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Intracellular and circulating neuronal antinuclear antibodies in human epilepsy.

ABSTRACT: There are overwhelming data supporting the inflammatory origin of some epilepsies (e.g., Rasmussen's encephalitis and limbic encephalitis). Inflammatory epilepsies with an autoimmune component are characterized by autoantibodies against membrane-bound, intracellular or secreted proteins (e.g., voltage gated potassium channels). Comparably, little is known regarding autoantibodies targeting nuclear antigen. We tested the hypothesis that in addition to known epilepsy-related autoantigens, the human brain tissue and serum from patients with epilepsy contain autoantibodies recognizing nuclear targets. We also determined the specific nuclear proteins acting as autoantigen in patients with epilepsy. Brain tissue samples were obtained from patients undergoing brain resections to treat refractory seizures, from the brain with arteriovenous malformations or from post-mortem multiple sclerosis brain. Patients with epilepsy had no known history of autoimmune disease and were not diagnosed with autoimmune epilepsy. Tissue was processed for immunohistochemical staining. We also obtained subcellular fractions to extract intracellular IgGs. After separating nuclear antibody-antigen complexes, the purified autoantigen was analyzed by mass spectrometry. Western blots using autoantigen or total histones were probed to detect the presence of antinuclear antibodies in the serum of patients with epilepsy. Additionally, HEp-2 assays and antinuclear antibody ELISA were used to detect the staining pattern and specific presence of antinuclear antibodies in the serum of patients with epilepsy. Brain regions from patients with epilepsy characterized by blood-brain barrier disruption (visualized by extravasated albumin) contained extravasated IgGs. Intracellular antibodies were found in epilepsy (n=13/13) but not in multiple sclerosis brain (n=4/4). In the brain from patients with epilepsy, neurons displayed higher levels of nuclear IgGs compared to glia. IgG colocalized with extravasated albumin. All subcellular fractions from brain resections of patients with epilepsy contained extravasated IgGs (n=10/10), but epileptogenic cortex, where seizures originated from, displayed the highest levels of chromatin-bound IgGs. In the nuclear IgG pool, anti-histone autoantibodies were identified by two independent immunodetection methods. HEp-2 assay and ELISA confirmed the presence of anti-histone (n=5/8) and anti-chromatin antibodies in the serum from patients with epilepsy. We developed a multi-step approach to unmask autoantigens in the brain and sera of patients with epilepsy. This approach revealed antigen-bound antinuclear antibodies in neurons and free antinuclear IgGs in the serum of patients with epilepsy. Conditions with blood-brain barrier disruption but not seizures, were characterized by extravasated but not chromatin-bound IgGs. Our results show that the pool of intracellular IgG in the brain of patients with epilepsy consists of nucleus-specific autoantibodies targeting chromatin and histones. Seizures may be the trigger of neuronal uptake of antinuclear antibodies.

SUBMITTER: Iffland PH

PROVIDER: S-EPMC3900287 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Intracellular and circulating neuronal antinuclear antibodies in human epilepsy.

Iffland Philip H PH Carvalho-Tavares Juliana J Trigunaite Abhishek A Man Shumei S Rasmussen Peter P Alexopoulos Andreas A Ghosh Chaitali C Jørgensen Trine N TN Janigro Damir D

Neurobiology of disease 20130721

There are overwhelming data supporting the inflammatory origin of some epilepsies (e.g., Rasmussen's encephalitis and limbic encephalitis). Inflammatory epilepsies with an autoimmune component are characterized by autoantibodies against membrane-bound, intracellular or secreted proteins (e.g., voltage gated potassium channels). Comparably, little is known regarding autoantibodies targeting nuclear antigen. We tested the hypothesis that in addition to known epilepsy-related autoantigens, the huma ...[more]

PMID: 23880401

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Project description:BACKGROUND:Clinical reports link specific medications with the development of antinuclear antibodies (ANA), but population-based evidence is limited. OBJECTIVE:The present study investigated associations between prescription medication use and ANA in a representative sample of the adult noninstitutionalized US population, first focusing on medications previously related to ANA and then considering all medications reported in the National Health and Nutrition Examination Survey (NHANES). METHODS:Based on NHANES data (1999-2004) for 3608 adults (ages ?18 years), we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess associations between recent medication use and ANA (overall and in sex and age subgroups), adjusted for potential confounders and the survey sampling design. RESULTS:We found no evidence that most medications previously associated with ANA in specific individuals were risk factors for ANA in the general population, although statistical power was limited for some medications. Overall, ANA were less prevalent in adults who recently used any prescription medications compared with those who did not (OR?=?0.73; CI?=?0.57,0.93), and likewise several classes of medications were inversely associated with ANA, including hormones (OR?=?0.73; CI?=?0.55,0.98), thiazide diuretics (OR?=?0.43; CI?=?0.24,0.79), sulfonylureas (OR?=?0.41; CI?=?0.19,0.89), and selective serotonin reuptake inhibitor antidepressants (OR?=?0.65; CI?=?0.42,0.98). Positive associations with ANA were seen for loop diuretics (OR?=?1.72; CI?=?1.03,2.88) in all adults, and for benzodiazepines (OR?=?2.11; CI?=?1.09,4.10) and bronchodilators (OR?=?1.83; CI?=?1.00,3.38) in older (ages ?60) adults. Estrogens were positively associated with ANA in older women (OR?=?1.80; CI?=?1.00,3.23) but inversely associated with ANA in younger (ages 18-59) women (OR?=?0.43; CI?=?0.20,0.93). Regarding individual medications, ANA were positively associated with ciprofloxacin (OR?=?4.23; CI?=?1.21,14.8), furosemide (OR?=?1.79; CI?=?1.09,2.93), and omeprazole (OR?=?2.05; CI?=?1.03,4.10) in all adults, and with salmeterol (OR?=?3.76; CI?=?1.66,8.52), tolterodine (OR?=?6.64; CI?=?1.45,30.5), and triamterene (OR?=?3.10; CI?=?1.08,8.88) in older adults. Also, in younger adults, hydrochlorothiazide was inversely associated with ANA (OR?=?0.44; CI?=?0.20,0.98). CONCLUSIONS:Our findings in the general population do not confirm most clinically reported positive associations between specific medications and ANA in some individuals. However, novel positive ANA associations with other medications, as well as unexplained inverse associations with certain classes of medications and overall medication use, deserve further research to clarify the possible roles of medications as risk and protective factors in the development of autoantibodies and autoimmune disease.

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Intracellular and circulating neuronal antinuclear antibodies in human epilepsy.

Publications

Intracellular and circulating neuronal antinuclear antibodies in human epilepsy.

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