Specific Autoantibodies Research Articles

Determination of specific autoantibodies in patients with systemic lupus erythematosus by Line immunoassay, ELISA and CLIF assay.

Detection of specific antinuclear-antibodies is very importance in term of diagnosis, prognosis and management of patients with systemic lupus erythematosus (SLE). To date, Line immunoassay (LIA), enzyme-linked immunosorbent assay (ELISA) and Crithidia luciliae indirect immunofluorescence (CLIF) assay are commonly used for detection of specific antinuclear-antibodies. To determine the performance of LIA, ELISA and CLIF for the detection of anti-double-stranded DNA (dsDNA), anti-nucleosome, and anti-extractable nuclear antigens (ENA) antibodies in patients with SLE. A total 100 sera from 50 patients with SLE, 25 patients with disease control and 25 healthy control subjects were tested for anti-dsDNA, anti-nucleosome, and anti-ENA antibodies by LIA, ELISA, and CLIF assay. Agreement and diagnostic performance of each assay were analyzed using Cohen's kappa coefficient and receiver operating characteristic curve analysis. For the detection of anti-dsDNA antibody, ELISA had a substantial agreement with CLIF assay (? = 0.74) but LIA had a fair agreement with ELISA and CLIF assay (? = 0.37, and 0.35 respectively). For the detection of anti-nucleosome, anti-nRNP/Sm, anti-Sm, anti-SSA, and anti-SSB antibodies, LIA had a substantial to perfect agreement with ELISA (? = 0.64, 0.78, 0.68, 0.91, and 0.74, respectively). Anti-dsDNA-NcX ELISA and anti-dsDNA CLIF assay had equally diagnostic performance (sensitivity, 66% vs. 68%, and specificity, 96% vs. 94%, respectively) whereas, anti-dsDNA LIA has low sensitivity (22%) but high specificity (100%). LIA, ELISA, and CLIF demonstrated comparable performance for the detection of specific antinuclear-antibodies. However, there were some discrepancy between assays particularly in the detection of anti-dsDNA antibody.

Juvenile dermatomyositis, the dermatologist's point of view

Juvenile dermatomyositis is a rare multi-system auto-immune disease, particularly causing inflammation of skin and muscles of children. The diagnosis is based on the clinical picture with typical cutaneous lesions, which frequently are the first signs of the disease in contrast to muscle involvement. Muscular MRI is nowadays the first line investigation to diagnose myositis. Recently specific auto-antibodies have been detected allowing a better understanding of the disease and being important prognostic factors. An early diagnosis and aggressive treatment is crucial to induce remission of the disease, especially restore muscular function and to prevent severe complications such as calcinosis and lipodystrophy, which are difficult to treat as well as vital organ dysfunction.

SPECTRUM OF CLINICAL MANIFESTATIONS, AUTOANTIBODIES AND LEVELS OF INFLAMMATORY MARKERS IN MEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Relevance. The proportion of men among patients with systemic lupus erythematosus (SLE) is only 4-22%, but possible differences in the context of the clinical course and prognosis of the disease in this group of patients require more detailed study.
 Objective: to assess the spectrum of clinical manifestations, autoantibodies and the level of inflammatory markers in men with SLE.
 Materials and methods. 371 patients with SLE were examined, including 321 women (86.5%) and 50 men (13.5%). Clinical data, SLEDAI index and SLICC/DI damage, levels of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) and spectrum of specific autoantibodies (antibodies to dsDNA, Sm, Ro/SSA, La/SSB, RNP, antiphospholipid antibodies) were evaluated.
 Results. Alopecia (18.0% vs 33.0%; p=0.036) and arthralgia (22.0% vs 40.0%; p=0.016) were significantly less common in men with SLE. In contrast, nephritis with nephrotic syndrome was more than three times more common in male SLE patients (14.3%) than in women (4.1%; p=0.032). There was also a difference in the frequency of serositis: men were significantly more likely to have pleurisy (36.7%) than women (21.6%; p=0.044). Nervous system involvement was less common in men (12.0% vs 29.6%; p=0.007), as well as Raynaud's syndrome (16.0% vs 29.8%; p=0.05) and Sjogren's syndrome (0% vs 8.0%, p=0.023) compared with women. However, trophic ulcers were three times more common in men with SLE (14.3% vs 3.5%; p=0.019). Involvement of the mononuclear phagocyte system, heart, lungs, constitutional symptoms, antiphospholipid syndrome, hematological manifestations did not differ significantly between the representatives of both sexes. There were also no gender differences in SLEDAI indices and SLICC damage, erythrocyte sedimentation rate, C-reactive protein, C3, C4 complement levels. Antibodies to Ro/SSA were significantly less common in male SLE patients than in women (23.1% and 58.5%, respectively, p=0.033).
 Conclusions. Men with SLE are less likely to have alopecia, arthralgia, Raynaud's syndrome, nervous system involvement and Sjogren's syndrome than women. However, males with SLE are more likely to have kidney disease with nephrotic syndrome, pleuritis and trophic ulcers. Presence of anti-Ro/SSA antibodies in men with SLE is less common than in women.

Scleroderma specific autoantibodies in rheumatoid arthritis and Sjögren's syndrome patients with interstitial lung disease: Prevalence and associations

Systemic sclerosis (SSc) has been classically linked to interstitial lung disease (ILD) development, often in association with specific SSc autoantibodies. In the present report, we aimed to estimate the prevalence of SSc autoantibodies in 60 seropositive RA and 41 primary SS patients complicated or not by ILD. SSc autoantibodies were determined in patients’ sera by a commercial immunoblot assay. RA ILD patients displayed higher frequency of SSc-specific antibodies at strong titers compared to RA-with no lung involvement (25% vs 3.1%, p = 0.01)[OR 95% CI:10.9 (1.2–94.5)], with no differences detected between primary SS groups. These data indicate that many seropositive RA ILD patients probably represent an overlap RA/SSc entity, requiring tailored diagnostic and therapeutic approach.

Determinants of health-related quality of life across the spectrum of connective tissue diseases using latent profile analysis: results from the LEAP cohort.

Poor health-related quality of life (HRQoL) is well recognized in patients with CTD. We hypothesized that subgroups of patients across the spectrum of CTD experience different HRQoL patterns and aimed to determine patient-level characteristics associated with these different subgroups. Using the eight continuous domains of the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire we performed data-driven clustering to derive latent profiles (LPs) of patients with distinct HRQoL patterns. Multivariable ordinal logistic regression was used to determine patient-level characteristics associated with each HRQoL subgroup identified. A total of 309 CTD patients completed the SF-36 questionnaire. The most impaired SF-36 domains in each disease group were vitality, general health and bodily pain. The physical component of the SF-36 was consistently more impaired compared with the mental component, with similar scores across disease groups. Three LPs were identified with poor [n = 89 (29%)], average [n = 190 (61.4%)] and excellent [n = 30 (9.7%)] HRQoL. LPs were not associated with diagnostic grouping or autoantibody profiles. Black background [odds ratio (OR) 0.22 (95% CI 0.08, 0.63)], Indo-Asian background [OR 0.39 (95% CI 0.19, 0.78)], concomitant fibromyalgia [OR 0.40 (95% CI 0.20, 0.78)], sicca symptoms [OR 0.56 (95% CI 0.32, 0.98)] and multimorbidity [Charlson Comorbidity Index; OR 0.81 (95% CI 0.67, 0.97)] were associated with the 'poor' HRQoL LP. Distinct HRQoL subgroups exist that are not primarily driven by a specific diagnosis or autoantibody profiles. We identified a number of key demographic and clinical factors associated with poor HRQoL. These factors need to be addressed across the whole CTD spectrum as part of a holistic management approach aimed at improving overall patient outcomes.

Malignant complications of celiac disease: a case series and review of the literature

BackgroundCeliac disease is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. Diagnosis is based on evaluating specific autoantibodies and histopathologic findings of duodenal biopsy specimens. The only therapy for celiac disease is a gluten-free diet. Celiac disease can be complicated by malnutrition, other autoimmune diseases, refractoriness to treatment, and gastrointestinal tumors. This article presents seven cases of malignancies in patients with celiac disease. Its objective is to raise awareness of the malignant complications of celiac disease, leading to earlier diagnosis and improved outcomes.Case presentationSeven cases of malignant complications of celiac disease occurred among 190 patients followed at the Department of Internal Medicine and Gastroenterology, University Hospital Brno from 2014 to 2021. We describe these cases and the presentation, diagnostic process, course, management, and outcomes for each, along with proposed potential risk factors of malignant complications. There was one Caucasian man who was 70 years old and six Caucasian women who were 36, 46, 48, 55, 73, and 82 years old in our cohort. Of the seven cases of malignancies in our cohort, four patients were diagnosed with small bowel adenocarcinoma, one with diffuse large B-cell lymphoma, one with carcinoma of the tongue, and one with colorectal carcinoma.ConclusionsMalignancies occurred in 3.7% of patients followed up for celiac disease. Awareness of the malignant complications of celiac disease, risk factors, presentation, and disease course could lead to earlier diagnosis and improved outcomes.

The third inactivated vaccine booster dramatically enhanced SARS-CoV-2 antibody responses and did not influence the profile of prothrombotic antibody.

The purpose of this study is to investigate the production of both severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2)-specific antibodies and autoantibodies in serum following the third booster vaccination of the inactivated COVID-19 vaccine, and to study the effect of B cell subsets with CD27 and CD38 phenotypes in peripheral blood on antibody production.Routine blood indexes, SARS-CoV-2 antibodies, platelet factor 4 and seven antiphospholipid antibodies were detected both before and 2 months after vaccination in the medical staff of the Zhongnan Hospital of Wuhan University. Peripheral blood B cell subtypes were detected before vaccination.Following immunization, the positive rate of anti-N-S1 immunoglobulin (IgG) had increased from 24.8% to 91.3% and the average antibody concentration had increased by 11 times. The positive rate of neutralizing antibodyhad increased from 24.8% to 91.3%, the average antibody concentration had increased by 12 times, and the primary increased anti-S1 IgG subtype was that of IgG1. Peripheral blood CD27 + CD38+B cells were positively correlated with antibody levels after vaccination and were a predictor of the antibody response. In addition, although some indicators showed slight absolute changes, the blood parameters and antiphospholipid antibodies of most volunteers were normal both before and after COVID-19 inactivated vaccine inoculation, and there was no statistical difference in abnormal rates either before or after inoculation.Antibodies in vivo were increased after vaccination with the inactivated vaccine, and IgG1 was the main subtype involved in response to the vaccine. Vaccination with the inactivated COVID-19 vaccine did not appear to affect thrombus-related autoantibodies.

Caveolae-Associated Protein (cavin)-4 Autoantibodies in Immune Mediated Rippling Muscle Disease

Objective To describe a novel autoantibody biomarker of Immune mediated rippling muscle disease (iRMD). Background iRMD is a rare immunotherapy-responsive myopathy characterized by wave-like muscle contractions (rippling) and percussion/stretch-induced muscle mounding. However, serological biomarker of this disease is lacking. Design/Methods A Retrospective review was done to identify iRMD patients with stored sera in Mayo Neuroimmunology laboratory. Archived sera from IRMD patients were evaluated for a common biomarker of IRMD using phage immunoprecipitation sequencing (PhIP-Seq). Results Archival sera from 10 patients with clinical diagnosis of iRMD were retrieved. Whole human proteome PhIP-Seq identified peptides corresponding to different regions of the cavin-4 in sera of iRMD patients. Eight of the ten iRMD cases were positive for cavin-4 IgG by immunofluorescent cell-based-assay (CBA) using cavin-4-transfected COS7 cells. The cavin-4-reactive IgG in all 8 positive sera was of IgG1 subclass. None of the disease control sera (98 immune-mediated myopathy/neuromuscular junction disorders, 20 autoimmune CNS diseases and 123 healthy subjects) contained cavin-4-reactive IgG. Furthermore, none of the iRMD patients' sera were positive for caveolin-3 IgG. The majority of seropositive cases were males (6/8, 75%) with median age of 51 years (range 18-76). Three seropositive patients had co-existing myasthenia gravis (38%). Creatine Kinase was elevated in 6/7 tested patients (median 771 U/L, range: 132-2625 U/L). Muscle biopsy was performed in 7 of the 8 cavin-4 IgG seropositive patients; 6/6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 seropositive patients who received immunotherapy had complete resolution of symptoms; one had mild improvement and two had no change. Conclusions Cavin-4 IgG is a novel and specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in iRMD patient muscle biopsies suggests the potential role of this autoantigen in disease pathogenesis.

Vibrance-mg: Clinical Trial of Nipocalimab in Pediatric Myasthenia Gravis

Objective We describe an open-label study of nipocalimab to determine the effect of nipocalimab in pediatric participants with gMG. Background Nipocalimab is a high affinity, fully human, aglycosylated, effectorless IgG1 anti FcRn monoclonal antibody that targets the neonatal Fc receptor (FcRn) with high affinity, thereby lowering IgG pathogenic antibodies in autoimmune disease. Data from Vivacity-MG, a Phase 2, multicenter, randomized, double-blind, placebo-controlled study of nipocalimab demonstrated safety, tolerability, and efficacy of nipocalimab in adult generalized myasthenia gravis (gMG) (clinicaltrials.gov NCT03772587). Design/Methods This global study will enroll at least 12 participants, aged 2 to <18, with a diagnosis of gMG and an insufficient clinical response to ongoing, stable standard-of-care therapy, as reflected by a Myasthenia Gravis Foundation of America (MGFA) Class of IIa/b through IVa at screening. Participants must have a positive serologic test for either acetylcholine receptor or Muscle Specific Tyrosine Kinase pathogenic autoantibody. The study will consist of a screening period of up to 4 weeks, a 24-week open-label Active Treatment Phase where participants will receive nipocalimab intravenously every two weeks, and a Long-term Extension phase; after last dose, a safety follow-up assessment will be conducted at 8 weeks. The primary outcome is the effect of nipocalimab on total serum IgG, safety and tolerability, and PK in pediatric participants with gMG. Results Study enrollment will begin in 2022. Conclusions The vibrance-mg study will assess the PK/PD, safety and activity of Nipocalimab in pediatric gMG.

The importance of specific autoimmune disorders in the pathogenesis of psoriasis and the prospects of immunobiological therapy of dermatosis

Objective — to analyze the features of specific autoimmune disorders in patients with psoriasis, determine their importance in the pathogenesis of this dermatosis, and assess the prospects of immunobiological therapy for dermatosis.
 Materials and methods. Based on an in-depth analysis of the results of modern special studies, the leading role of specific autoantigens and autoantibodies in the body of patients with this dermatosis has been confirmed in the pathogenesis of psoriasis.
 Results and discussion. The article analyzes the importance of specific autoantigens, including keratin-17, LL-37, ADAMTSL5, and lipid antigens generated by PLA2G4D, which are essential in the pathogenesis of psoriasis. Emphasis is placed on the potential importance of immunobiological therapy, which significantly decrease levels of autoantigens LL-37 and ADAMTSL5 in areas of skin affected by psoriatic rash. The prospects of therapeutic approaches to the inhibition of cytokines derived from T cells and innate cells, such as IL-17, as well as to the inhibition of PLA2G4D or CD1a are also considered. Further study of specific autoimmune disorders in patients with psoriasis is important to improve therapeutic approaches to the treatment of psoriasis.
 Conclusions. Autoimmune disorders, combined with genetic and a number of other factors, are one of the important of the development of psoriasis. Analysis of the results of current special studies has promising therapeutic value because, in addition to supporting approaches to inhibiting cytokines derived from T cells and dendritic cells, they support the development of approaches to inhibiting autoantigens directly.

Characterization of Cardiac Bradyarrhythmia Associated With LGI1-IgG Autoimmune Encephalitis

Objective To evaluate and characterize cardiac arrhythmias associated with LGI1-IgG (Leucine-rich glioma inactivated 1–IgG) autoimmune encephalitis (AE). Background AE is increasingly identified as a potentially treatable cause of encephalitis. LGI1-IgG is one of the most common pathogenic neural specific autoantibodies associated with AE in adults. Prior cases of bradyarrhythmias and sudden death have been reported in LGI1-IgG AE, however, larger cohort studies are lacking. Design/Methods In this retrospective descriptive study, we identified Mayo Clinic patients (May 1, 2008–December 31, 2020) with LGI1-IgG AE who had electrocardiogram proven bradyarrhythmias during the initial presentation. Inclusion criteria were 1) LGI1-IgG positivity with a consistent clinical syndrome; 2) electrocardiographic evidence of bradyarrhythmia; and 3) sufficient clinical details. We excluded patients with alternate reason for bradyarrhythmias. We collected demographic/clinical data including details of bradyarrhythmia (severity, duration, treatments), and neurologic and cardiac outcomes. Results We found that patients with LGI1-IgG AE had bradyarrhythmia at a frequency of 8% during the initial presentation. The bradyarrhythmia was often asymptomatic (6/11, 55%); however, the episode was severe with one patient requiring a pacemaker. Outcome was also generally favorable with the majority (8/11, 73%) having full resolution without further cardiac intervention. Lastly, we found that mouse and human cardiac tissues express LGI1 (mRNA and protein), suggesting that LGI1-IgG may influence cardiac tissue itself. Conclusions LGI1-IgG AE can be rarely associated with bradyarrhythmias. Although the disease course is mostly favorable, some cases may require pacemaker placement to avoid devastating outcomes.

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies

ObjectivesAutoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM. MethodsPlasma samples from 217 patients with IIM according to 2017 EULAR/ACR criteria, including 50 patients with ASSD, 165 without, and two with unknown ASSD status were identified retrospectively, as well as age and gender-matched sera from 156 population controls, and 219 disease controls. Patients with previously documented ASSD had to test positive for at least one of the five most common anti-aaRS autoantibodies (anti-Jo1, -PL7, -PL12, -EJ, and -OJ) and present with one or more of the following clinical manifestations: interstitial lung disease, myositis, arthritis, Raynaud's phenomenon, fever, or mechanic's hands. Demographics, laboratory, and clinical data of the IIM cohort (ASSD and non-ASSD) were compared. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 117 recombinant protein variants, representing 33 myositis-related proteins, including all nineteen cytoplasmic aaRS. Prospectively collected clinical data for the IIM cohort were retrieved and compared between groups within the IIM cohort and correlated with the results of the autoantibody screening. Principal component analysis was used to analyze clinical manifestations between ASSD, non-ASSD groups, and individuals with novel anti-aaRS autoantibodies. ResultsWe identified reactivity towards 16 aaRS in 72 of the 217 IIM patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four previously seronegative patients for myositis-specific autoantibodies and eight with previously detected myositis-specific autoantibodies. IIM individuals with novel anti-aaRS autoantibodies (n = 12) all had signs of myositis, and they had either muscle weakness and/or muscle enzyme elevation, 2/12 had mechanic's hands, 3/12 had interstitial lung disease, and 2/12 had arthritis. The individuals with novel anti-aaRS and a pathological muscle biopsy all presented widespread up-regulation of major histocompatibility complex class I. The reactivities against novel aaRS could be confirmed in ELISA and western blot. Using the multiplex bead array assay, we could confirm previously known reactivities to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n = 45)) and identified patients positive for anti-Zo, -KS, and -HA (n = 10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was also detected in controls. ConclusionOur results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.

Micro Rnas as Potential Biomarkers for Early-Stage Diagnosis of Hyperglycemia Induced Cardiac Autoimmunity

In autoimmune disorder of Type 1 diabetes mellitus (T1DM), T cells mediated destruction of pancreatic beta cells results in insulin deficiency leads to hyperglycemia. Hyperglycemia induced autoimmunity develops oxidative stress, disrupt endothelium function, causes inflammation by upregulating C- reactive proteins, free fatty acids, and inflammatory cytokines in blood, and cardiac specific autoantibodies result in death of cardiomyocytes. There is a need to further evaluate the relation between hyperglycemia, cardiac autoimmunity, inflammation and find effective target to diagnose cardiac autoimmunity at early stage before progression to heart failure. Micro RNAs (miRNAs) are known to regulate post transcriptional expression of their target genes. We used gene target registry (GTR) for finding genes involved in hyperglycemia induced cardiac autoimmunity. Different miRNAs targeting these genes were identified by using bioinformatics tools NCBI, miRanda, TargetScan, miRBase, and TarBase. With the help of these bioinformatics repositories, we found following genes and their putative miRNAs that targets them by binding at 8mer units: TP53 (let-7i-5p, miR-98-5p), VEGFA (miR-15a-5p, miR-195-5p, miR-424-5p, miR-497-5p, miR-29a-3p), RUNX1 (miR-27a-3p, miR-30a-5p, miR-18a-5p), IGF1 (miR-1-3p, miR-206, miR-29a-3p, let-7a-5p, miR-98-5p, miR-130a-3p, miR-29a-3p), STAT3 (miR-124-3p.1, miR-125a-5p), PTEN (miR-26a-5p, miR-148a-3p, miR-29a-3p, miR-19a-3p, miR-25-3p, miR-22-3p, miR-26a-5p), MAPK14 (miR-128-3p, miR-124-3p.1, miR-124-3p.2, miR-506-3p), PPARG (miR-130b-3p, miR-301a-3p, miR-454-3p), FOXO1 (miR-96-5p, miR-1271-5p, miR-135a-5p), TNFRSF1B (let-7a-5p, miR-98-5p), TCF7L2 (miR-96-5p, miR-1271-5p), PRKCD (miR-26a-5p), ANXA2 (miR-1-3p, miR-206), INSR (let-7a-5p, miR-98-5p), TET2 (miR-153-3p, miR-29a-3p, miR-26a-5p, miR-29a-3p, miR-148a-3p, miR-152-3p), ENTPD1 (miR-135a-5p). In conclusion, we predict that given miRNAs can be investigated as potential miRNA-based early-stage diagnostic biomarkers for the hyper glycemia induced cardiac autoimmunity.

Association Between Neuropsychiatric Symptoms and Blood‐Based Autoantibody Biomarkers

AbstractBackgroundNeuropsychiatric symptoms are frequently observed along the Alzheimer disease (AD) continuum. Recent research has shown that blood‐based biomarkers are able to identify early AD‐related pathological changes associated with (1) preclinical AD (before the onset of clinical/functional symptoms), (2) mild cognitive impairment (MCI; with clinical symptoms and relatively spared functional decline), and (3) AD (obvious clinical and functional symptoms). Evidence for the potential diagnostic utility of serum autoantibodies has been extensively studied. The purpose of this study is to explore whether blood levels of specific autoantibodies used in the diagnostic biomarkers panels are linked with specific behavioral changes observed along the AD continuum.MethodUsing a customized panel of three AD‐specific autoantibody biomarkers and Luminex xMAP® technology, sera from patients (n=46; female = 30, mean age = 73.4) from the Memory and Aging Program at Rowan University were analyzed. All patients, irrespective of diagnosis (cognitively normal, MCI, AD) were included. The Neuropsychiatric Inventory (NPI) was used to gather data pertaining to neuropsychiatric symptoms. Partial correlations, controlling for age and education, for each neuropsychiatric symptom was employed.ResultTwo of the three autoantibody biomarkers showed an association with neuropsychiatric symptoms. Biomarkers 2 and 3 both showed a significant correlation with total neuropsychiatric score (r= .255, p= .047; r= .345, p= .01, respectively). Delusions, hallucinations, depression, anxiety, and irritability symptoms were not associated with either biomarker. Biomarker 2 was associated with apathy (r= .365, p=.007), agitation (r= .345, p= .011), disinhibition (r=.316, p=.018), and appetite changes (r= .302, p= .023). Biomarker 3 was associated with elation (r= .328, p= .015), aberrant motor behaviors (r= .331, p=.014), sleep behaviors (r= .483, p=.001), and appetite changes (r= .372, p=.006).ConclusionResults demonstrate an association between neuropsychiatric symptoms often observed in the AD continuum and specific blood‐based autoantibody biomarkers using Luminex xMAP® bead‐based technology. The autoantibody biomarker panel serves as an accurate, non‐invasive, and inexpensive diagnostic screener for preclinical AD, MCI, and AD. These biomarkers can not only distinguish different stages of AD, typically diagnosed using cognitive/functional assessments, increased blood levels of specific autoantibody biomarkers are also associated with commonly observed neuropsychiatric features.

Anti-Ki/anti-PA28γ autoantibodies contribute to the HEp-2 indirect immunofluorescence nuclear speckled pattern.

Antinuclear antibodies (ANAs) are associated with several autoimmune diseases. Indirect immunofluorescence (IIF) on human epithelial type 2 (HEp-2) cells is the golden standard for ANA detection in the clinic. In case of a positive HEp-2 IIF test result, follow-up tests are done to determine autoantibody specificity. For a fraction of the HEp-2 IIF-positive samples, the nature of the autoantigens remains uncharacterized. Our objective was to characterize autoantigens in such samples. To characterize autoantigens in an unbiased way, we combined protein immunoprecipitation with liquid chromatography (LC) tandem mass spectrometry (MS/MS) sequencing. Using such approach we detected the Ki antigen, also referred to as PA28γ, in the immunoprecipitate of serum samples of three individuals with an autoimmune disease. The HEp-2 nuclear speckled IIF fluorescent signal of all three serum samples was abolished after pre-absorption of the serum with recombinant Ki antigen, confirming that autoantibodies against Ki underlie the HEp-2 IIF signal. Our data suggest that anti-Ki autoantibodies can underlie a nuclear speckled HEp-2 IIF pattern.

Clinical utility of nailfold capillaroscopy.

Nailfold capillaroscopy (NFC) is a simple noninvasive microscopic technique used to identify characteristic morphological abnormalities in the nailfold capillaries. The presence of this microvasculopathy appears to be of fundamental importance in the pathological processes that underlie the scleroderma spectrum disorders (including dermatomyositis and antisynthetase myositis). This review discusses the different methodologies and techniques in performing NFC and stresses the diagnostic utility achieved with simple 'bedside' techniques utilising the ophthalmoscope, dermatoscope or smart phone. Recent advances in reporting abnormal microvascular patterns and vascular metrics (e.g. capillary density and dropout) are discussed. The aetiopathogenesis of the microvasculopathy is currently unknown but its close association with Raynaud Phenomena and specific autoantibodies together with recent observations from sequential NFC allows speculations on its possible mechanism. Finally, future developments in the use of NFC as a possible biomarker in the management of the scleroderma spectrum disorders are discussed, with a recommendation that NFC becomes more widely available, particularly in rheumatological, immunological and dermatological practice. NFC provides a clinically accessible window on the pathologic process fundamental to scleroderma-related disease.

Psychopathology of psychiatric patients presenting autoantibodies against neuroglial antigens.

Autoantibody-mediated psychiatric disorder is often difficult to diagnose as the clinical features of psychiatric disorder associated with neural autoantibodies are often similar. Thus, it is of major relevance to investigate whether psychopathology can differentiate between both disease entities as a biomarker and help us in searching for specific autoantibodies associated with psychiatric symptoms. We enrolled 154 patients of the Department of Psychiatry and Psychotherapy of the University Medical Center Göttingen with psychopathology data and retrospectively evaluated their patient records using the classification systems AMDP (Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie) and HiTOP (Hierarchical Taxonomy of Psychopathology). We identified 35 psychiatric patients revealing autoantibodies in their serum and/or cerebrospinal fluid (CSF) and 119 with no autoantibodies. Relying on the AMDP system, many more psychiatric patients with serum autoantibodies (51%) had problems with orientation than those without autoantibodies (32%) (p < 0.05). Furthermore, fewer psychiatric patients with serum autoantibodies exhibited a blunted affect (11.4 vs. 32.8%, p < 0.01) and affective rigidity (20 vs. 45%, p < 0.01). In particular, psychiatric patients presenting CSF autoantibodies (indicating an autoimmune symptomatic basis) experience more loss of vitality (5%) than those without autoantibodies (0%) (p < 0.05). Another interesting finding is that according to the AMDP classification, a manic syndrome is much more frequent in autoantibody-positive (8.6%) than autoantibody-negative psychiatric patients (0.8%) (p < 0.05). Another aspect is the more frequent occurrence of attention and memory deficits in patients with autoantibodies against intracellular targets compared with targets on the membrane surface. Our findings indicate that neural autoantibodies in psychiatric patients could indicate a phenotype more often characterized by a manic syndrome, orientation disturbances within the cognitive spectrum, and fewer affect disturbances characterized by less blunted affect and not as seriously impaired feelings of vitality compared to controls. The novelty of our approach is the extensive autoantibody tests for various psychiatric syndromes in combination with a profound psychometric measurement with two different scales.

Renal manifestations in vasculitides of small and medium-sized vessels

Small-vessel vasculitides, in particular, are frequently manifested in the kidneys. A distinction is made between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and immune complex vasculitides. Even within the AAVs there are differences with respect to renal involvement, which manifest as necrotizing glomerulonephritis (GN) but renal involvement is much rarer in eosinophilic granulomatosis with polyangiitis than in microscopic polyangiitis and granulomatosis with polyangiitis. Disease progression, organ manifestation and prognosis vary according to the ANCA status. In immune complex vasculitides (cryoglobulinemic vasculitis, IgA vasculitis, hypocomplementemic urticarial vasculitis and antiglomerular basement membrane, GBM, disease), endothelial-adjacent activation of neutrophilic granulocytes leads to local vessel wall damage with subsequent ischemic tissue damage, similar to AAV. The sparse evidence of immune complexes is different in pauci-immune AAV. Polyarteritis nodosa is adisease with variable clinical presentations with necrotizing vasculitis of small and medium-sized arteries. Intrarenal aneurysms and hemorrhages but not GN lead to renal damage. Diagnostically, the detection of specific autoantibodies (e.g. anti-GBM), cryoglobulins or increased complement turnover can be decisive. Renal biopsy with qualified immunohistopathology is particularly important in cases of initial manifestation and unclear constellation of findings. The treatment of renal vasculitis is adapted to the severity, stage of disease, extrarenal organ manifestation and pathogenesis. It ranges from glucocorticoid monotherapy to moderate immunosuppression, up to targeted biologic therapy, chemotherapy and plasmapheresis.

IgG subclass and Fc glycosylation shifts are linked to the transition from pre- to inflammatory autoimmune conditions.

A crucial factor for the development of inflammatory autoimmune diseases is the occurrence of antibodies directed against self-tissues and structures, which leads to damage and inflammation. While little is known about the cause of the development of mis-directed, disease-specific T and B cells and resulting IgG autoantibody responses, there is increasing evidence that their induction can occur years before disease symptoms appear. However, a certain proportion of healthy individuals express specific IgG autoantibodies without disease symptoms and not all subjects who generate autoantibodies may develop disease symptoms. Thus, the development of inflammatory autoimmune diseases seems to involve two steps. Increasing evidence suggests that harmless self-directed T and B cell and resulting IgG autoantibody responses in the pre-autoimmune disease stage might switch to more inflammatory T and B cell and IgG autoantibody responses that trigger the inflammatory autoimmune disease stage. Here, we summarize findings on the transition from the pre-disease to the disease stage and vice versa, e.g. by pregnancy and treatment, with a focus on low-/anti-inflammatory versus pro-inflammatory IgG autoantibody responses, including IgG subclass and Fc glycosylation features. Characterization of biomarkers that identify the transition from the pre-disease to the disease stage might facilitate recognition of the ideal time point of treatment initiation and the development of therapeutic strategies for re-directing inflammatory autoimmune conditions.

Differential Modes of Action of α1- and α1γ2-Autoantibodies Derived from Patients with GABAAR Encephalitis.

Autoantibodies against central nervous system proteins are increasingly being recognized in association with neurologic disorders. Although a growing number of neural autoantibodies have been identified, a causal link between specific autoantibodies and disease symptoms remains unclear, as most studies use patient-derived CSF-containing mixtures of autoantibodies. This raises questions concerning mechanism of action and which autoantibodies truly contribute to disease progression. To address this issue, monoclonal autoantibodies were isolated from a young girl with a range of neurologic symptoms, some of which reacted with specific GABAA receptor (GABAAR) subunits, α1-subunit and α1γ2-subunit, which in this study we have characterized in detail using a combination of cellular imaging and electrophysiological techniques. These studies in neurons from wild-type mice (C57BL/6J; RRID:IMSR_JAX:000664) of mixed-sex revealed that the α1 and α1γ2 subunit-specific antibodies have differential effects on the GABAA receptor. Namely, the α1-antibody was found to directly affect GABAA receptor function on a short time scale that diminished GABA currents, leading to increased network excitability. On longer time scales those antibodies also triggered a redistribution of the GABAA receptor away from synapses. In contrast, the α1γ2-antibody had no direct effect on GABAA receptor function and could possibly mediate its effect through other actors of the immune system. Taken together, these data highlight the complexity underlying autoimmune disorders and show that antibodies can exert their effect through many mechanisms within the same disease.