Introduction/Aims
Cytosolic 5′‐nucleotidase 1A (cN‐1A) autoantibodies have been recognized as myositis‐related autoantibodies. However, their correlations with clinical characteristics and other ...myositis‐specific and myositis‐associated autoantibodies (MSAs/MAAs) are still unclear. We aimed to establish the prevalence and clinical and laboratory associations of cN‐1A autoantibodies in a cohort of patients with connective tissue diseases.
Methods
A total of 567 participants (182 idiopathic inflammatory myopathies IIM, 164 systemic lupus erythematosus SLE, 121 systemic sclerosis SSc, and 100 blood donors BD) were tested for the presence of cN‐1A autoantibodies and other myositis‐specific and myositis‐associated autoantibodies (MSAs/MAAs). Clinical and laboratory characteristics were compared between anti‐cN‐1A positive and negative patients with sporadic inclusion body myositis (sIBM) and between anti‐cN‐1A positive and negative patients with non‐IBM IIM.
Results
In the sIBM cohort, 30 patients (46.9%) were anti‐cN‐1A positive vs. 18 (15.2%) in the non‐IBM IIM cohort, 17 (10%) were anti‐cN‐1A positive in the SLE cohort and none in the SSc or the BD cohorts. Anti‐cN‐1A positivity had an overall sensitivity of 46.9% and a specificity of 93.2% for sIBM. Dysphagia was more frequent in the anti‐cN‐1A positive vs. negative sIBM patients (p = .04). In the non‐IBM IIM group, being anti‐cN‐1A antibody positive was associated with the diagnosis polymyositis (p = .04) and overlap‐myositis (p = .04) and less disease damage evaluated by physician global damage score (p < .001).
Discussion
cN‐1A autoantibodies were predominantly found in IIM patients and was associated with dysphagia in sIBM patients. Notably, anti‐cN‐1A appears to identify a distinct phenotype of anti‐cN‐1A positive non‐IBM IIM patients with a milder disease course.
Aims/hypothesis Insulin autoantibodies (IAA) are important in type 1 diabetes risk assessment. However, their determination varies more between laboratories than other diabetes autoantibodies. The ...Diabetes Antibody Standardization Program (DASP) aims to improve and standardise measurement of autoantibodies associated with type 1 diabetes. We report the results of measurement of IAA from DASP workshops in 2002, 2003 and 2005. Methods Up to 32 laboratories in 14 countries participated in each workshop. Aliquots of coded sera from 50 patients with newly diagnosed type 1 diabetes and 100 blood donor controls were circulated to participating laboratories. Reported results were analysed using receiver operator characteristic (ROC) curves. We compared concordance of antibody levels by ranking, IAA and insulin antibody (IA) indices and units derived from an IA standard curve. Results In all three workshops IAA assay performance had improved compared with DASP 2000. The median area under the ROC curve was 0.73 in DASP 2002, 0.78 in 2003 and 0.80 in 2005 (p = 0.0012), and median laboratory-assigned sensitivity was 26% in 2002, 36% in 2003 and 45% in 2005 (p < 0.0001). There was, however, marked variation between assays. The range of AUC was 0.36-0.91 and that of laboratory-assigned sensitivity was 22-57%. Concordance of ranking of patient serum samples was related to AUC (p < 0.001). Using an index related to common IAA and IA-positive or -negative control sera improved the concordance between assays (p < 0.0001). Conclusions/interpretation The overall performance of IAA assays has improved but there is still wide variation between laboratories. Concordance between assays would be improved by the use of a common reference reagent.
An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) ...where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation.
Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin.
Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin.
The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.
IMPORTANCE: Identifying the course of demyelinating disease associated with myelin oligodendrocyte glycoprotein (MOG) autoantibodies is critical to guide appropriate treatment choices. OBJECTIVE: To ...characterize serial anti-MOG antibody serologies and clinical and imaging features at presentation and during follow-up in an inception cohort of prospectively monitored children with acquired demyelination. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, study participants were recruited from July 2004 to February 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study. Inclusion criteria included (1) incident central nervous system demyelination, (2) at least 1 serum sample obtained within 45 days from onset, and (3) complete clinical information. Of 430 participants with acquired demyelinating syndrome recruited, 274 were included in analyses. Of 156 excluded participants, 154 were excluded owing to missing baseline samples and 2 owing to incomplete clinical information. Data were analyzed from May to October 2018. MAIN OUTCOMES AND MEASURES: Presence of anti-MOG antibodies was blindly assessed in serial samples collected over a median of 4 years. Clinical, magnetic resonance imaging, and cerebrospinal fluid features were characterized at presentation, and subsequent disease course was assessed by development of new brain magnetic resonance imaging lesions, total lesion volume at last evaluation, annualized relapse rates, Expanded Disability Status Scale score and visual functional score at 4 years, and any disease-modifying treatment exposure. RESULTS: Of the 274 included participants, 140 (51.1%) were female, and the median (interquartile range) age of all participants was 10.8 (6.2-13.9) years. One-third of children were positive for anti-MOG antibodies at the time of incident demyelination. Clinical presentations included a combination of optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis for 81 of 84 anti-MOG antibody–positive children (96%). Brain lesions were present in 51 of 76 anti-MOG antibody–positive participants (67%), but magnetic resonance imaging characteristics differed with age at presentation. Complete resolution of baseline lesions was observed in 26 of 49 anti-MOG antibody–positive participants (53%). On serial serum analysis, 38 of 67 participants (57%) who were seropositive at onset became seronegative (median time to conversion, 1 year). Among all participants who were positive for anti-MOG antibodies at presentation, clinical relapses occurred in 9 of 24 children (38%) who remained persistently seropositive and in 5 of 38 children (13%) who converted to seronegative status. CONCLUSIONS AND RELEVANCE: Myelin oligodendrocyte glycoprotein antibodies are common in children with acquired demyelinating syndrome and are transient in approximatively half of cases. Even when persistently positive, most anti-MOG antibody–positive children experience a monophasic disease. The presence of anti-MOG antibodies at the time of incident demyelination should not immediately prompt the initiation of long-term immunomodulatory therapy.
AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of ...hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms.
•Human GluA2 autoantibodies (ABs) cause changes in AMPA receptor subunit composition•ABs mediate internalization of AMPA receptors and synaptic scaling-like mechanisms•Passive transfer of ABs impairs synaptic plasticity and triggers disease symptoms•Disease symptoms may be caused by AMPA receptor subunit rearrangement
Haselmann et al. explore molecular mechanisms of autoimmune encephalitis with autoantibodies to the AMPA receptor. Human anti-GluA2 autoantibodies induce internalization of AMPA receptors followed by synaptic scaling-like changes leading to defective synaptic transmission and plasticity resulting in memory dysfunction.
Background: T1D autoantibodies can be detected months to years before disease onset, but few people undergo screening. We explored attitudes toward autoantibody screening in people with T1D and ...caregivers and relatives of people with T1D.
Methods: Participants were recruited from the T1D Exchange Registry or referred by an Online Registry participant. Guided by the Health Belief Model, we conducted 4 focus groups with 26 participants (11 adults with T1D with a child without T1D; 8 caregivers to a child with T1D and a child without T1D; 7 biological siblings to a person with T1D). Transcripts were analyzed using NVivo.
Results: Responses are summarized in Table 1. Most participants held positive attitudes toward screening. The most common perceived benefit was to obtain knowledge; the anticipated emotional burden of a positive screen was the most frequently reported barrier. Anxiety and relief were emotions associated with a positive and negative screen, respectively. Participants desired information about antibody screening and its interpretation and accuracy. A healthcare providers’ recommendation might prompt the decision to screen.
Conclusions: Participants expressed positive attitudes and perceived benefits of autoantibody screening but also reported barriers to screening, particularly the emotional burden of a positive result.
Disclosure
M.Peter: None. K.S.M.Chapman: None. J.L.Dunne: Employee; Janssen Research & Development, LLC. C.S.Kelly: None. W.Wolf: None.
The TrialNet abatacept randomized-controlled trial tested for the ability to delay the progression of T1D in Stage 1 multiple autoantibody (Ab) positive and normal glucose on OGTT individuals aged ...6-45. No drug effect was detected on the primary endpoint of either dysglycemia or T1D (whichever came first). Based on evidence that C-peptide-based metabolic measures are more specific for T1D and detect an early impact of disease-modifying therapy, we performed post-hoc analyses using these variables and stratified on baseline metabolic profiles. In participants with lower baseline metabolic risk (Index60 <0.00) we assessed if changes in metabolic measures would differ between treatment groups. A favorable effect was evident for the combined glucose and C-peptide endpoints within 1 year of treatment (Table). Next we compared individuals with Index60<0.00 at baseline for exceeding an Index60 threshold of 1.00 on follow-up. 5-year risks were 38.9% for the placebo and 21.1% for the abatacept groups (p=0.016). In summary, for Stage 1 individuals with low baseline metabolic risk, combined glucose and C-peptide endpoints can detect a favorable abatacept effect at 1 year and, more conventionally, a decreased T1D progression risk on follow-up. Future trials of abatacept or other agents in Stage 1 T1D should include combined glucose and C-peptide measures as pre-specified endpoints.
Disclosure
E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. W.E.Russell: None. K.C.Herold: Board Member; NexImmune, Consultant; Provention Bio, Inc. J.Sosenko: None.
The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative ...presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating autoantibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients' NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role.
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