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Multiple sclerosis (MS) is a debilitating autoimmune disease of the CNS, which is characterized by demyelination and axonal injury and frequently preceded by a demyelinating event called clinically isolated syndrome (CIS). Despite the importance of B cells and autoantibodies in MS pathology, their target specificities remain largely unknown. For an agnostic and comprehensive evaluation of autoantibodies in MS, we developed and employed what we believe to be a novel autoantigen discovery technology, the Antigenome Platform. This Platform is a high-throughput assay comprising large-fragment (approximately 100 amino acids) cDNA libraries, phage display, serum antibody screening technology, and robust bioinformatics analysis pipelines. For autoantibody discovery, we assayed serum samples from CIS patients who received either placebo or treatment who were enrolled in the REFLEX clinical trial, which assessed the effects of IFN-β-1a (Rebif) clinical and MRI activity in patients with CIS. Serum autoantibodies from patients with CIS were significantly and reproducibly enriched for known and previously unreported protein targets; 166 targets were selected by over 10% of patients’ sera. Further, 10 autoantibody biomarkers associated with disease activity and 17 associated with patient response to IFN-β-1a therapy. These findings indicate widespread autoantibody production in MS and provide biomarkers for continued study and prediction of disease progression.

Underlying type 1 diabetes is a genetic aetiology dominated by the influence of specific HLA haplotypes involving primarily the class II DR-DQ region. In genetically predisposed children with the DR4-DQ8 haplotype, exogenous factors, yet to be identified, are thought to trigger an autoimmune reaction against insulin, signalled by insulin autoantibodies as the first autoantibody to appear. In children with the DR3-DQ2 haplotype, the triggering reaction is primarily against GAD signalled by GAD autoantibodies (GADA) as the first-appearing autoantibody. The incidence rate of insulin autoantibodies as the first-appearing autoantibody peaks during the first years of life and declines thereafter. The incidence rate of GADA as the first-appearing autoantibody peaks later but does not decline. The first autoantibody may variably be followed, in an apparently non-HLA-associated pathogenesis, by a second, third or fourth autoantibody. Although not all persons with a single type of autoantibody progress to diabetes, the presence of multiple autoantibodies seems invariably to be followed by loss of functional beta cell mass and eventually by dysglycaemia and symptoms. Infiltration of mononuclear cells in and around the islets appears to be a late phenomenon appearing in the multiple-autoantibody-positive with dysglycaemia. As our understanding of the aetiology and pathogenesis of type 1 diabetes advances, the improved capability for early prediction should guide new strategies for the prevention of type 1 diabetes.

ObjectivesAnti-Ro52 autoantibodies are associated with more severe interstitial lung disease (ILD) in adult myositis patients with antiaminoacyl transfer (t)RNA synthetase autoantibodies. However, few studies have examined anti-Ro52 autoantibodies in juvenile myositis. The purpose of this study was to define the prevalence and clinical features associated with anti-Ro52 autoantibodies in a large cohort of patients with juvenile myositis.MethodsWe screened sera from 302 patients with juvenile dermatomyositis (JDM), 25 patients with juvenile polymyositis (JPM) and 44 patients with juvenile connective tissue disease–myositis overlap (JCTM) for anti-Ro52 autoantibodies by ELISA. Clinical characteristics were compared between myositis patients with and without anti-Ro52 autoantibodies.ResultsAnti-Ro52 autoantibodies were found in 14% patients with JDM, 12% with JPM and 18% with JCTM. Anti-Ro52 autoantibodies were more frequent in patients with antiaminoacyl tRNA synthetase (64%, p<0.001) and anti-MDA5 (31%, p<0.05) autoantibodies. After controlling for the presence of myositis-specific autoantibodies, anti-Ro52 autoantibodies were associated with the presence of ILD (36% vs 4%, p<0.001). Disease course was more frequently chronic, remission was less common, and an increased number of medications was received in anti-Ro52 positive patients.ConclusionsAnti-Ro52 autoantibodies are present in 14% of patients with juvenile myositis and are strongly associated with anti-MDA5 and antiaminoacyl tRNA synthetase autoantibodies. In all patients with juvenile myositis, those with anti-Ro52 autoantibodies were more likely to have ILD. Furthermore, patients with anti-Ro52 autoantibodies have more severe disease and a poorer prognosis.

This study aims to report three cases of autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis. Data of relevant patients treated between 2019 and 2022 were retrospectively collected from the Department of Neurology at the Second Affiliated Hospital of Guangzhou Medical University. The age at onset of the three patients was 37, 63, and 36 years, respectively. All three patients were female and presented with cognitive dysfunction and seizures. Behavioral and psychological symptoms were also observed in two cases. All patients were positive for autoantibodies in both the cerebrospinal fluid and serum, while two showed multiple abnormal brain signals on magnetic resonance imaging. All patients exhibited hypocytosis and elevated soluble CD25 and serum ferritin levels. The final diagnoses in two cases were lymphomas, while the remaining case without tumors suffered from a severe infection. All patients received immunotherapy, and the two with lymphoma received anti-tumor treatment. The patient with infection died, and two patients with tumors improved after chemotherapy. Autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis is a rare and severe condition. Prompt attention should be paid to the decline in blood cell counts, particularly in patients who show a slight improvement after immunotherapy or have a risk of lymphoma. Screening for potential tumors and infections and early treatment may help these patients.

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Anti-proteinase 3 are one of the main ANCA subtypes. There are contradictory studies on the relation between ANCA levels and the severity of the disease and its prognosis [1]. In patients with positive anti-PR3 antibodies from a university hospital we assess: a) associated diseases, b) specificity in diagnosing AAV and, c) determine if there is a cut-off point that allows to correlate the levels of anti-PR3 antibodies with the severity and prognosis of AAV. Observational study of patients with positive anti-PR3 from a University Hospital, from 2003 to 2022. ANCA was determined by chemiluminescence. The specificity of anti-PR3 for AAV diagnosis, predictive value of severity and prognosis were determined with Receiver Operating Characteristic (ROC) curves. At diagnosis, AAV with renal disease (hematuria and/or proteinuria) and lung involvement (hemoptysis, asthma and/or respiratory failure) were considered severe. During follow-up, the prognosis was considered worse if the patient needed dialysis, a transplant, or died. We study 54 patients with positive PR3. Most of them (81.5%) had an underlying AAV being the most frequent GPA (61.1%). The non vasculitic disease more frequent was Ulcerative colitis (11.1%). Table 1 summarizes the prevalence of these antibodies in different diseases. The frequencies are equivalent to those previously described and it is noteworthy the presence of anti-PR3 in drug-induced vasculitis, mainly by cocaine. Anti-PR3 antibodies for a diagnosis of vasculitis (n=44), an area under the curve (AUC) was calculated (AUC=0.7318), and a cut-off point of 20.5 IU/ml was determined (Figure 1). Significant differences in anti-PR3 levels were observed between those patients with renal or pulmonary dysfunction (n=30) and those without them (n=24) (p=0.0048), and a cut-off threshold of 41.5 IU/ml was established. Finally, after examining the illness's prognosis an AUC= 0.5643 was obtained, being no significant differences between those patients who had a worse disease progression (n=14) and those who did not (n=40) (p=0.4847). The presence of anti-PR3 is mainly associated with AAV, although in up to a fifth of cases it can be associated with other diseases. Anti-PR3 antibodies levels, at the moment of AAV diagnosis, correlates with disease diagnosis (specificity) and with severity but not with disease outcome. [1]Walker BS, et al. Autoimmun Rev. 2022 Jun;21(6):103100. [2]Kitching AR, et al. Nat Rev Dis Primers. 2020 Aug 27;6(1):71 NIL. Vanesa Calvo-Río Speakers bureau: AbbVie, Lilly, MSD, UCB Pharma, Grunenthal and Celgene., Salma Al Fazazi: None declared, Mónica Renuncio-García: None declared, Maria Rodriguez Vidriales: None declared, Clara Escagedo Cagigas: None declared, Juan Irure-Ventura: None declared, Luis Martín-Penagos: None declared, Alba Herrero-Morant: None declared, Marcos Lopez-Hoyos: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD, Grant/research support from: Abbvie, MSD and Roche. [Display omitted] Table 1Diseases associated with positive anti-PR3 antibodies (n=54).GroupDiseaseNumber (n)Frequency (%)Vasculitis(n=44; 81.5%)Granulomatosis with polyangeiitis3361.1Drug-induced vasculitis59.2Pauci-immune glomerulonephritis23.7Microscopic polyangeiitis23.7Large vessel vasculitis11.9Unclassified vasculitis11.9No vasculitis(n=10; 18.5%)Ulcerative colitis611.1Chron's disease11.9Infection11.9Diffuse interstitial lung disease11.9Hypereosinophil syndrome11.9

In this study, interferon-γ was found to play a large role in the pathogenesis of APS-1. Results were confirmed in studies in animals and led to a trial of ruxolitinib in five patients, who had dramatic responses.

Background Autoantibodies are found in up to 80% of patients with idiopathic inflammatory myopathies (IIM) and are associated with distinct clinical phenotypes [1]. Autoantibodies targeting cytosolic 5´-nucleotidase 1A (anti-cN1A) are currently the only known serum biomarker for the subgroup inclusion body myositis (IBM) (2), although detected even in other autoimmune diseases.Objectives To identify new autoimmune targets in IIM by antigen bead array assay.Methods In a first cross-sectional exploratory study, 357 antigens representing 268 proteins were incubated with plasma samples from 219 IIM (108 Polymyositis (PM), 80 Dermatomyositis (DM) and 31 IBM) patients, 349 Systemic Lupus Erythematosus (SLE) patients and 306 population controls for screening of IgG reactivity by antigen bead array. All samples were identified in the local biobank of the Rheumatology clinic, Karolinska University Hospital. Interesting results obtained for the IBM subgroup were then validated in an independent larger cohort of 287 patients with IBM followed at nine European rheumatological or neurological centers. IBM serum samples were explored by antigen bead array and results validated by western blot. As controls, serum samples from 30 patients with PM and 30 with DM, HLA-matched with the IBM Swedish cohort, were included. Demographics, laboratory, clinical, and muscle biopsy data of the IBM cohort was retrieved.Results In the exploratory study IgG reactivity towards NADH dehydrogenase 1 α subcomplex 11 (NDUFA11), a subunit of the membrane-bound mitochondrial respiratory chain complex I, was discovered with higher frequency in the IBM (9,7%) than PM (2,8%) and DM samples (2,5%), although the difference was not statistically significant. Anti-NDUFA11 IgG was also found in 2,3% of SLE and 2,6% of population control samples. In the validation study anti-NDUFA11 autoantibodies were detected in 11/287 IBM patients (3,8%), 0/30 PM and 0/30 DM patients. Reactivity against NDUFA11 could be confirmed by western blot (Table 1, Figure 1). The eleven anti-NDUFA11 positive patients showed a trend of lower frequency of wheelchair/walker ever use and higher creatine kinase levels at time of IBM diagnosis compared to the anti-NDUFA11 negative group. Ragged red fibers were significantly more prevalent in anti-NDUFA11 positive than negative patients (p=0.04). Anti-cN1A autoantibodies were detected in 98/287 (34,1%) of IBM, 3/30 (10%) DM and 9/29 (31%) PM patients, p=0.03. Coexistence of anti NDUFA11 and anti-cN1A antibodies was observed in 3 IBM patients.Conclusion Our results reveal a new autoimmune target in the mitochondrial respiratory chain complex I that might be specifically associated with IBM. This is of particular interest as mitochondrial abnormalities are known histological findings in muscle biopsies of IBM patients.References [1]Galindo-Feria AS, Wang G, Lundberg IE. Autoantibodies: Pathogenic or epiphenomenon. Best Pract Res Clin Rheumatol. 2022;36(2):101767. [2]Herbert MK,et al. Disease specificity of autoantibodies to cytosolic 5’-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Ann Rheum Dis. 2016;75(4):696-701.