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.
Identifying the course of demyelinating disease associated with myelin oligodendrocyte glycoprotein (MOG) autoantibodies is critical to guide appropriate treatment choices.
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.
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.
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.
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.
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.
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.
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.
Abstract Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most devastating presentations of SLE and comprises of psychiatric, central and peripheral neurological signs and ...symptoms. Previous studies suggest the possible associations between various autoantibodies (Abs) and NPSLE. The magnitudes of such association varied between studies. We performed a meta-analysis to pool data on serum and cerebrospinal fluid (CSF) levels and positivity of Abs in blood and cerebrospinal fluid in patients with NPSLE and SLE. A systematic literature search was conducted to identify studies that fulfilled inclusion criteria. A random-effects model was used to calculate overall combined odd ratio (OR) and mean levels with its corresponding 95% confidence interval to evaluate the relationship between individual Abs and NPSLE patients relative to SLE patients. Forty-one studies met the inclusion criteria and were used in this analysis. There was a significantly greater proportion of NPSLE patients who demonstrated positivity for serum anti-cardiolipin (aCL) Abs (OR = 1.63, p = 0.016), lupus anticoagulants (LA) Abs (OR = 1.91 p = 0.01), anti-phospholipid (APL) Abs (OR = 2.08, p = 0.001), anti-ribosomal P Abs (OR = 2.29, p < 0.001), anti-neuronal Abs (OR = 9.50, p < 0.001) as compared to SLE patients. In NPSLE patients, there was a significant increased prevalence of positive titres for CSF anti-neuronal Abs (OR = 36.84, p = 0.001) as compared to SLE patients. Among the 19 neuropsychiatric syndromes, the positivity of these serum autoantibodies were found specifically significantly associated with the manifestations of mood disorder, psychosis, cerebrovascular disease, seizure disorders, acute confusional state, cognitive dysfunction, headache, movement disorder, demyelinating syndrome and polyneuropathy, with ORs ranging from 1.84 to 4.73. Meta-regression identified proportion of women as significant moderator for the heterogeneity of aCL (p = 0.004) and anti-neuronal Abs (p = 0.0007); mean age for the heterogeneity of aCL (p = 0.042) and LA (p = 0.020) Abs, mean duration of illness for the heterogeneity of aCL Abs (p = 0.035), and mean SLEDAI scores for the heterogeneity of anti-ribosomal P Abs (p = 0.014). NPSLE patients are more likely to have elevated serum levels of aCL, LA, APL, anti-ribosomal P Abs and anti-neuronal Abs compared with SLE patients. Further research is required to evaluate the accuracy of using the above antibodies as an adjunct diagnostic tool in NPSLE.
We review how polyreactive natural IgM autoantibodies (IgM-NAA) protect the host from invading micro-organisms and host neo-antigens that are constantly being produced by oxidation mechanisms and ...cell apoptosis. Second, we discuss how IgM-NAA and IgM anti-leukocyte antibodies (IgM-ALA) inhibits autoimmune inflammation by anti-idiotypic mechanisms, enhancing removal of apoptotic cells, masking neo-antigens, and regulating the function of dendritic cells (DC) and effector cells. Third, we review how natural IgM prevents autoimmune disorders arising from pathogenic IgG autoantibodies, triggered by genetic mechanisms (e.g., SLE) or micro-organisms, as well as by autoreactive B and T cells that have escaped tolerance mechanisms. Studies in IgM knockout mice have clearly demonstrated that regulatory B and T cells require IgM to effectively regulate inflammation mediated by innate, adaptive, and autoimmune mechanisms. It is, therefore, not surprising why the host positively selects such autoreactive B1 cells that generate IgM-NAA, which are also evolutionarily conserved. Fourth, we show that IgM-ALA levels and their repertoire can vary in normal humans and disease states and this variation may partly explain the observed differences in the inflammatory response after infection, ischemic injury, or after a transplant. We also show how protective IgM-NAA can be rendered pathogenic under non-physiological conditions. We also review IgG-NAA that are more abundant than IgM-NAA in plasma. However, we need to understand if the (Fab)(2) region of IgG-NAA has physiological relevance in non-disease states, as in plasma, their functional activity is blocked by IgM-NAA having anti-idiotypic activity. Some IgG-NAA are produced by B2 cells that have escaped tolerance mechanisms and we show how such pathogenic IgG-NAA are regulated to prevent autoimmune disease. The Fc region of IgG-NAA can influence inflammation and B cell function in vivo by binding to activating and inhibitory FcγR. IgM-NAA has therapeutic potential. Polyclonal IgM infusions can be used to abrogate on-going inflammation. Additionally, inflammation arising after ischemic kidney injury, e.g., during high-risk elective cardiac surgery or after allograft transplantation, can be prevented by pre-emptively infusing polyclonal IgM or DC pretreated ex vivo with IgM or by increasing in vivo IgM with a vaccine approach. Cell therapy is appealing as less IgM will be required.
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