To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder.
Serum and CSF samples were assessed at 2 ...neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients' informed consent.
Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses.
Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.
This nationwide study gives a detailed description of the clinical features and long-term outcome of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.
We collected patients prospectively ...from October 2013, and retrospectively from samples sent to our laboratory from January 2007. LGI1 antibodies were confirmed with both cell-based assay and immunohistochemistry. Clinical information was obtained in interviews with patients and their relatives and from medical records. Initial MRI and follow-up MRI were revised blindly. Neuropsychological assessment was performed in those patients with follow-up over 2 years.
Annual incidence in the Netherlands was 0.83/million. A total of 34/38 patients had a limbic encephalitis. Subtle focal seizures (66%, autonomic or dyscognitive) and faciobrachial dystonic seizures (FBDS, 47%) mostly occurred before onset of memory disturbance. Later in the disease course, 63% had tonic-clonic seizures. Initial MRI showed hippocampal T2 hyperintensity in 74% of the patients. These lesions evolved regularly into mesial temporal sclerosis (44%). Substantial response to immunotherapy was seen in 80%, with early response of seizures and slow recovery of cognition. At follow-up ≥2 years, most surviving patients reported mild residual cognitive deficit with spatial disorientation. A total of 86% had persistent amnesia for the disease period. Relapses were common (35%) and presented up to 8 years after initial disease. Two-year case fatality rate was 19%.
Anti-LGI1 encephalitis is a homogenous clinical syndrome, showing early FBDS and other focal seizures with subtle clinical manifestations, followed by memory disturbances. Better recognition will lead to earlier diagnosis, essential for prompt start of treatment. Long-term outcome of surviving patients is mostly favorable, but relapses are common.
To assess the clinical relevance of a positive voltage-gated potassium channel (VGKC) test in patients lacking antibodies to LGI1 and Caspr2.
VGKC-positive patients were tested for LGI1 and Caspr2 ...antibodies. Patients lacking both antibodies were matched (1:2) to VGKC-negative patients. Clinical and paraclinical criteria were used to blindly determine evidence for autoimmune inflammation in both groups. Patients with an inconclusive VGKC titer were analyzed in the same way.
A total of 1,455 patients were tested by VGKC radioimmunoassay. Fifty-six patients tested positive, 50 of whom were available to be included. Twenty-five patients had antibodies to LGI1 (n = 19) or Caspr2 (n = 6) and 25 patients lacked both antibodies. Evidence for autoimmune inflammation was present in 7 (28%) of the VGKC-positive patients lacking LGI1 and Caspr2, compared to 9 (18%) of the VGKC-negative controls (p = 0.38). Evidence for autoimmune inflammation was mainly found in patients with limbic encephalitis/encephalomyelitis (57%), but not in other clinical phenotypes (5%, p < 0.01). VGKC titers were significantly higher in patients with antibodies to LGI1 or Caspr2 (p < 0.001). However, antibodies to Caspr2 could also be detected in patients with inconclusive low VGKC titer, while many VGKC-positive patients had no evidence for autoimmune inflammation.
VGKC positivity in the absence of antibodies to LGI1 and Caspr2 is not a clear marker for autoimmune inflammation and seems not to contribute in clinical practice. No cutoff value for the VGKC titer was appropriate to discriminate between patients with and without autoimmune inflammation.
Although multiple serum antiretinal autoantibodies (ARAs) have been reported in patients with paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR), not all retinal antigens involved ...in (n)pAIR are specified. This study aims to serologically identify patients with presumed (n)pAIR through determination of both known and unknown ARAs by autoantibody profiling.
An antigen suspension bead array using 188 different antigens representing 97 ocular proteins was performed to detect ARAs in serum samples of patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Logistic regressions were used to estimate the associations between ocular antigens and diagnosis. Validation of interphotoreceptor matrix proteoglycan 2 (IMPG2) and recoverin antigens was performed by immunohistochemistry and immunoblot, respectively.
Samples of patients with presumed (n)pAIR exhibited a broad spectrum of ARAs. We identified retinal antigens that have already been described previously (e.g. recoverin), but also identified novel ARA targets. Most ARAs were not specific for (n)pAIR since their presence was also observed in patients with cataract or uveitis. High titers of autoantibodies directed against photoreceptor-specific nuclear receptor and retinol-binding protein 3 were more common in patients with presumed (n)pAIR compared to uveitis (p = 0.015 and p = 0.018, respectively). The presence of all other ARAs did not significantly differ between groups. In patients with presumed (n)pAIR, anti-recoverin autoantibodies were the most prevalent ARAs. Validation of bead array results by immunohistochemistry (anti-IMPG2) and immunoblot (anti-recoverin) showed concordant results in (n)pAIR patients.
Patients with (n)pAIR are characterized by the presence of a broad spectrum of ARAs. The diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs, as these are also commonly present in uveitis as well as in age-related cataract patients.
To report the main syndrome of dipeptidyl-peptidase-like protein 6 (DPPX) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and the antibody effects on DPPX/Kv4.2 potassium channels.
...A retrospective analysis of new patients and cases reported since 2013 was performed. IgG subclass and effects of antibodies on cultured neurons were determined with described techniques.
Nine new patients were identified (median age 57 years, range 36-69 years). All developed severe prodromal weight loss or diarrhea followed by cognitive dysfunction (9), memory deficits (5), CNS hyperexcitability (8; hyperekplexia, myoclonus, tremor, or seizures), or brainstem or cerebellar dysfunction (7). The peak of the disease was reached 8 months (range 1-54 months) after onset. All patients had both IgG4 and IgG1 DPPX antibodies. In cultured neurons, the antibodies caused a decrease of DPPX clusters and Kv4.2 protein that was reversible on removal of the antibodies. Considering the current series and previously reported cases (total 39), 67% developed the triad: weight loss (median 20 kg; range 8-53 kg)/gastrointestinal symptoms, cognitive-mental dysfunction, and CNS hyperexcitability. Outcome was available from 35 patients (8 not treated with immunotherapy): 60% had substantial or moderate improvement, 23% had no improvement (most of them not treated), and 17% died. Relapses occurred in 8 of 35 patients (23%) and were responsive to immunotherapy.
DPPX antibodies are predominantly IgG1 and IgG4 and associate with cognitive-mental deficits and symptoms of CNS hyperexcitability that are usually preceded by diarrhea, other gastrointestinal symptoms, and weight loss. The disorder is responsive to immunotherapy, and this is supported by the reversibility of the antibody effects in cultured neurons.
Quantitative or qualitative differences in immunity may drive clinical severity in COVID-19. Although longitudinal studies to record the course of immunological changes are ample, they do not ...necessarily predict clinical progression at the time of hospital admission. Here we show, by a machine learning approach using serum pro-inflammatory, anti-inflammatory and anti-viral cytokine and anti-SARS-CoV-2 antibody measurements as input data, that COVID-19 patients cluster into three distinct immune phenotype groups. These immune-types, determined by unsupervised hierarchical clustering that is agnostic to severity, predict clinical course. The identified immune-types do not associate with disease duration at hospital admittance, but rather reflect variations in the nature and kinetics of individual patient's immune response. Thus, our work provides an immune-type based scheme to stratify COVID-19 patients at hospital admittance into high and low risk clinical categories with distinct cytokine and antibody profiles that may guide personalized therapy.
Leucine‐rich glioma‐inactivated1 (LGI1) encephalitis is an antibody‐associated inflammation of the limbic area. An autoimmune etiology is suspected but not yet proven. We performed human leukocyte ...antigen (HLA) analysis in 25 nontumor anti‐LGI1 patients and discovered a remarkably strong HLA association. HLA‐DR7 was present in 88% compared to 19.6% in healthy controls (p = 4.1 × 10−11). HLA‐DRB4 was present in all patients and in 46.5% controls (p = 1.19 × 10−7). These findings support the autoimmune hypothesis. An exploratory analysis was performed in a small group of 4 tumor‐LGI1 patients. The strong HLA association seems not applicable in these patients. Therefore, the absence of HLA‐DR7 or HLA‐DRB4 could raise tumor suspicion in anti‐LGI1 patients. Ann Neurol 2017;81:193–198
Celiac disease is a gluten-sensitive enteropathy that affects people of all ages worldwide. This disease has emerged as a major health-care problem, as advances in diagnostic and screening methods ...have revealed its global prevalence. Environmental factors such as gluten introduction at childhood, infectious agents and socioeconomic features, as well as the presence of HLA-DQ2 and/or HLA-DQ8 haplotypes or genetic variations in several non-HLA genes contribute to the development of celiac disease. Growing insight into the variable clinical and histopathological presentation features of this disease has opened new perspectives for future research. A strict life-long gluten-free diet is the only safe and efficient available treatment, yet it results in a social burden. Alternative treatment modalities focus on modification of dietary components, enzymatic degradation of gluten, inhibition of intestinal permeability and modulation of the immune response. A small group of patients with celiac disease (2-5%), however, fail to improve clinically and histologically upon elimination of dietary gluten. This complication is referred to as refractory celiac disease, and imposes a serious risk of developing a virtually lethal enteropathy-associated T-cell lymphoma.
Purpose
To analyse intraocular cytokine levels and prevalence of intraocular antiretinal antibodies (ARAs) in patients with retinitis pigmentosa (RP), age‐related macular degeneration (AMD), glaucoma ...and cataract, and correlate the results to clinical manifestations.
Methods
We collected intraocular fluid samples from patients with RP (n = 25), AMD (n = 12), glaucoma (n = 28) and cataract (n = 22), and serum samples paired with the intraocular fluids from patients with RP (N = 7) and cataract (n = 10). Interleukin (IL)‐1β, IL‐1ra, IL‐2, IL‐6, IL‐6rα, IL‐7, IL‐8, IL‐10, IL‐17A, IL‐23, thymus‐ and activation‐regulated chemokine (TARC), monocyte chemoattractant protein‐1 (MCP‐1), tumour necrosis factor‐alpha (TNF‐α), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) were measured using a multiplex assay. Antiretinal antibodies (ARA) detection was performed by indirect immunofluorescence.
Results
Increasing age was associated with increasing levels of IL‐6, IL‐8, TNF‐α and VEGF. All patient groups exhibited distinct profiles of intraocular cytokines. Intraocular levels of IL‐8 were highest in patients with AMD and glaucoma. Cataract patients exhibited high intraocular levels of IL‐23. Intraocular levels of IL‐2, IL‐6, MCP‐1 and PlGF in RP patients exceeded the levels of serum, indicating intraocular production. Intraocular ARAs were found in only one patient with AMD.
Conclusion
Increased levels of inflammatory cytokines in intraocular fluid of patients with originally noninflammatory ocular diseases show that intraocular inflammation is involved in their pathogenesis of these entities. Moreover, we show that increasing age is associated with increasing levels of intraocular cytokines and conclude that future studies on intraocular mediators should be corrected for age of patients.
Abstract
Objective
To assess the relationships between systemic IFN type I (IFN-I) and II (IFN-II) activity and disease manifestations in primary SS (pSS).
Methods
RT-PCR of multiple IFN-induced ...genes followed by principal component analysis of whole blood RNA of 50 pSS patients was used to identify indicator genes of systemic IFN-I and IFN-II activities. Systemic IFN activation levels were analysed in two independent European cohorts (n = 86 and 55, respectively) and their relationships with clinical features were analysed.
Results
Three groups could be stratified according to systemic IFN activity: IFN inactive (19-47%), IFN-I (53-81%) and IFN-I + II (35-55%). No patient had isolated IFN-II activation. IgG levels were highest in patients with IFN-I + II, followed by IFN-I and IFN inactive patients. The prevalence of anti-SSA and anti-SSB was higher among those with IFN activation. There was no difference in total-EULAR SS Disease Activity Index (ESSDAI) or ClinESSDAI between the three subject groups. For individual ESSDAI domains, only the biological domain scores differed between the three groups (higher among the IFN active groups). For patient reported outcomes, there were no differences in EULAR Sjögren's syndrome patient reported index (ESSPRI), fatigue or dryness between groups, but pain scores were lower in the IFN active groups. Systemic IFN-I but not IFN-I + II activity appeared to be relatively stable over time.
Conclusions
Systemic IFN activation is associated with higher activity only in the ESSDAI biological domain but not in other domains or the total score. Our data raise the possibility that the ESSDAI biological domain score may be a more sensitive endpoint for trials targeting either IFN pathway.
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