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At one time considered a possible form of neuromyelitis optica (NMO) spectrum disorder (NMOSD), it is now accepted that myelin oligodendrocyte glycoprotein (MOG) antibody (Ab)-associated disorder (MOGAD) is a distinct entity from either NMO or multiple sclerosis (MS) and represents a broad spectrum of clinical phenotypes. Whereas Abs targeting aquaporin-4 (AQP4) in NMO are pathogenic, the extent that anti-MOG Abs contribute to CNS damage in MOGAD is unclear. Both AQP4-specific Abs in NMO and MOG-specific Abs in MOGAD are predominantly IgG1, a T cell-dependent immunoglobulin (Ig) subclass. Key insights in neuroimmunology and MOGAD pathogenesis have been learned from MOG experimental autoimmune encephalomyelitis (EAE), described 2 decades before the term MOGAD was introduced. MOG-specific T cells are required in MOG EAE, and while anti-MOG Abs can exacerbate EAE and CNS demyelination, those Abs are neither necessary nor sufficient to cause EAE. Knowledge regarding the spectrum of MOGAD clinical and radiologic presentations is advancing rapidly, yet our grasp of MOGAD pathogenesis is incomplete. Understanding both the humoral and cellular immunology of MOGAD has implications for diagnosis, treatment, and prognosis.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Autoimmune encephalitis is a relatively novel nosological entity characterized by an immune-mediated damage of the central nervous system. While originally described as a paraneoplastic inflammatory phenomenon affecting limbic structures, numerous instances of non-paraneoplastic pathogenesis, as well as extra-limbic involvement, have been characterized. Given the wide spectrum of insidious clinical presentations ranging from cognitive impairment to psychiatric symptoms or seizures, it is crucial to raise awareness about this disease category. In fact, an early diagnosis can be dramatically beneficial for the prognosis both to achieve an early therapeutic intervention and to detect a potential underlying malignancy. In this scenario, the radiologist can be the first to pose the hypothesis of autoimmune encephalitis and refer the patient to a comprehensive diagnostic work-up - including clinical, serological, and neurophysiological assessments.In this article, we illustrate the main radiological characteristics of autoimmune encephalitis and its subtypes, including the typical limbic presentation, the features of extra-limbic involvement, and also peculiar imaging findings. In addition, we review the most relevant alternative diagnoses that should be considered, ranging from other encephalitides to neoplasms, vascular conditions, and post-seizure alterations. Finally, we discuss the most appropriate imaging diagnostic work-up, also proposing a suggested MRI protocol.

BACKGROUND: High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human angiotensin-converting enzyme 2 (ACE2) cross-reactive anti-severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain (SARS-CoV-2 RBD) antibodies (CR Abs) have been reported as one of the sources of anti-ACE2 autoantibodies. However, the pathological implications of CR Abs in NET formation remain unknown. METHODS: In this study, we first assessed the presence of CR Abs in the sera of COVID-19 patients with different severity by serological analysis. Sera and purified IgG from CR Abs positive COVID-19 patients as well as a mouse monoclonal Ab (mAb 127) that can recognize both ACE2 and the RBD were tested for their influence on NETosis and the possible mechanisms involved were studied. RESULTS: An association between CR Abs levels and the severity of COVID-19 in 120 patients was found. The CR Abs-positive sera and IgG from severe COVID-19 patients and mAb 127 significantly activated human leukocytes and triggered NETosis, in the presence of RBD. This NETosis, triggered by the coexistence of CR Abs and RBD, activated thrombus-related cells but was abolished when the interaction between CR Abs and ACE2 or Fc receptors was disrupted. We also revealed that CR Abs-induced NETosis was suppressed in the presence of recombinant ACE2 or the Src family kinase inhibitor, dasatinib. Furthermore, we found that COVID-19 vaccination not only reduced COVID-19 severity but also prevented the production of CR Abs after SARS-CoV-2 infection. CONCLUSIONS: Our findings provide possible pathogenic effects of CR Abs in exacerbating COVID-19 by enhancing NETosis, highlighting ACE2 and dasatinib as potential treatments, and supporting the benefit of vaccination in reducing disease severity and CR Abs production in COVID-19 patients.

BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. METHODS: A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. RESULTS: Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. CONCLUSION: These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations.

ObjectivePrimary Sjögren's syndrome (pSS) is the second most common chronic autoimmune connective tissue disease. Autoantibodies, immunoglobulin (IgG) anti-SSA/Ro, in serum is a key diagnostic feature of pSS. Since pSS is a disease of the salivary gland, we investigated anti-SSA/Ro52 in saliva.MethodsUsing a novel electrochemical detection platform, Electric Field-Induced Release and Measurement, we measured IgG/M/A, IgG, IgA, IgA isotypes (IgA1 and IgA2) and IgA1 subclasses (polymeric and monomeric IgA1) to anti-SSA/Ro52 in saliva supernatant of 34 pSS, 35 dry eyes and dry mouth (patients with Sicca) and 41 health controls.ResultsSaliva IgG/M/A, IgG, IgA, IgA isotypes and IgA1 subclasses to anti-SSA/Ro52 differed significantly between pSS, non-pSS Sicca and healthy subjects. Elevated monomeric IgA1 was observed in patients with non-pSS Sicca while elevated polymeric IgA1 (pIgA1) was observed in patients with pSS. Salivary polymeric but not monomeric IgA1 (mIgA1) isoform correlated with focus score (r2=0.467, p=0.001) CONCLUSIONS: Salivary anti-Ro52 polymeric IgA1 isoform is associated with glandular inflammation in pSS, while salivary monomeric IgA1 is associated with Sicca. Whether IgA1 isotope switching plays a role in the progression of the Sicca to pSS warrants further investigation.

BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Unions Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour lenfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantics Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantics Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste daccueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).

Autoimmune responses against NMDA receptors (NMDAR) and GABAA receptors (GABAAR) can cause encephalitis, which has been described as feeling like one’s brain is on fire (Dalmau et al, 2019). The molecular mechanisms of how the autoantibodies affect neuronal functions are incompletely defined. Hunter et al (2024) now describe effects of autoantibodies from patients against NMDARs and GABAARs on the lateral mobility and thereby localization and function of NMDARs and GABAARs as well as AMPA receptors (AMPARs), the main glutamatergic receptors that mediate basal synaptic transmission. The study provides evidence for crossover effects of autoantibodies on the opposite receptor that depend on neuronal activity and the interaction of NMDAR with the dopaminergic receptor D1.

BACKGROUND: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers). METHODS: This epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre- vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7). RESULTS: The median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions. CONCLUSION: Differentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function.

Glycoprotein 2 (GP2) is a widely distributed protein in the digestive tract, contributing to mucosal barrier maintenance, immune homeostasis, and antigen-specific immune response, while also being linked to inflammatory bowel disease (IBD) pathogenesis. This review sheds light on the extensive distribution of GP2 within the gastrointestinal tract and its intricate interplay with the immune system. Furthermore, the significance of GP2 autoantibodies in diagnosing and categorizing IBD is underscored, alongside the promising therapeutic avenues for modulating GP2 to regulate immunity and maintain mucosal balance.

Smooth muscle antibodies (SMA) with anti-microfilament actin (MF-SMA) specificity are regarded as highly specific markers of type 1 autoimmune hepatitis (AIH-1) but their recognition relying on immunofluorescence of vessel, glomeruli, and tubules (SMA-VGT pattern) in rodent kidney tissue, is restricted by operator-dependent interpretation. A gold standard method for their identification is not available. We assessed and compared the diagnostic accuracy for AIH-1 of an embryonal aorta vascular smooth muscle (VSM) cell line-based assay with those of the rodent tissue-based assay for the detection of MF-SMA pattern in AIH-1 patients and controls. Sera from 138 AIH-1 patients and 295 controls (105 primary biliary cholangitis, 40 primary sclerosing cholangitis, 50 chronic viral hepatitis, 20 alcohol-related liver disease, 40 steatotic liver disease, and 40 healthy controls) were assayed for MF-SMA and SMA-VGT using VSM-based and rodent tissue-based assays, respectively. MF-SMA and SMA-VGT were found in 96 (70%) and 87 (63%) AIH-1 patients, and 2 controls (P < 0.0001). Compared with SMA-VGT, MF-SMA showed similar specificity (99%), higher sensitivity (70% vs 63%, P = ns) and likelihood ratio for a positive test (70 vs 65). Nine (7%) AIH-1 patients were MF-SMA positive despite being SMA-VGT negative. Overall agreement between SMA-VGT and MF-SMA was 87% (kappa coefficient 0.870, [0.789–0.952]). MF-SMA were associated with higher serum γ‐globulin [26 (12–55) vs 20 g/l (13–34), P < 0.005] and immunoglobulin G (IgG) levels [3155 (1296–7344) vs 2050 mg/dl (1377–3357), P < 0.002]. The easily recognizable IFL MF-SMA pattern on VSM cells strongly correlated with SMA-VGT and has an equally high specificity for AIH-1. Confirmation of these results in other laboratories would support the clinical application of the VSM cell-based assay for reliable detection of AIH-specific SMA. (i) The search for smooth muscle antibodies (SMA) is a cornerstone of hepatic autoimmune serology, being one of the diagnostic criteria of autoimmune hepatitis (AIH). (ii) SMA are directed against structures of the cytoskeleton such as microfilaments, intermediate filaments, and microtubules. Although they may be detected in sera of patients with viral hepatitis, drug-induced hepatitis, and alcohol-related and non-alcohol-related fatty liver disease, SMA directed against actin microfilaments (MF-SMA) are highly AIH-specific. (iii) The recommended rodent tissue-based IFL for detecting MF-SMA is somewhat complicated, and the interpretation of the results depends on the operator's experience. The use of an embryonal aorta vascular smooth muscle cell line-based IFL assay provides high accuracy and easy detection of MF-SMA, the most AIH-specific SMA. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to determine the associations of protein‐specific anti–malondialdehyde‐acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis–interstitial lung disease (RA‐ILD). Methods: Within a multicenter, prospective cohort of US veterans with RA, RA‐ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA‐albumin, MAA‐collagen, MAA‐fibrinogen, and MAA‐vimentin (IgA, IgM, and IgG) were measured by a standardized enzyme‐linked immunosorbent assay. Associations of anti‐MAA antibodies with prevalent and incident RA‐ILD were assessed using multivariable regression models adjusting for established RA‐ILD risk factors. Results: Among 2,739 participants with RA (88% male, mean age of 64 years), there were 114 with prevalent and 136 with incident RA‐ILD (average time to diagnosis: 6.6 years). Higher IgM anti–MAA‐collagen (per 1 SD: adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.02–1.61), IgA anti–MAA‐fibrinogen (aOR 1.48, 95% CI 1.14–1.92), and IgA (aOR 1.78, 95% CI 1.34–2.37) and IgG (aOR 1.48, 95% CI 1.14–1.92) anti–MAA‐vimentin antibodies were associated with prevalent RA‐ILD. In incident analyses, higher IgA (per one SD: adjusted hazards ratio [aHR] 1.40, 95% CI 1.11–1.76) and IgM (aHR 1.29, 95% CI 1.04–1.60) anti–MAA‐albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13, 95% CI 1.16–3.90) or IgM (aHR 1.98, 95% CI 1.08–3.64) anti–MAA‐albumin antibody concentrations in the highest quartile had an approximately two‐fold increased risk of incident RA‐ILD. Across all isotypes, anti–MAA‐fibrinogen, anti–MAA‐collagen, and anti–MAA‐vimentin antibodies were not significantly associated with incident RA‐ILD. Conclusion: Protein‐specific anti‐MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA‐ILD. IgA and IgM anti–MAA‐albumin antibodies were associated with a higher risk of incident RA‐ILD. These findings suggest that MAA modifications and resultant immune responses may contribute to RA‐ILD pathogenesis. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that primarily affects young women and causes a wide range of inflammatory manifestations. The hallmark of SLE is the production of antibodies to components of the cell nucleus (antinuclear antibodies [ANAs]). These antibodies can bind to DNA, RNA, and protein complexes with nucleic acids. Among ANAs, antibodies to DNA (anti‐DNA) are markers for classification and disease activity, waxing and waning disease activity in many patients. In the blood, anti‐DNA antibodies can bind to DNA to form immune complexes with two distinct roles in pathogenesis: (1) renal deposition to provoke nephritis and (2) stimulation of cytokine production following uptake into innate immune cells and interaction with internal nucleic acid sensors. These sensors are part of an internal host defense system in the cell cytoplasm that can respond to DNA from infecting organisms; during cell stress, DNA from nuclear and mitochondrial sources can also trigger these sensors. The formation of immune complexes requires a source of extracellular DNA in an immunologically accessible form. As shown in in vivo and in vitro systems, extracellular DNA can emerge from dead and dying cells in both a free and a particulate form. Neutrophils undergoing the process of NETosis can release DNA in mesh‐like structures called neutrophil extracellular traps. In SLE, therefore, the combination of ANAs and immunologically active DNA can create new structures that can promote inflammation throughout the body as well as drive organ inflammation and damage. [ABSTRACT FROM AUTHOR]

Objective: Glucocorticoid‐induced tumor necrosis factor receptor superfamily–related protein (GITR), with its ligand (GITRL), plays an important role in CD4+ T cell–mediated autoimmunity. This study aimed to investigate the underlying mechanisms of GITRL in primary Sjögren syndrome (pSS). Methods: Patients with pSS and healthy controls were recruited. Serum GITRL and Th17‐related cytokines were determined. RNA sequencing was performed to decipher key signal pathways. Nonobese diabetes (NOD) mice were adopted as experimental Sjögren models and recombinant adeno‐associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo. Results: Serum GITRL was significantly higher in patients with pSS and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement, and disease activity. Serum GITRL was correlated with Th17‐related cytokines. GITRL promoted the expansion of Th17 and Th17.1 cells. Expansion of granulocyte‐macrophage colony‐stimulating factor positive (GM‐CSF+) CD4+ T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM‐CSF could stimulate GITRL expression on monocytes. RNA sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and the expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL–mTORC1–GM‐CSF positive loop in pathogenic Th17 response in pSS. Administration of an rAAV vector expressing short hairpin RNA targeting GITRL alleviated disease progression in NOD mice. Conclusion: Our results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL–mTORC1–GM‐CSF loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate disparities in clinical profiles and autoantibody patterns between patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) in a cohort and to identify risk factors associated with NPSLE in the Chinese population. Methods: SLE patients were retrospectively reviewed from two tertiary hospitals. The relationships between NPSLE and immunological biomarkers were explored. Results: Among the 945 SLE patients, 75 (7.94%) were diagnosed with NPSLE. The most prevalent NP manifestations involved cognitive disorder (30.67%), headache (26.67%), seizure disorder (26.67%), and psychosis (26.67%).We observed significant associations between psychosis and anti-β2GPI antibodies (F = 6.092, p = 0.015), polyneuropathy and anti-Scl70 antibodies (F = 20.161, p < 0.001), demyelinating syndrome and anti-cardiolipin antibodies (F = 6.637, p = 0.011), myasthenia gravis and anti-RNP (F = 5.864, p = 0.017), and anti-Smith antibodies (F = 5.096, p = 0.026). Multivariate logistics analysis showed that anti-prothrombin (aPT) IgM antibodies (OR = 10.985, CI 1.279–94.343, p = 0.029), age (OR = 1.169, CI 1.032–1.325, p = 0.014), and serum creatinine (SCr) (OR = 1.014, CI 1.003–1.025, p = 0.009) were independent risk factors of NPSLE, while anti-Sjogren syndrome antigen B (SSB) antibodies (OR 0.023, CI 0.002–0.622, p = 0.023) and high complement C3 (OR = 0.001, CI 0–0.045, p < 0.001) indicated reduced risk of NPSLE. Conclusion: Various neuropsychiatric manifestations in SLE were found to be correlated with specific autoantibodies. Independent risk factors for NPSLE included aPT IgM antibodies, age, and elevated serum creatinine, while the absence of anti-SSB antibodies and low complement C3 levels were associated with increased risk. Key points: •Significant associations were found between specific autoantibodies and neuropsychiatric symptoms, shedding light on potential biomarkers for predicting and understanding NPSLE. •The study identifies independent risk factors for NPSLE in the Chinese population, including the presence of anti-prothrombin IgM antibodies, older age, elevated serum creatinine, and lower complement C3 levels. [ABSTRACT FROM AUTHOR]

Postiodization era has experienced a change in pediatric thyroid disorders with autoimmune disorders and subclinical hypothyroidism (SCH) now more frequently diagnosed. The aims of this study were to evaluate the clinical spectrum of thyroid disorders among children referred to us, to ascertain characteristics that influence treatment, and to follow them for various outcome measures. An observational longitudinal study where all treatment-naïve children (<18 years) with suspected thyroid disorders were recruited. Data collected were anthropometry, serum TSH, TT4, TT3, antithyroid autoantibodies, family history, and clinical symptoms. The management was based on the clinical judgment of the endocrinologist with the first follow-up at six weeks and subsequent visits three monthly for one year. A total of 241 subjects aged 28 days to 17 years were included. Overall, SCH was the most common abnormality (39%) detected among subjects, followed by overt hypothyroidism (OH) (33%), congenital hypothyroidism (CH) (18%), and overt thyrotoxicosis (5%). A total of 85.5% (n = 204) of subjects were treated and in follow-up, 81% of them were found to be adequately managed. Comparative analysis of OH and SCH revealed pubertal age, female predominance, and the presence of autoimmunity (positive anti-TPO and anti-TG Ab) statically significant variables in the OH group. A major independent predictor of treatment in treated SCH (72/96) in comparison with nontreated SCH (24/96) was anti-TPO positivity (P = 0.029). Eight of 24 nontreated SCH were eventually treated in follow-up and positive family history was observed as a significant variable among them (P < 0.05). Subjects with CH presented at a mean age of 6 months (28 days to 2 years). However, guidelines for the management of SCH are still evolving, autoimmunity and positive family history should be considered as decisive factors while initializing treatment. Delayed presentation of CH in our study warrants active surveillance of children at birth for thyroid disorders for their mental well-being. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. Methods: Pre‐diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen‐2 (IA‐2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t‐tests. Results: Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody‐positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA‐positivity was higher in insulin‐treated relatives than in non‐insulin‐treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA‐positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody‐positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). Conclusion: This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis. [ABSTRACT FROM AUTHOR]

Objective: Although many studies have shown the relationship between type 1 diabetes mellitus (T1DM) and autoimmune thyroid diseases, few studies have conducted a morphological evaluation of the thyroid gland in T1DM without thyroid disease. This study aimed to compare thyroid ultrasonography findings of the healthy control group with the T1DM group without thyroid disease and examine the relationship between β-cell autoantibodies and the presence of thyroid nodules. Methods: This cross-sectional study included 119 patients with T1DM and 105 healthy controls. Thyroid function tests, thyroid volume, and presence of thyroid nodules were compared between the two groups. Patients with T1DM were divided into two groups according to the presence of thyroid nodules, and risk factors that may affect the development of thyroid nodules were tried to be determined. Results: No significant difference was found between the control group and the T1DM group in terms of thyroid function tests, thyroid volume, and presence of thyroid nodules. In the T1DM group, the number of female patients and the islet cell antibody (ICA) positivity rate were higher in the presence of thyroid nodules. As a result of regression analysis, ICA positivity in the T1DM group increased threefold the risk of having thyroid nodules. Conclusion: A relationship was observed between ICA positivity and thyroid nodules in T1DM. Thus, cases with ICA positivity may have a higher probability of nodules in the thyroid gland, and neck examinations should be performed more frequently. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS. [ABSTRACT FROM AUTHOR]

The spectrum of pediatric rheumatological disorders is diverse and they are important differential diagnoses in a variety of clinical scenarios. Basic investigations not only provide supporting evidence for the diagnosis of a rheumatological illness but also help in exclusion of other diseases as well as for monitoring the activity of disease. Among these, complete blood count, biochemical assays including tests for inflammatory response, urine analysis, and various autoantibodies are often used. In addition, depending on the clinical features, imaging and tissue biopsies are used to confirm the diagnosis. [ABSTRACT FROM AUTHOR]

Background: Contactin-associated protein-2(CASPR2) antibody-associated autoimmune encephalitis(AE) is rare in children. This study aimed to report the clinical characteristics and long-term outcome of CASPR2 autoimmunity in children to expand the disease spectrum. Methods: Children who were hospitalized in our hospital with clinically suspected AE from May 2015 to April 2022 and underwent neuronal surface antibodies detections were retrospectively analyzed. Clinical data of patients with CASPR2 autoimmunity were collected. Results: Patients who were positive for NMDAR-IgG, CASPR2-IgG, LGI1-IgG and IgLON5-IgG occupied 95.2%(119/125),3.2%(4/125),0.8%(1/125) and 0.8%(1/125), respectively.The median onset age of the 4 patients with CASPR2-IgG was 5.6 years. The most common symptoms were psychiatric symptoms/abnormal behavior(3/4) and sleep dysfunction(3/4). One patient developed a phenotype of Rasmussen encephalitis(RE). Tumor was absent in our patients. Two patients showed abnormal findings on initial brain magnetic resonance imaging(MRI) scans. All the patients showed favorable response to immunotherapy except the patient with RE experienced recurrent symptoms who finally achieved remission after surgery. All the patients had a favorable long-term outcome at the last follow-up(33-58months). Conclusions: CASPR2 autoimmunity may be the second most common anti-neuronal surface antibodies associated neurological disease in children. Psychiatric symptoms/abnormal behavior and sleep disorder were common in children with CASPR2-associated AE. Tumor was rare in those patients. Most pediatric patients had a favorable long-term outcome. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) is an autoimmune blistering disease primarily affecting the elderly, whereas cases of juvenile BP are rare. Both types of BP are typically mediated by autoantibodies targeting the NC16A region of BP180; however, a small subset of adult patient sera react to other regions of the protein. The incidence of a similar occurrence in juvenile BP is unknown. This case of juvenile BP with a negative BP180 ELISA highlights diagnostic pitfalls that can lead to a delay in the correct diagnosis in the pediatric population. [ABSTRACT FROM AUTHOR]

Introduction: New onset refractory status epilepticus (NORSE) is a rare and devastating condition characterised by the sudden onset of refractory status epilepticus (RSE) without an identifiable acute or active structural, toxic, or metabolic cause in an individual without a pre-existing diagnosis of epilepsy. Febrile infection-related epilepsy syndrome (FIRES) is considered a subcategory of NORSE and presents following a febrile illness prior to seizure onset. NORSE/FIRES is associated with high morbidity and mortality in children and adults. Methods and results: In this review we first briefly summarise the reported clinical, paraclinical, treatment and outcome data in the literature. We then report on existing knowledge of the underlying pathophysiology in relation to in vitro and in vivo pre-clinical seizure and epilepsy models of potential relevance to NORSE/FIRES. Discussion: We highlight how pre-clinical models can enhance our understanding of FIRES/NORSE and propose future directions for research. [ABSTRACT FROM AUTHOR]

The liver-derived selenium (Se) transporter selenoprotein P (SELENOP) declines in critical illness as a negative acute phase reactant and has recently been identified as an autoantigen. Hepatic selenoprotein biosynthesis and cotranslational selenocysteine insertion are sensitive to inflammation, therapeutic drugs, Se deficiency, and other modifiers. As severe burn injury induces a heavy inflammatory burden with concomitant Se depletion, we hypothesized an impairment of selenoprotein biosynthesis in the acute postburn phase, potentially triggering the development of autoantibodies to SELENOP (SELENOP-aAb). To test this hypothesis, longitudinal serum samples from severely burned patients were analyzed over a period of six months. Newly occurring SELENOP-aAb were detected in 8.4% (7/83) of the burn patients, with onset not earlier than two weeks after injury. Prevalence of SELENOP-aAb was associated with injury severity, as aAb-positive patients have suffered more severe burns than their aAb-negative counterparts (median [IQR] ABSI: 11 [7-12] vs. 7 [5.8-8], p = 0.023). Autoimmunity to SELENOP was not associated with differences in total serum Se or SELENOP concentrations. A positive correlation of kidney-derived glutathione peroxidase (GPx3) with serum SELENOP was not present in the patients with SELENOP-aAb, who showed delayed normalization of GPx3 activity post-burn. Overall, the data suggest that SELENOP-aAb emerge after severe injury in a subset of patients and have antagonistic effects on Se transport. The nature of burn injury as a sudden event allowed a time-resolved analysis of a direct trigger for new-onset SELENOP-aAb, which may be relevant for severely affected patients requiring intensified acute and long-term care. [ABSTRACT FROM AUTHOR]

Multiple factors contribute to the development of connective tissue diseases (CTD), often alongside a range of interstitial lung diseases (ILD), including Sjögren's syndrome-associated ILD, systemic sclerosis-associated ILD, systemic lupus erythematosus-associated ILD, idiopathic inflammatory myositis-associated ILD. TRIM21(or Ro52), an E3 ubiquitin ligase, plays a vital role in managing innate and adaptive immunity, and maintaining cellular homeostasis, and is a focal target for autoantibodies in various rheumatic autoimmune diseases. However, the effectiveness of anti-TRIM21 antibodies in diagnosing CTD remains a matter of debate because of their non-specific nature. Recent studies indicate that TRIM21 and its autoantibody are involved in the pathogenesis of CTD-ILD and play an important role in diagnosis and prognosis. In this review, we focus on the contribution of TRIM21 in the pathogenesis of CTD-ILD, as well as the potential diagnostic value of its autoantibodies in different types of CTD-ILD for disease progression and potential as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions A variety of myositis‐specific autoantibodies have been identified in sera from patients with idiopathic inflammatory myopathies, and they play a crucial role in tailoring personalized disease management. In particular, autoantibodies against 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) are now recognized as a key tool for diagnosing immune‐mediated necrotizing myopathy. The current gold standard for detecting anti‐HMGCR autoantibodies involves immunoprecipitation (IP) using radiolabeled proteins from cell extracts or purified proteins produced by in vitro transcription/translation (IVTT). Unfortunately, this radioisotope labeling is technically intricate and not suitable for routine laboratory use. To address this, we developed a novel assay called “Bio‐IVTT‐IP” for detecting anti‐HMGCR autoantibodies, which uses a nonradioactive biotinylated recombinant HMGCR protein produced by IVTT.We collected 14 clinical specimens containing anti‐HMGCR autoantibodies from patients with immune‐mediated necrotizing myopathy, which were validated using the gold standard IP assay, and a set of 35 control samples from patients with other autoimmune diseases, such as systemic lupus erythematosus.The Bio‐IVTT‐IP assay successfully identified 14 clinical samples positive for anti‐HMGCR. We confirmed that the performance of the Bio‐IVTT‐IP assay was completely consistent with that of the gold standard IP assay using radiolabeled proteins. Notably, no immunoprecipitates were found in control samples from patients with other autoimmune diseases.These findings show that the Bio‐IVTT‐IP assay can serve as a potential alternative to the gold standard IP assay for detecting anti‐HMGCR autoantibodies. It can be considered a practical immunodiagnostic tool for diagnosing immune‐mediated necrotizing myopathy, particularly owing to its accessibility in routine laboratory settings. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD. [ABSTRACT FROM AUTHOR]

Early intervention has been the cornerstone of improving outcomes in patients with rheumatoid arthritis. Over the past decade, the boundaries have been pushed in an attempt to achieve effective prevention strategies in those who are at high risk of developing rheumatoid arthritis. Core risk factors including the presence of serum anti-citrullinated protein antibodies, arthralgia and subclinical inflammation on imaging are highly predictive of arthritis development. The influence of air pollution, diet and the role of microbiome on disease progression are less clear. In turn, therapeutic focus has shifted to an earlier pre-arthritis phase of the disease continuum where the clinically apparent arthritis may potentially be intercepted. Seven proof-of-concept interventional trials in at-risk individuals have been conducted so far. Whether true prevention of rheumatoid arthritis is possible remains elusive. Promising signals towards permanent disease modulation and improvement in symptom burden were seen with some immunomodulatory therapies, whilst others were unsuccessful. Long-term follow-up is required to ascertain a true effect. Looking forward, a better understanding of the natural history and underlying biological mechanisms of arthritis development and more accurate, validated risk stratification is needed. [ABSTRACT FROM AUTHOR]

Background Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe disease with increased morbidity and mortality among certain risk groups. The presence of autoantibodies against type I interferons (aIFN-Abs) is one mechanism that contributes to severe coronavirus disease 2019 (COVID-19). Methods This study aimed to investigate the presence of aIFN-Abs in relation to the soluble proteome, circulating immune cell numbers, and cellular phenotypes, as well as development of adaptive immunity. Results aIFN-Abs were more prevalent in critical compared to severe COVID-19 but largely absent in the other viral and bacterial infections studied here. The antibody and T-cell response to SARS-CoV-2 remained largely unaffected by the presence aIFN-Abs. Similarly, the inflammatory response in COVID-19 was comparable in individuals with and without aIFN-Abs. Instead, presence of aIFN-Abs had an impact on cellular immune system composition and skewing of cellular immune pathways. Conclusions Our data suggest that aIFN-Abs do not significantly influence development of adaptive immunity but covary with alterations in immune cell numbers. [ABSTRACT FROM AUTHOR]

Cells exposed to stressors of various origin activate protective mechanisms that include the expression of heat shock proteins (Hsps)/molecular chaperones belonging to several families. Well-characterized inducible Hsp70 is present in all human cell-types and biological fluids, including blood, urine, and saliva. The presence of anti-Hsp70 autoantibodies in the serum of healthy individuals has already been confirmed, and their elevated titers positively correlated with the severity of several pathological conditions, including coeliac disease and dermatitis herpetiformis - a cutaneous manifestation of coeliac disease. Here, using an indirect enzyme-linked immunosorbent assay, we demonstrate, for the first time, that anti-Hsp70 autoantibodies are present in the saliva and urine of healthy individuals. Although the occurrence of anti-Hsp70 autoantibodies in the biological fluids of healthy individuals is intriguing, their physiological role is currently unknown. It is believed that antibodies reacting with self-molecules present in the serum of healthy individuals are part of natural autoantibody pool with multiple regulatory functions. On the other hand, some autoantibodies (e.g., typical of autoimmune bullous skin diseases or systemic lupus erythematosus) may be present before the onset of the disease and serve as specific predictive biomarkers. Therefore, we would like to initiate a discussion or future research direction on the use of anti-Hsp70 autoantibodies as a potential "biomarker" in the diagnosis or prediction of autoimmune diseases. Our findings can be considered in biomedical research to develop noninvasive, inexpensive and easy-to-use tests. Nevertheless, large-scale comparative studies should be initiated, involving the collection and analysis of biological samples such as saliva or urine from patients suffering from autoimmune diseases or other inflammatory or neoplastic diseases, to determine whether the levels of anti-Hsp70 autoantibodies are indeed elevated and whether they correlate with the clinical picture of any disease or established biomarkers. [ABSTRACT FROM AUTHOR]

Background: Factor H (FH) is a major soluble inhibitor of the complement system and part of a family comprising five related proteins (FHRs 1-5). Deficiency of FHR1 was described to be linked to an elevated risk of systemic lupus erythematosus (SLE). As FHR1 can partially antagonize the functionality of FH, an altered FHR1/FH ratio could not only enhance SLE vulnerability but also affect the disease expression. This study focuses on the analysis of FH and FHR1 at a protein level, and the occurrence of anti-FH autoantibodies (anti-FH) in a large cohort of SLE patients to explore their association with disease activity and/or expression. Methods: We assessed FH and FHR1 levels in plasma from 378 SLE patients compared to 84 healthy controls (normal human plasma, NHP), and sera from another cohort of 84 healthy individuals (normal human serum, NHS), using RayBio® CFH and CFHR1 ELISA kits. Patients were recruited by the Swiss SLE Cohort Study (SSCS). Unmeasurable FHR1 levels were all confirmed by Western blot, and in a subgroup of patients by PCR. Anti-FH were measured in SLE patients with non-detectable FHR1 levels and matched control patients using Abnova's CFH IgG ELISA kit. Results: Overall, FH and FHR1 levels were significantly higher in healthy controls, but there was no significant difference in FHR1/FH ratios between SLE patients and NHPs. However, SLE patients showed a significantly higher prevalence of undetectable FHR1 compared to all healthy controls (35/378 SLE patients versus 6/168 healthy controls; p= 0.0214, OR=2.751, 95% CI = 1.115 - 8.164), with a consistent trend across all ethnic subgroups. Levels of FH and FHR1, FHR1/FH ratios and absence of FHR1 were not consistently associated with disease activity and/or specific disease manifestations, but absence of FHR1 (primarily equivalent to CFHR1 deficiency) was linked to the presence of anti-FH in SLE patients (p=0.039). Conclusions: Deficiency of FHR1 is associated with a markedly elevated risk of developing SLE. A small proportion of FHR1-deficient SLE patients was found to have autoantibodies against FH but did not show clinical signs of microangiopathy. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions Acetylcholine receptor antibody (AChR‐Ab) detection is crucial in myasthenia gravis (MG) diagnosis and, currently, the radioimmunoassay (RIA) is the gold standard. However, RIA may detect AChR‐Ab against nonpathogenic intracellular epitopes. In this study, we performed fixed cell‐based assay (F‐CBA) in RIA‐AChR‐Ab positive subjects without MG symptoms, to assess whether F‐CBA could show a higher specificity compared to RIA in detecting pathogenic Abs.We reviewed medical records of patients referred to our MG outpatient clinic because of RIA‐AChR‐Ab detection. MG diagnosis was based on clinical examination, electrophysiology and Ab detection. AChR‐Abs were tested by RIA in the whole cohort. Serum samples from RIA‐positive asymptomatic subjects were retested by F‐CBA.Of 605 subjects who tested RIA‐AChR‐Ab positive, MG diagnosis was confirmed in 599. Six subjects were RIA‐AChR‐Ab positive although they had never had MG symptoms; in four of these subjects AChR‐Abs were not detected by F‐CBA, whereas the remaining two (both non‐MG thymoma cases) were positive also by F‐CBA.RIA false positivity for AChR‐Ab is very rare. Previous literature has demonstrated that F‐CBA has higher sensitivity than RIA for MG, especially in ocular cases. Our preliminary results show that, in rare instances, F‐CBA may be more specific than RIA for MG diagnosis. [ABSTRACT FROM AUTHOR]

Background & aims: HBV infection initiates autoimmune responses, leading to autoantibody generation. This research explores the role of autoantibodies in HBV-related Acute-on-Chronic Liver Failure (ACLF), offering novel perspectives for clinical management. Method: We applied immunoprecipitation and iTRAQ techniques to screen for autoantibodies in serum from HBV-related cirrhosis patients and conducted detection with conformation-stabilizing ELISA in a cohort of 238 HBV-infected individuals and 49 health controls. Our results were validated in a retrospective cohort comprising 106 ACLF patients and further assessed through immunohistochemical analysis in liver tissues from an additional 10 ACLF cases. Results: Utilizing iTRAQ, we identified Argonaute1-3 autoantibodies (AGO-Abs) in this research. AGO2-Abs notably increased in cirrhosis, decompensation, and further in ACLF, unlike AGO1-Abs and AGO3-Abs. This reflects disease severity correlation. Logistic regression and COX models confirmed AGO2-Abs as independent prognostic indicators for decompensated liver cirrhosis (DLC) and ACLF. In the ROC analysis, AGO2-Abs showed significant diagnostic value for predicting 28- and 90-day mortality (AUROC = 0.853 and 0.854, respectively). Furthermore, combining AGO2-Abs with the Child-Pugh, MELD, and AARC scores significantly improved their predictive accuracy (P < 0.05). Kaplan-Meier analysis showed poorer survival for AGO2-Abs levels above 99.14mg/ml. These findings were supported by a retrospective validation cohort. Additionally, immunohistochemistry revealed band-like AGO2 expression in periportal liver areas, with AGO2-Abs levels correlating with total bilirubin, indicating a potential role in exacerbating liver damage through periportal functions. Conclusions: AGO2-Abs is a robust biomarker for predicting the mortality of patients with HBV-related ACLF. [ABSTRACT FROM AUTHOR]

Background: Production of anti-phosphatidylserine (anti-PS) antibodies has been associated with malaria and can aggravate pathology. How these autoantibodies develop during early childhood in a malaria context is not known. We examined levels of anti-PS IgG and IgM antibodies in a longitudinal cohort of mother-baby pairs during birth, in the infants at 2.5, 6 months, and in mothers and their babies at 9 months postpartum. Results: There was no difference between levels of anti-PS IgG in cord blood and the mothers' peripheral blood at birth. However, anti-PS IgM levels were significantly higher in the mothers compared to the infants' cord blood, and IgM levels were steadily increasing during the first 9 months of the infants' life. In infants that had the highest anti-PS IgM levels at birth, there was a decline until 6 months with a rise at 9 months. Infants that possessed high anti-PS IgG at birth also exhibited a progressive decline in levels. When anti-PS were correlated to different fractions of B-cells, there were several correlations with P. falciparum specific atypical B cells both at birth and at 2.5 months for the infants, especially for anti-PS IgM. Anti-PS also correlated strongly to C1q-fixing antibodies at birth. Conclusion: These results show that anti-PS IgG acquired by mothers could be transferred transplacentally and that IgM antibodies targeting PS are acquired during the first year of life. These results have increased the knowledge about autoimmune responses associated with infections in early life and is critical for a comprehensive understanding of malaria vaccine functionality in endemic areas. [ABSTRACT FROM AUTHOR]

Fetal autoimmune atrioventricular block (AVB) is a rare but potentially lifethreatening condition. It results from the passage of maternal anti-SSA/Ro or Anti SSB/La auto-antibodies into the fetal circulation, leading to inflammation and fibrosis of the AV node and often to irreversible damage. Besides AVB, these antibodies can also cause cardiomyopathies, but there is no evidence linking them to tachyarrhythmias. We present the case of a patient with significant risk factors for fetal AVB: a prior history of hydrops fetalis, high anti-SSA/Ro antibody levels and hypothyroidism. In this case, the use of dexamethasone and intravenous immunoglobulin may have contributed to reversing the first degree atrioventricular block detected at 19 weeks of gestation. Additionally, at 21 weeks, the fetus developed a tachyarrhythmia that needed treatment with flecainide. Soon after the birth, the newborn underwent ECG Holter and Wolff-Parkinson-White Syndrome (WPWS) was diagnosed. To our knowledge, the coexistence of fetal AVB and WPWS has never been described. [ABSTRACT FROM AUTHOR]

Introduction: Arthralgias are prevalent in systemic autoimmune rheumatic diseases (SARD), emphasizing the need for early recognition. This study aimed to estimate SARD frequency and compare clinical, laboratory, and imaging findings among SARD, non‐inflammatory arthralgia (NIA), and RA in patients with hand arthralgias. Methods: A prospective evaluation program included individuals aged ≥18 with hand arthralgias. Baseline assessments covered clinical, laboratory, ultrasound, and radiography. Follow‐up diagnoses categorized patients into SARD, NIA, and RA groups. Comparison between groups was performed using parametric and non‐parametric tests. Two multivariate logistic regression analyzes were performed using the final diagnosis of SARD as the dependent variable (NIA and RA). ROC curves were calculated in those variables that presented an independent association in the multivariate analysis. Results: Among 1053 patients, 9.6% were SARD (SLE 47%). Comparing SARD with NIA revealed higher CRP levels, power Doppler, less rhizarthrosis in ultrasound, and more ANA positivity in SARD patients. Distinct differences were observed between SARD and RA patients in terms of pain levels, swollen joints, metacarpophalangeal involvement and morning symptoms. Diagnostic markers demonstrated specific sensitivities and specificities: ANA for SARD versus NIA (82%, 34%), US not finding rhizarthrosis for SARD versus NIA (66%, 85%), CRP (cut‐off >2.5 mg/L) sensitivity 52%, specificity 60%, AUC 0.62, RA antibodies (RF, 11 IU/mL) sensitivity 76%, specificity 74%, AUC 0.8, ACPA (1.25) sensitivity 50%, specificity 98%, AUC 0.7, ANA+ sensitivity 95%, specificity 32%, AUC 0.7, and US absence of synovitis sensitivity 82%, specificity 34%, AUC 0.75. Conclusion: This study highlights distinct clinical, laboratory, and imaging features differentiating SARD‐related hand arthralgia from non‐SARD hand arthralgia and RA. [ABSTRACT FROM AUTHOR]

Inflammatory arthritis may be the principal feature or one component of an inflammatory rheumatological disease. It is a clinical diagnosis, principally made based on the patient’s history and examination. Specific investigations, such as rheumatoid factor and human leucocyte antigen B27 gene, may support the diagnosis in the context of a suggestive clinical presentation, but a diagnosis cannot be made based on these tests alone because positive results may also be seen in healthy individuals. To reduce the likelihood of false positive results, laboratory and radiological investigations should be tailored to the suspected diagnosis based on pretest probability. While musculoskeletal symptoms are a common presentation in general practice, specific features that increase suspicion of an inflammatory arthritis include prolonged morning stiffness (more than 1 hour) that is improved by exercise or movement. A broad ‘rheumatological panel’ increases the likelihood of false positive results and should be avoided to prevent unnecessary further investigations and treatment, and unwarranted anxiety in both the patient and the doctor. [ABSTRACT FROM AUTHOR]

Introduction: Hashimoto's thyroiditis (HT) is one of the most common autoimmune endocrine disorders in the pediatric age group. In this study, it was aimed to retrospectively examine our cases, who were children and adolescents diagnosed with HT. Materials and Methods: We retrospectively examined 119 patients between the ages of 1 and 18, who were diagnosed with HT. In all of the cases, physical examination findings, thyroid function tests, anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (Anti-Tg) antibodies, thyroid ultrasonographies and accompanying autoimmune diseases were evaluated. Results: The female/male ratio was 3.5/1. In our cases, the median age at the time of diagnosis was 12.29 years and 10 (8.4%) of the cases were under the age of five. At the time of diagnosis, 37% of the cases were euthyroid, 21.8% had overt hypothyroidism, 34.5% had subclinical hypothyroidism, 2.5% had subclinical hyperthyroidism and 4.2% had overt hyperthyroidism. At the time of diagnosis, 102 cases (85.7%) had anti-TPO and 82 cases (68.9%) had anti-Tg positivity. The Anti-TPO levels at the time of admission were found to be significantly higher in the hypothyroid group compared to the euthyroid group. Conclusion: Thyroid function test results of patients with Hashimoto's thyroiditis may vary in the follow-up period. Even though most cases with euthyroidism remain euthyroid, some might progress to hypothyroidism. Although Hashimoto's thyroiditis is most frequently seen in adolescents, approximately 10% of the cases are under the age of five. Therefore, autoimmune thyroiditis should be considered in hypothyroidism occurring in the early stages of life. [ABSTRACT FROM AUTHOR]

Background: To investigate Ranvier's autoantibodies prevalence and isotypes in various peripheral neuropathy variants, compare clinical features between seronegative and seropositive patients, and elucidate immune mechanisms underlying antibody generation. Methods: Antibodies against anti-neurofascin-155 (NF155), NF186, contactin-1 (CNTN1), CNTN2, contactin-associated protein 1 (CASPR1), and CASPR2 were identified through cell-based assays. Plasma cytokines were analyzed in anti-NF155 antibody-positive chronic inflammatory demyelinating polyneuropathy (NF155+ CIDP) and Ranvier's antibodies-negative CIDP (Ab− CIDP) patients using a multiplexed fluorescent immunoassay, validated in vitro in a cell culture model. Results: In 368 plasma samples, 50 Ranvier's autoantibodies were found in 45 individuals, primarily in CIDP cases (25 out of 69 patients) and in 10 out of 122 Guillain-Barré syndrome patients. Anti-NF155 and CNTN1-IgG were exclusive to CIDP. Fourteen samples were NF155-IgG, primarily IgG4 subclass, linked to CIDP features including early onset, tremor, sensory disturbance, elevated CSF protein, prolonged motor latency, conduction block, and poor treatment response. NF155-IgG had low sensitivity (20.28%) but high specificity (100%) for CIDP, rising to 88.88% with tremor and prolonged motor latency. Cytokine profiling in NF155+ CIDP revealed distinct immune responses involving helper T cells, toll-like receptor pathways. Some NF155+ CIDP patients had circulating NF155-specific B cells producing NF155-IgG without antigen presence, suggesting therapeutic potential. Conclusion: The study emphasizes the high specificity and sensitivity of NF155-IgG for diagnosing CIDP characterized by distinctive features. Further investigation into circulating NF155-specific B cell phenotypes may pave the way for B cell directed therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated a new blood test (9G testTM Cancer/Lung) for early lung cancer detection. This test measures complexes of autoantibodies with specific lung cancer antigens for CYFRA 21-1 and p53. This study found that the diagnostic performances were significantly better than traditional methods at identifying LC, especially in early stages. The test showed good overall accuracy (AUC of 0.945) and detected early-stage lung cancer with high sensitivity (87.5%). This suggests it could be a valuable tool alongside existing scans like X-rays and LDCT for improving early LC detection. The early detection of lung cancer (LC) improves patient outcomes, but current methods have limitations. Autoantibodies against tumor-associated antigens have potential as early biomarkers. This study evaluated the 9G testTM Cancer/Lung, measuring circulating complexes of two antigen–autoantibody immune complexes (AIC) against their respective free antigens (CYFRA 21-1 and p53) for LC diagnosis. We analyzed 100 LC patients and 119 healthy controls using the 9G testTM Cancer/Lung, quantifying the levels of AICs (CYFRA 21-1-Anti-CYFRA 21-1 autoantibody immune complex (CIC) and p53-Anti-p53 autoantibody immune complex (PIC)), free antigens (CYFRA 21-1 and p53), and ratios of AICs/antigens (LC index). The levels of the CICs and PICs were significantly elevated in LC compared to the controls (p < 0.0062 and p < 0.0026), while free antigens showed no significant difference. The CIC/CYFRA 21-1 and PIC/p53 ratios were also significantly higher in LC (all, p < 0.0001). The LC index, when combining both ratios, exhibited the best diagnostic performance with an area under the curve (AUC) of 0.945, exceeding individual CICs, PICs, and free antigens (AUCs ≤ 0.887). At a cut-off of 3.60, the LC index achieved 81% sensitivity and 95% specificity for LC diagnosis. It detected early-stage (Stage I–II) LC with 87.5% sensitivity, exceeding its performance in advanced stages (72.7%). The LC index showed no significant differences based on age, gender, smoking status (former, current, or never smoker), or pack years smoked. The LC index demonstrates promising potential for early LC diagnosis, exceeding conventional free antigen markers. [ABSTRACT FROM AUTHOR]

Background: There is a need for searching for biomarkers indicating patients who will benefit the most from treatment with omalizumab for chronic spontaneous urticaria (CSU). The aim of this study was to assess whether the eosinophil/neutrophil/platelet/basophil-to-lymphocyte ratio (ELR, NLR, PLR, BLR) may predict the response to omalizumab treatment of chronic spontaneous urticaria. Methods: A retrospective data analysis of CSU patients treated s-c with 300 mg of omalizumab every four weeks under the drug program was carried out. NLR, ELR, PLR and BLR, DLQI, UAS-7, CRP, anti-TPO and tIgE were assessed before (V0) and after three (V3) and six months (V6) of treatment. Results: Among 52 patients with CSU, 21 were responders, 24 were partially responders and 6 were non-responders to treatment with 300 mg omalizumab every four weeks. An amount of 18 patients had features of type I autoallergic CSU (CSUaiTI) and 34 patients had autoimmunity type IIb CSU with mast cell-directed activating autoantibodies (CSUaiTIIb). NLR, ELR, PLR and BLR indices did not change during a six-month-course of biological treatment. Initial values of ELR and BLR were significantly correlated with the initial tIgE level and anti-TPO/IgE ratio. Initial values of NLR, ELR and BLR were significantly correlated with initial CRP. Comparisons between type I autoallergic CSU (CSUaiTI) and autoimmunity type IIb CSU (CSUaiTIIb) revealed that the absolute number and percentage of eosinophils, basophils, BLR and tIgE were significantly higher in type CSUaiTI and anti-TPO and anti-TPO/IgE were significantly lower in type CSUaiTI. Conclusions: NLR, ELR, PLR and BLR do not change significantly during six months of omalizumab treatment and do not appear to be useful in predicting its efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Two distinct chronic spontaneous urticaria (CSU) endotypes, IgE-mediated autoallergic and IgG-mediated autoimmune, were defined based on the response patterns to omalizumab. However, the coexistence of IgE and IgG autoantibodies in a subset of patients might complicate the prediction of the treatment outcomes. This study aimed to evaluate the effectiveness and safety of omalizumab in CSU patients, focusing on the factors predicting the response patterns. Methods: This was a retrospective cross-sectional single-center study investigating CSU patients treated with omalizumab for at least 6 months between September 2015 and February 2023. Patients were evaluated regarding demographics, clinical findings, baseline laboratory parameters, treatment outcomes, and side effects. Early and late responders were defined depending on the time for response, within or after 3 months, respectively. Results: Among 82 patients, 75 (91.5%) responded to omalizumab during the first 6 months, classified as early (n = 51) and late responders (n = 24). The IgG anti-thyroid peroxidase (anti-TPO)/total IgE ratio was an independent predictor for determining the speed of response (p < 0.05). Of 29 patients who discontinued omalizumab, 19 (65.5%) experienced relapse with a good response to retreatment (n = 18/19, 94.7%). Early responders relapsed more frequently than late responders (77.3% vs. 28.6%) (p < 0.05). Only mild side effects were observed in a minority of patients (n = 8/82, 9.8%). Conclusion: Omalizumab is an effective and safe treatment in CSU. The IgG anti-TPO/total IgE ratio seems a valuable tool to predict the early and late responders, the former having a higher possibility of relapse upon drug withdrawal. [ABSTRACT FROM AUTHOR]

Objective Anti-melanoma differentiation–associated gene 5 (Anti-MDA5)–positive DM is a rare but life-threatening autoimmune disorder that is associated with a high risk of developing rapidly progressive interstitial lung disease. Current empirical therapies offer limited benefit in terms of patient survival, as little is known about the aetiology of anti-MDA5 DM. To best understand its immune landscape, we applied single-cell RNA sequencing (scRNA-seq) to peripheral blood samples from DM patients and healthy controls. Methods Peripheral blood mononuclear cells (PBMCs) from eight DM patients (including three distinct subtypes of DM) and two healthy donors were sequenced using the 10X Genomics platform. Additional scRNA-seq data for four healthy donors were incorporated for further bioinformatic analysis. Results Aberrantly increased proportions of CD14+ monocytes and plasma cells were observed in anti-MDA5 DM PBMC samples. Moreover, we found an overactivated type I IFN response and antiviral immunity in both innate and adaptive immune cells derived from anti-MDA5 DM patients that was positively correlated with disease severity. Importantly, a unique subset of CD14+ monocytes that highly expressed IFN alpha–inducible protein 27 (IFI27), a biomarker for viral infection, and IFN induced with helicase C domain 1 (IFIH1 , which encodes MDA5) was specifically identified in anti-MDA5 DM samples for the first time. Conclusion Our study has illustrated the peripheral immune cell atlas of a number of DM subtypes, has provided compelling evidence for a viral infection–derived origin for anti-MDA5 DM, and has indicated potential targets for innovative therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objectives To investigate, in anti-CCP antibody–positive individuals with musculoskeletal symptoms but no clinical synovitis (CCP+ at-risk), the additional value of US for the prediction of inflammatory arthritis. Furthermore, to define a concise US protocol for feasible risk prediction. Methods Demographic and clinical data were collected in 417 CCP+ at-risk (Leeds CCP cohort) with a baseline US scan assessing synovitis and bone erosions in 36 joints, and a follow-up duration ≥24 months. Multivariable binary regression models for inflammatory arthritis development at 24 months evaluated routine clinical variables associated with inflammatory arthritis alone ('clinical' model) and combined with a 36-joint US scanning protocol ('clinical-US extended' model). A 'clinical-US short' model was also developed. Results At 24 months, 92/417 (22.1%) CCP+ at-risk developed inflammatory arthritis (median time 7 months, interquartile range 3–12). The 'clinical-US extended' model performed better than the 'clinical' model [area under the curve (AUC) 0.788 vs AUC 0.731, respectively, P  < 0.001] with an odds ratio for inflammatory arthritis development of 3.18 (95% CI 1.80–5.63) for US synovitis and 2.54 (95% CI 1.21–5.37) for bone erosions. The 'clinical-US short' model, which retained the wrists, knees and MTP5 joints, performed better (AUC 0.782) than the 'clinical' model (P  < 0.001) and similarly (difference in Akaike information criteria <2) to the 'clinical-US extended' model. Conclusions US provides valuable information for predicting progression to inflammatory arthritis in CCP+ individuals both alone and in addition to clinical variables. US synovitis was associated with a 3-fold increase risk of inflammatory arthritis development. A concise US protocol of six joints provides clinically feasible risk prediction in CCP+ at-risk. [ABSTRACT FROM AUTHOR]

Objectives Systemic sclerosis (SSc)-specific autoantibodies allow the diagnosis and predict the prognosis of SSc patients with different clinical characteristics. The aim of this study was to describe new SSc-related autoantibodies by a novel protein immunoprecipitation (IP) assay. Methods Serum samples and clinical data were collected from 307 SSc patients. Antinuclear autoantibodies were tested in all patients by indirect immunofluorescence (IIF) on HEp-2 cells. SSc-specific autoantibodies were evaluated with a commercial immunoblot and chemiluminescence immunoassay, and traditional RNA-IP. Patients negative for all these autoantibodies (n  = 51) were further tested with a non-radioactive protein IP assay. Protein bands detected on SDS–PAGE were then analysed by mass spectrometry (MS) and confirmed by western blot (WB). Additional 56 patients with nucleolar pattern by IIF were tested by protein IP-WB. Results Five patients who underwent protein IP testing showed a 110-115kDa molecular weight band on SDS–PAGE and a homogeneous nucleolar pattern by IIF. MS identified the bands as nuclear valosin-containing protein-like (NVL). An additional positive patient was detected by IP-WB. As compared with the remaining 101 negative patients, anti-NVL positive patients showed a greater prevalence of calcinosis (100% vs 18.9%, P  < 0.001), and cancer (66.7% vs 8.9%, P  = 0.002), with a particular association with synchronous cancer (OR = 16.3; P  = 0.024). Conclusion We identified NVL as a new autoantibody target by a novel protein IP assay in SSc patients with a homogeneous nucleolar IIF pattern, testing negative for all known SSc-specific autoantibodies by commercial assays and RNA IP. Anti-NVL identifies a new clinical phenotype, characterized by calcinosis and cancer. [ABSTRACT FROM AUTHOR]

Objectives To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM. Methods Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1γ/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash). Results In total 1054 patients were included (DM, n  = 405; ASyS, n  = 649). In the ASyS cohort, 31% (n  = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P  < 0.001), whereas higher frequency of any of four DM-type rashes—heliotrope rash (n  = 248, 61% vs n  = 90, 44%), violaceous rash (n  = 166, 41% vs n  = 57, 9%), V-sign (n  = 124, 31% vs n  = 28, 4%), and shawl sign (n  = 133, 33% vs n  = 18, 3%)—differentiated DM from ASyS-DMskin (all P  < 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n  = 67, 17%) compared with ASyS (n  = 21, 3%) and ASyS-DMskin (n  = 7, 3%) cohorts (both P  < 0.001). Conclusion DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management. [ABSTRACT FROM AUTHOR]