therefore, we examined the effects of immunization with HBVv or alum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBVv (Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze and the forced swimming tests) and brain histology. Immunization with HBVv induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (p < 0.01), early onset of proteinuria (p < 0.05), histological damage and deposition of HBs antigen in the kidney. Mice immunized with HBVv and/or alum had decreased cells counts mainly of the red cell lineage (p < 0.001), memory deficits (p < 0.01), and increased activated microglia in different areas of the brain compare with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with alum. In conclusion, herein we report that immunization with the HBVv aggravated kidney disease in an animal model of SLE. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Our data support the concept that different component of vaccines may be linked with immune and autoimmune mediated adverse events.

16/6-idiotype expressing antibodies induce brain inflammation and cognitive impairment in mice: the mosaic of central nervous system involvement in lupus.

BACKGROUND: The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naïve mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intra-cerebra-ventricularly (ICV) with the 16/6-Id antibody. METHODS: C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes. RESULTS: 16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression-like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control. CONCLUSIONS: Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus.See related Commentary article: http://www.biomedcentral.com/1741-7015/11/91.

Phospholipid supplementation can attenuate vaccine-induced depressive-like behavior in mice.

Human papillomavirus vaccine (HPVv) is used worldwide for prevention of infection. However several reports link this vaccine, with immune-mediated reactions, especially with neurological manifestations. Our previous results showed that HPVv-Gardasil and aluminum-immunized mice developed behavioral impairments. Studies have shown a positive effect of phospholipid supplementation on depression and cognitive functions in mice. Therefore, our goal was to evaluate the effect of a dietary supplement on vaccine-induced depression. Sixty C57BL/6 female mice were immunized with HPVv-Gardasil, aluminum or the vehicle (n = 20 each group), and half of each group were fed 5 times per week with 0.2 ml of a dietary supplement enriched with phosphatidylcholine. The mice were evaluated for depression at 3 months of age, by the forced swimming test. Both the Gardasil and the aluminum-treated mice developed depressive-like behavior when compared to the control group. The HPVv-Gardasil-immunized mice supplemented with phosphatidylcholine significantly reduced their depressive symptoms. This study confirms our previous studies demonstrating depressive-like behavior in mice vaccinated with HPVv-Gardasil. In addition, it demonstrates the ability of phosphatidylcholine-enriched diet to attenuate depressive-like behavior in the HPVv-Gardasil-vaccinated mice. We suggest that phosphatidylcholine supplementation may serve as a treatment for patients suffering vaccine-related neurological manifestations.

HLA-DRB1 the notorious gene in the mosaic of autoimmunity.

The major histocompatibility complex system is the most polymorphic gene cluster of the mammal genome. In humans, this is a genomic locus known as the human leukocyte antigen (HLA) system. The HLA encodes mostly immune-associated proteins whose main effect is the presentation of antigens to the immune cells. Thus, it is clear that it is essential for to the proper function of the immune response against pathogens and strongly implicated in the development of autoimmune diseases. Nonetheless, there are hundreds of polymorphisms of HLA-DRB1 which have been associated with different autoimmune disorders as well as with immune response to infection and vaccines. It is possible that the interaction of specific HLA with pathogenic antigens is one of the keys favoring (or protecting) toward the development of an autoimmune disease. In the era of personalized medicine, it would be of great help to build a map of the genomic risk of each individual to evaluate the risk of developing an autoimmune condition.

Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil.

Vaccine adjuvants and vaccines may induce autoimmune and inflammatory manifestations in susceptible individuals. To date most human vaccine trials utilize aluminum (Al) adjuvants as placebos despite much evidence showing that Al in vaccine-relevant exposures can be toxic to humans and animals. We sought to evaluate the effects of Al adjuvant and the HPV vaccine Gardasil versus the true placebo on behavioral and inflammatory parameters in female mice. Six-week-old C57BL/6 female mice were injected with either, Gardasil, Gardasil + pertussis toxin (Pt), Al hydroxide, or, vehicle control in amounts equivalent to human exposure. At 7.5 months of age, Gardasil and Al-injected mice spent significantly more time floating in the forced swimming test (FST) in comparison with vehicle-injected mice (Al, p = 0.009; Gardasil, p = 0.025; Gardasil + Pt, p = 0.005). The increase in floating time was already highly significant at 4.5 months of age for the Gardasil and Gardasil + Pt group (p ≤ 0.0001). No significant differences were observed in the number of stairs climbed in the staircase test which measures locomotor activity. These results indicate that differences observed in the FST were unlikely due to locomotor dysfunction, but rather due to depression. Moreover, anti-HPV antibodies from the sera of Gardasil and Gardasil + Pt-injected mice showed cross-reactivity with the mouse brain protein extract. Immunohistochemistry analysis revealed microglial activation in the CA1 area of the hippocampus of Gardasil-injected mice. It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.

Pharmacologic management of neuropsychiatric lupus.

Neuropsychiatric lupus affects above 50% of patients with systemic lupus erythematosus and may span from mild symptoms to acute devastating life-threatening ones. Owing to the clinical variability, most pharmacological data rely on small, uncontrolled trials and case reports. The mainstay of therapy relies on immune-suppression by glucocorticoids, in adjunction with cyclophosphamide or anti-B-cell therapy, in moderate to severe cases. In selected scenarios (e.g., chorea) intravenous immunoglobulin or plasmapheresis may be effective. Anticoagulation is warranted if anti-phospholipid antibodies are present. In parallel there may be a need for symptomatic treatment such as anti-epileptic or anti-depressive treatments, etc. In the future, more studies addressed to assess pathogenesis and preferred treatments of specific manifestations are needed in order to personalize treatments.

WITHDRAWN: Behavioral abnormalities in young female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil.

This article has been withdrawn at the request of the Editor-in-Chief due to serious concerns regarding the scientific soundness of the article. Review by the Editor-in-Chief and evaluation by outside experts, confirmed that the methodology is seriously flawed, and the claims that the article makes are unjustified. As an international peer-reviewed journal we believe it is our duty to withdraw the article from further circulation, and to notify the community of this issue. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Prevalence of celiac disease in latin america: a systematic review and meta-regression.

BACKGROUND: Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in susceptible individuals, and its prevalence varies depending on the studied population. Given that information on CD in Latin America is scarce, we aimed to investigate the prevalence of CD in this region of the world through a systematic review and meta-analysis. METHODS AND FINDINGS: This was a two-phase study. First, a cross-sectional analysis from 981 individuals of the Colombian population was made. Second, a systematic review and meta-regression analysis were performed following the Preferred Reporting Items for Systematic Meta- Analyses (PRISMA) guidelines. Our results disclosed a lack of celiac autoimmunity in the studied Colombian population (i.e., anti-tissue transglutaminase (tTG) and IgA anti-endomysium (EMA)). In the systematic review, 72 studies were considered. The estimated prevalence of CD in Latin Americans ranged between 0.46% and 0.64%. The prevalence of CD in first-degree relatives of CD probands was 5.5%. The coexistence of CD and type 1 diabetes mellitus varied from 4.6% to 8.7%, depending on the diagnosis methods (i.e., autoantibodies and/or biopsies). CONCLUSIONS: Although CD seems to be a rare condition in Colombians; the general prevalence of the disease in Latin Americans seemingly corresponds to a similar scenario observed in Europeans.

Shared HLA Class II in Six Autoimmune Diseases in Latin America: A Meta-Analysis.

The prevalence and genetic susceptibility of autoimmune diseases (ADs) may vary depending on latitudinal gradient and ethnicity. The aims of this study were to identify common human leukocyte antigen (HLA) class II alleles that contribute to susceptibility to six ADs in Latin Americans through a meta-analysis and to review additional clinical, immunological, and genetic characteristics of those ADs sharing HLA alleles. DRB1(∗)03:01 (OR: 4.04; 95%CI: 1.41-11.53) was found to be a risk factor for systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and type 1 diabetes mellitus (T1D). DRB1(∗)04:05 (OR: 4.64; 95%CI: 2.14-10.05) influences autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and T1D; DRB1(∗)04:01 (OR: 3.86; 95%CI: 2.32-6.42) is a susceptibility factor for RA and T1D. Opposite associations were found between multiple sclerosis (MS) and T1D. DQB1(∗)06:02 and DRB1(∗)15 alleles were risk factors for MS but protective factors for T1D. Likewise, DQB1(∗)06:03 allele was a risk factor for AIH but a protective one for T1D. Several common autoantibodies and clinical associations as well as additional shared genes have been reported in these ADs, which are reviewed herein. These results indicate that in Latin Americans ADs share major loci and immune characteristics.

[Genetic characterization of the interleukin 1 b polymorphisms -511, -31 y +3954 in a Colombian population with dyspepsia]. / Genotipificación de los polimorfismos -511, -31 y +3954 del gen de la interleucina-1 ß humana en una población colombiana con cuadro de dispepsia.

INTRODUCTION: The human interleukin-1b gen (IL-1 b) polymorphisms such as -511, -31 and +3954 have been associated with the presence of gastric cancer, due to the inhibitor effect that this protein has on acid secretion in the stomach. This facility can enhance the colonization and infection by agents like Helicobactor. pylori and the genesis of preneoplastic states that can lead to cancer development. OBJECTIVE: Three polymorphisms of IL-1ß (+3954, -511 and -31) will be genetically characterized and their frequencies established in a population of patients with gastric symptoms. MATERIALS AND METHODS: Gastric antrum biopsies were obtained from 111 patients that showed signs of gastric disorder. A PCR was done to detect the H. pylori presence; a PCR using designed primers for specific regions was done to define the three polymorphic regions of IL-1ß, and a RFLP was carried out using Aval, Alul and TaqI for the position -511, -231 and +3954 for each case. RESULTS: Helicobacter pylori was detected in 59.5% of the evaluated gastric while the histopathology study revealed that 82.9% of patients had some pathology. Characterization of polymorphic regions of IL-1ß gen were joined to RFLP typing evidenced that all described genotypes were present in the study population. However, patients with benign pathologies infected with H. pylori had a high frequency of the CC genotype (28.6%) in the -31 polymorphic regions. CONCLUSION: No significant differences were found between the genotype frequencies of the H. pylori-infected and the non-infected populations with one exception. The CC genotype in the -31 polymorphic region was associated with benign pathologies.

Genotificación de los polimorfismos -511, -31 y +3954 del gen de la interleucina 1 beta humana en una población colombiana con cuadro de dispepsia / Genetic characterization of the interleukin 1 beta polymorphisms -511, -31 y +3954 in a Colombian population with dyspepsia

Introducción. Varios estudios sugieren que algunos polimorfismos del gen de la interleucina-1beta humana (IL-1beta), como -511, -31 y +3954, están asociados al cáncer gástrico, debido al efecto inhibidor que esta citocina tiene sobre la secreción ácida del estómago, lo cual facilita la colonización e infección por agentes como Helicobacter pylori, así como la génesis de estados preneoplásicos que pueden conducir al desarrollo de cáncer. Objetivo. Genotipificar los polimorfismos +3954,-511 y -31 de la IL-1beta y establecer sus frecuencias en una población de pacientes con diferente sintomatología gástrica. Materiales y métodos. Se analizaron 111 biopsias del antro gástrico obtenidas de pacientes con sintomatología de alguna alteración gástrica. La detección de H. pylori en las muestras se realizó mediante PCR empleando iniciadores específicos para cada región y la genotipificación de las regiones polimórficas de la IL-1beta se realizó por RFLP empleando las enzimas Aval, Alul y Taql para -511, -31 y +3954, respectivamente. Resultados. Se detectó H. pylori en 59,5% de las biopsias gástricas, mientras que el estudio histopatológico reveló que 82,9% de los pacientes padecía alguna enfermedad. La caracterización de las regiones polimórficas del gen de la IL-1beta, seguida de la tipificación por RFLP, permitió evidenciar los tres posibles genotipos de cada uno de los polimorfismos en la población. En los pacientes infectados por H. pylori se encontró con mayor frecuencia (28,6%) el genotipo CC en la región polimórfica -31. Conclusión. No se encontraron diferencias significativas en los genotipos de los individuos infectados y los no infectados por H. pylori, a excepción del genotipo CC en la región polimórfica -31, el cual se encontró con mayor frecuencia en los pacientes con enfermedades benignas.

Introduction. The human interleukin-1beta gen (IL-1 beta) polymorphisms such as -511, -31 and +3954 have been associated with the presence of gastric cancer, due to the inhibitor effect that this protein has on acid secretion in the stomach. Thisfacility can enhance the colonization and infection by agents like Helicobactor. pylori and the genesis of preneoplastic states that can lead to cancer development. Objective. Three polymorphisms of IL-1beta (+3954, -511 and -31) will be genetically characterized and their frequencies established in a population of patients with gastric symptoms. Materials and methods. Gastric antrum biopsies were obtained from 111 patients that showed signs of gastric disorder. A PCR was done to detect the H. pylori presence; a PCR using designed primers for specific regions was done to define the three polymorphic regions of IL-1beta, and a RFLP was carried out using Aval, Alul and TaqI for the position -511, -231 and +3954 for each case. Results. Helicobacter pylori was detected in 59.5% of the evaluated gastric while the histopathology study revealed that 82.9% of patients had some pathology. Characterization of polymorphic regions of IL-1beta gen were joined to RFLP typing evidenced that all descfribed genotypes were present in the study population. However, patients with benign pathologies infected with H. pylori had a high frequency of the CC genotype (28.6%) in the -31 polymorphic regions.Conclusion. No significant differences were found between the genotype frequenciess of the H. pylori-infected and the non-infected populations with one exception. The CC genotype in the -31 polymorphic region was associated with benign pathologies.