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Human inborn errors of the type I IFN response pathway and auto-Abs neutralizing IFN-α, -β, and/or -ω can underlie severe viral illnesses. We report a simple assay for the detection of both types of condition. We stimulate whole blood from healthy individuals and patients with either inborn errors of type I IFN immunity or auto-Abs against type I IFNs with glycosylated human IFN-α2, -β, or -ω. As controls, we add a monoclonal antibody (mAb) blocking the type I IFN receptors and stimulated blood with IFN-γ (type II IFN). Of the molecules we test, IP-10 (encoded by the interferon-stimulated gene (ISG) CXCL10) is the molecule most strongly induced by type I and type II IFNs in the whole blood of healthy donors in an ELISA-like assay. In patients with inherited IFNAR1, IFNAR2, TYK2, or IRF9 deficiency, IP-10 is induced only by IFN-γ, whereas, in those with auto-Abs neutralizing specific type I IFNs, IP-10 is also induced by the type I IFNs not neutralized by the auto-Abs. The measurement of type I and type II IFN-dependent IP-10 induction therefore constitutes a simple procedure for detecting rare inborn errors of the type I IFN response pathway and more common auto-Abs neutralizing type I IFNs. [ABSTRACT FROM AUTHOR]

Purpose: The pathogenesis of life-threatening coronavirus disease 2019 (COVID-19) pneumonia in ICU patients can involve pre-existing auto-antibodies (auto-Abs) neutralizing type I interferons (IFNs). The impact of these auto-Abs on SARS-CoV-2 clearance in the lower respiratory tract (LRT) is unclear. Methods: We performed a retrospective study in 99 ICU patients with COVID-19 pneumonia between March and May 2020. LRT SARS-CoV-2 load (intensity and duration) was analyzed according to the presence or not of circulating auto-Abs neutralizing type I IFNs. Results: Among the 99 included patients, 38 (38%) were positive for auto-Abs neutralizing type I IFNs, with 5 (5%) harboring auto-Abs neutralizing IFN-α2 at any concentration, while 33 (33%) had auto-Abs neutralizing only IFN-ω at the lower concentration. SARS-CoV-2 load in the LRT and duration of viral shedding, were similar in patients with or without auto-Abs neutralizing type I IFNs. Patients with auto-Abs had the same mortality than those without auto-Abs, despite greater occurrence of renal failure and ECMO support, and longer duration of mechanical ventilation and ICU stay. Conclusion: In summary, 5% of patients with critical COVID-19 pneumonia carried auto-Abs neutralizing IFN-α2, while about 1/3 harbored auto-Abs neutralizing low concentrations of IFN-ω. The detection of either type of auto-Abs did not impact LRT viral clearance and mortality, although it was associated with greater morbidity and a longer hospitalization. These findings suggest that similar albeit hitherto unknown mechanisms of disease drive critical COVID-19 pneumonia in patients without auto-Abs against type I IFNs. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSAs/MAAs) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD (n = 558). Our PH cohort (n = 121) showed a significantly higher prevalence of overall weak positive MSAs/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group (p < 0.001). Notably, MSAs/MAAs were found in PH patients both with and without ILD, though more prevalent in those with ILD. Anti-synthetase and anti-overlap syndrome antibodies were the most common. Our study is the first to systematically show a high MSA/MAA prevalence in PH without IIM presentation. This highlights the need to consider PH when diagnosing MSA/MAA-associated conditions. We recommend MSA/MAA screening for newly diagnosed PH, especially in those with ILD, for early detection and potential immunomodulatory treatment. Further research should explore the link between MSAs/MAAs and PH, and the value of monitoring patients with weak MSA/MAA positivity over time. [ABSTRACT FROM AUTHOR]

Acquired hemophilia is a rare but potentially life-threatening disorder characterized by the development of acquired hemophilia A, leading to bleeding complications. Spontaneous, mild-to-life-threatening bleeding in typically elderly individuals without a personal or family history of bleeding is the hallmark of acquired hemophilia A (AHA), a rare autoimmune bleeding illness caused by the formation of auto-antibodies against endogenous factor VIII (FVIII). This hallmark represents our present case, with no obvious history related to the bleeding issue. Prompt detection and treatment of bleeding are essential for the best outcomes. We present a case of a 66-year-old male who had acute-onset severe abdominal pain and with constipation for five days, associated with nausea and loss of appetite. On physical examination, the patient appeared pale, and abdominal examination revealed diffuse tenderness with guarding. Initial evaluation revealed tachycardia and hypotension. Initial abdomen X-rays revealed features suggestive of small bowel obstruction. The patient was stabilized with intravenous fluids, referred to a surgical team, and admitted to the acute bed in the general ward for further management. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the first involved joints and associated factors in Turkish patients with rheumatoid arthritis (RA). Patients and methods: This retrospective cross-sectional study included 300 newly diagnosed and disease-modifying antirheumatic drug-naïve RA patients (240 females, 60 males; mean age: 54±1.2 years; range, 18 to 82 years). Baseline demographic, clinical, and laboratory data were evaluated between January 2022 and December 2022. The patients were divided into four groups according to autoantibody profile: antibody-negative patients (Group 1; both RF and anti-CCP were negative in this group of patients), RF-positive patients (Group 2), anti-CCP-positive patients (Group 3), and patients with dual seropositivity with RF and anti- CCP (Group 4). The patients were also divided into two groups according to the size of the first affected joint: patients with SJI at diagnosis and patients without SJI involvement at diagnosis. Results: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibody positivity rates were 40.3% and 35.6%, respectively. The mean lag time to diagnosis was 25±36 months. At the disease onset, 20% of patients did not have small joint involvement (SJI). Seronegative patients tended to be female (p=0.001), had longer lag time (p=0.001), and had lower levels of C-reactive protein (p=0.025), white blood count (p=0.005), and neutrophil/lymphocyte ratio (p=0.001) compared to the dual seropositive group. Patients presenting with SJI had a younger age (p=0.002), tended to be female (p=0.001), and had lower RF (p=0.034) and anti-CCP (p=0.031) positivity. Only age (p=0.005) and dual seronegativity (RF and anti-CCP; p=0.035) were the independent predictors of SJI in multivariate analysis. Conclusion: The decreasing age and seronegative status were defined as independent risk factors of SJI at the onset of RA. Population-based, prospective studies are needed for earlier diagnosis. [ABSTRACT FROM AUTHOR]

A complex interaction among virulence factors, host-genes and host immune system is considered to be responsible for dengue virus (DENV) infection and disease progression. Generation of auto-antibodies during DENV infection is a major phenomenon that plays a role in the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. Hemostasis, thrombocytopenia, hepatic endothelial dysfunction, and autoimmune blistering skin disease (pemphigus) are different clinical manifestations of dengue pathogenesis; produced due to the molecular mimicry of DENV proteins with self-antigens like coagulation factors, platelets and endothelial cell proteins. This review elaborately describes the current advancements in auto-antibody-mediated immunopathogenesis which inhibits coagulation cascade and promotes hyperfibrinolysis. Auto-antibodies like anti-endothelial cell antibodies-mediated hepatic inflammation during severe DENV infection have also been discussed. Overall, this comprehensive review provides insight to target auto-antibodies that may act as potential biomarkers for disease severity, and a ground for the development of therapeutic strategy against DENV. [ABSTRACT FROM AUTHOR]

Les anticorps antinucléaires (ANA pour Anti-nuclear antibodies) sont en première ligne dans le diagnostic des connectivites dans notre pratique. Au-delà de leur utilité diagnostique et pronostique, ces biomarqueurs pourraient également avoir un rôle direct pathogénique. Ainsi, dans la sclérodermie systémique (ScS) les trois spécificités les plus fréquentes que sont les auto-anticorps (aAc) anti-topoisomérase-I (anti-TOPO-I ou Scl70), anti-centromères et anti-ARN polymérase-III sont intégrées dans la classification de la maladie. De nouvelles spécificités antigéniques sont également associées au diagnostic de la ScS. La chronologie d'apparition de ces auto-anticorps, leur corrélation à des phénotypes et/ou leur valeur pronostique, ainsi que l'efficacité de certaines biothérapies, plaident en faveur d'un rôle pathogénique de ces aAc au-delà de leur rôle de marqueur diagnostique. L'implication des ANA dans la physiopathologie de la ScS ouvre la voie à de nouveaux champs de recherche dans ce domaine. Anti-nuclear antibodies (ANA) are on the front line of diagnosing connective tissue disease. Beyond their diagnostic and prognostic utility, these biomarkers could also have a direct pathogenetic role. Thus, in systemic sclerosis the three most frequent specificities which are anti-topoisomerase-I aAb (anti-TOPO-I or Scl70), anti-centromeres and anti-RNA polymerase-III are integrated into the classification of the disease. New antigenic specificities are also associated with the diagnosis of systemic sclerosis. The time frame for theses autoantibodies appearance, their correlation with phenotypes and/or prognoses as well as the therapeutic efficacy of certain biotherapies argue in favor of a pathogenetic role of these aAb beyond their role as diagnostic marker. The involvement of ANA in the pathophysiology of SSc opens the way to new fields of research in this area. [ABSTRACT FROM AUTHOR]

Abstract Background Presence of autoantibodies against α-synuclein (α-syn AAb) in serum of the general population has been widely reported. That such peripheral factors may be involved in central nervous system pathophysiology was demonstrated by detection of immunoglobulins (IgGs) in cerebrospinal fluid and brain of Parkinson’s disease (PD) patients. Thus, blood-borne IgGs may reach the brain parenchyma through an impaired blood-brain barrier (BBB). Findings The present study aims to evaluate the patho-physiological impact of α-syn AAbs on primary brain cells, i.e., on spontaneously active neurons and on astrocytes. Exposure of neuron-astrocyte co-cultures to human serum containing α-syn AAbs mediated a dose-dependent reduction of spontaneous neuronal activity, and subsequent neurodegeneration. Removal specifically of α-syn AAbs from the serum prevented neurotoxicity, while purified, commercial antibodies against α-syn mimicked the neurodegenerative effect. Mechanistically, we found a strong calcium flux into neurons preceding α-syn AAbs-induced cell death, specifically through NMDA receptors. NMDA receptor antagonists prevented neurodegeneration upon treatment with α-syn (auto)antibodies. α-syn (auto)antibodies did not affect astrocyte survival. However, in presence of α-syn, astrocytes reacted to α-syn antibodies by secretion of the chemokine RANTES. Conclusion These findings provide a novel basis to explain how a combination of BBB impairment and infiltration of IgGs targeting synuclein may contribute to neurodegeneration in PD and argue for caution with α-syn immunization therapies for treatment of PD.

OBJECTIVE: This study aimed to describe the clinical spectrum of primary Sjögren's syndrome (pSS) patients with anti-Ro/ SS-A and anti-La/SS-B negativity. PATIENTS AND METHODS: From a single- center study population of consecutive SS patients fulfilling the 2016 ACR-EULAR classi- fication criteria, those with triple seronegativity anti-Ro/SS-A (anti--Sjögren's-syndrome-related antigen A autoantibody), anti-La/SS-B (anti-- Sjögren's-syndrome-related antigen B autoantibody), rheumatoid factor (RF) (-) and antinuclear antibody (ANA)(+)] or [anti-Ro/SS-A(-), anti- La/ SS-B(-), RF(+) and ANA(-)] and quadruple seronegativity [anti-Ro/SS-A(-), anti-La/SS-B(-), RF(-) and ANA(-)] were identified retrospectively. Clinical, serological, and laboratory features were compared. A comparison between triple and quadruple seronegative pSS patients was also performed. RESULTS: We included 184 patients (168 women, 16 men) with a mean age at diagnosis of 50.1±13.1 years. The most common subjective presenting features at the time of the diagnosis were dry mouth (94.5%) and dry eye (91.3 %). ANA positivity was 57.0%, and RF positivity was 30.4%. Salivary gland enlargement, arthritis, Raynaud's phenomenon, vasculitis, interstitial lung disease (ILD), neurological involvement, primary biliary cholangitis (PBC), lymphopenia, and thrombocytopenia were observed in ANA+ and RF+ patients but not in seronegative patients (p<0.0001). Arthritis was observed most frequently in RF-positive patients and secondly in ANA-positive patients, whereas arthritis was not observed in seronegative patients (p<0.0001). Autoimmune thyroiditis was present in 65 patients (35.0%), 84.6% of these patients were ANA positive while 12.3% were ANA negative (p=0.0014), RF positivity was 30.7% while RF negativity was 6.15% (p=0.001), 23.0% were both ANA and RF positive while 12.3% were seronegative (p<0.002). Cryoglobulinemia, renal disease, and lymphoma were not observed in any of the patients. CONCLUSIONS: We confirm the strong influence of immunological markers on the phenotype of primary SS at diagnosis. [ABSTRACT FROM AUTHOR]

Patients with decompensated liver cirrhosis, in particular those classified as Childs-Pugh class C, are at increased risk of severe coronavirus disease-2019 (COVID-19) upon infection with severe acute respiratory coronavirus 2 (SARS-CoV-2). The biological mechanisms underlying this are unknown. We aimed to examine the levels of serum intrinsic antiviral proteins as well as alterations in the innate antiviral immune response in patients with decompensated liver cirrhosis. Serum from 53 SARS-CoV-2 unexposed and unvaccinated individuals, with decompensated liver cirrhosis undergoing assessment for liver transplantation, were screened using SARS-CoV-2 pseudoparticle and SARS-CoV-2 virus assays. The ability of serum to inhibit interferon (IFN) signalling was assessed using a cell-based reporter assay. Severity of liver disease was assessed using two clinical scoring systems, the Child-Pugh class and the MELD-Na score. In the presence of serum from SARS-CoV-2 unexposed patients with decompensated liver cirrhosis there was no association between SARS-CoV-2 pseudoparticle infection or live SARS-CoV-2 virus infection and severity of liver disease. Type I IFNs are a key component of the innate antiviral response. Serum from patients with decompensated liver cirrhosis contained elevated levels of auto-antibodies capable of binding IFN-α2b compared to healthy controls. High MELD-Na scores were associated with the ability of these auto-antibodies to neutralize type I IFN signalling by IFN-α2b but not IFN-β1a. Our results demonstrate that neutralizing auto-antibodies targeting IFN-α2b are increased in patients with high MELD-Na scores. The presence of neutralizing type I IFN-specific auto-antibodies may increase the likelihood of viral infections, including severe COVID-19, in patients with decompensated liver cirrhosis. Serum from patients with decompensated liver cirrhosis inhibits type I interferon (IFN) signalling due to the presence of auto-antibodies capable of directly binding recombinant IFN-α2b. Depletion of IgG reverses the inhibition of type I IFN signalling. Our results demonstrate that type I IFN-neutralizing auto-antibodies are increased in a proportion of end-stage liver disease patients, which may increase the risk of viral infection in this patient cohort. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive T cells, auto-antibodies, reactivation of drug-specific T cells, and cytokine-driven inflammation culminating in AKI. ICI-AKI typically manifests weeks to months into treatment, often with other irAEs. Timely detection relies on monitoring creatinine levels and urine characteristics. Biomarkers, like soluble interleukin-2 receptor (sIL-2R) and urine cytokine levels, provide non-invasive insights, while renal biopsy remains the gold standard for confirmation. Management of ICI-AKI requires a balance between discontinuing ICI therapy and prompt immunosuppressive intervention, typically with corticosteroids. Some cases permit ICI therapy resumption, but varying renal recovery rates highlight the importance of vigilant monitoring and effective therapy. Beyond its clinical implications, the potential of irAEs to predict positive treatment responses in certain cancers raises intriguing questions. Data on nephritis–treatment response links are limited, and ongoing research explores this complex interaction. In summary, ICI therapy's transformative impact on cancer treatment is counterbalanced by irAEs, including nephritis. Early recognition and management are vital, with ongoing research refining diagnostic and treatment strategies. [ABSTRACT FROM AUTHOR]

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Auto-antibodies (Abs) to type I interferons (IFNs) are found in up to 25% of patients with severe COVID-19, and are implicated in disease pathogenesis. It has remained unknown, however, whether type I IFN auto-Abs are unique to COVID-19, or are also found in other types of severe respiratory illnesses. To address this, we studied a prospective cohort of 284 adults with acute respiratory failure due to causes other than COVID-19. We measured type I IFN auto-Abs by radio ligand binding assay and screened for respiratory viruses using clinical PCR and metagenomic sequencing. Three patients (1.1%) tested positive for type I IFN auto-Abs, and each had a different underlying clinical presentation. Of the 35 patients found to have viral infections, only one patient tested positive for type I IFN auto-Abs. Together, our data suggest that type I IFN auto-Abs are uncommon in critically ill patients with acute respiratory failure due to causes other than COVID-19.

Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSAs/MAAs) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD (n = 558). Our PH cohort (n = 121) showed a significantly higher prevalence of overall weak positive MSAs/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group (p < 0.001). Notably, MSAs/MAAs were found in PH patients both with and without ILD, though more prevalent in those with ILD. Anti-synthetase and anti-overlap syndrome antibodies were the most common. Our study is the first to systematically show a high MSA/MAA prevalence in PH without IIM presentation. This highlights the need to consider PH when diagnosing MSA/MAA-associated conditions. We recommend MSA/MAA screening for newly diagnosed PH, especially in those with ILD, for early detection and potential immunomodulatory treatment. Further research should explore the link between MSAs/MAAs and PH, and the value of monitoring patients with weak MSA/MAA positivity over time.

Background: Auto‐antibodies neutralizing the activity of type I interferons have been recently described in patients infected by SARS‐CoV‐2. They can be present even before the onset of the infection. Since type I interferons exert a dichotomous role in the pathogenesis of acute versus chronic HIV infection and auto‐antibodies are often found in untreated and anti‐retroviral treated HIV+ patients, we investigated whether auto‐antibodies anti‐type I interferons are present at high prevalence in those HIV+ patients with concomitant opportunistic infections (OIs). Methods: The analysis of auto‐antibodies against two types of type I interferons (IFN‐α2 and IFN‐ω) was performed using the ELISA test in 60 patients chronically infected by HIV who showed concomitant infections caused by mycobacterium tuberculosis or nontuberculosis mycobacterium or with active cytomegalovirus infections. Results were compared with those of 283 SARS‐CoV‐2 swab positive patients showing mild to severe pneumonia. A chi‐square (χ2) test or the Wilcoxon–Mann–Whitney test were used to compare the HIV+ patient categorical or continuous variables, respectively. Results: A high prevalence of auto‐antibodies to type I interferons was found in middle‐aged HIV‐infected patients with concomitant OIs (11.6% vs. 5.3% in COVID‐19 subjects; p <.05). No statistically differences were found for viro/immunological characteristics (CD4 and CD8 cell counts and viral load) between patients with and without type I interferons auto‐antibodies. Conclusions: This study, which is the first searching auto‐antibodies against type I interferons in HIV‐infected patients, demonstrated that their prevalence was higher than that expected by the age of these patients. Furthermore, it indicated that these auto‐antibodies are nonspecifically increased in critical SARS‐CoV‐2 infection but can be found also in other infections. [ABSTRACT FROM AUTHOR]

The presence of a certain group of auto-antibodies (AAbs) is known to correlate with the severity of COVID-19. It is, however, unknown if such AAbs are prevalent and impact COVID-19-related outcomes in lung transplant recipients (LTRs) who are immunosuppressed. We performed a retrospective study of LTRs with COVID-19 and analyzed samples before and after COVID-19 for IgG AAbs. AAbs analysis was carried out using autoimmune and coronavirus microarray and the resulting cross-sectional differences in Ab-scores and clinical variables were analyzed using Fischer's Exact test for categorical variables and a paired t-test for continuous variables. Linear regression was used to analyze the differences in Ab-scores and COVID-19 severity. LTRs with non-severe [NS gp (n = 10)], and severe [S gp (n = 8)] COVID-19 disease were included. Ferritin and acute respiratory failure were higher in the S group (p = 0.03; p < 0.0001). Among the AAbs analyzed, interferon-related AAbs (IFN-alpha2, IFN-beta, IFN lamba, IFN-epsilon), eight interleukin-related AAbs, and several tissue-related AAbs were also found to be changed significantly from pre- to post-COVID-19 (p < 0.05). IFN-lambda (p = 0.03) and IL-22 (p = 0.002) were significantly associated with COVID-19 severity and remained significant in linear regression analysis while controlling for other variables. AAbs are common in LTRs, and certain groups of antibodies are particularly enhanced in LTRs with severe COVID-19. Preliminary observations of this study need to be confirmed by a larger sample size. [ABSTRACT FROM AUTHOR]

La recherche des auto-anticorps (auto-Acs) est un outil précieux pour aider au diagnostic et suivre l'évolution de la maladie des patients affectés de maladies auto-immunes. Ils peuvent également apporter des éléments pronostiques précieux. De nombreux progrès scientifiques ont conduit à la découverte de nouveaux auto-Ac, notamment dans le domaine des myosites inflammatoires, améliorant la démarche diagnostique. Les outils technologiques ont également progressé, améliorant la standardisation des recherches. Toutefois, de nombreuses difficultés subsistent dans l'interprétation des résultats d'auto-immunité, tant sur le plan analytique que sur le plan de diagnostic. Cette revue a pour but de présenter ces difficultés et d'en expliquer les raisons qui tiennent, à la fois de la nature même de la réponse immunitaire, et des outils techniques utilisés pour la détection des auto-Acs. Enfin, nous terminerons par une présentation des grands enjeux à venir dans le domaine de l'auto-immunité biologique, et notamment de la place de l'intelligence artificielle. The search for autoantibodies (autoAbs) is a valuable tool to help in diagnosis, and follow the evolution of the disease of patients affected by autoimmune diseases. They can also provide helpful information's regarding the pronostic. Many scientific advances have led to the discovery of new autoAbs, particularly in the field of inflammatory myositis, improving the diagnostic approach. Technological tools have also progressed, improving the standardization of searches. However, many difficulties remain in the interpretation of autoimmune results, both analytically and diagnostically. The aim of this review is to present these difficulties and to explain the reasons that relate both to the very nature of the immune response and to the technical tools used for the detection of autoAbs. Finally, we will end with a presentation of the major challenges to come in the field of biological autoimmunity, and in particular the place of artificial intelligence. [ABSTRACT FROM AUTHOR]

Abstract Background Auto‐antibodies neutralizing the activity of type I interferons have been recently described in patients infected by SARS‐CoV‐2. They can be present even before the onset of the infection. Since type I interferons exert a dichotomous role in the pathogenesis of acute versus chronic HIV infection and auto‐antibodies are often found in untreated and anti‐retroviral treated HIV+ patients, we investigated whether auto‐antibodies anti‐type I interferons are present at high prevalence in those HIV+ patients with concomitant opportunistic infections (OIs). Methods The analysis of auto‐antibodies against two types of type I interferons (IFN‐α2 and IFN‐ω) was performed using the ELISA test in 60 patients chronically infected by HIV who showed concomitant infections caused by mycobacterium tuberculosis or nontuberculosis mycobacterium or with active cytomegalovirus infections. Results were compared with those of 283 SARS‐CoV‐2 swab positive patients showing mild to severe pneumonia. A chi‐square (χ2) test or the Wilcoxon–Mann–Whitney test were used to compare the HIV+ patient categorical or continuous variables, respectively. Results A high prevalence of auto‐antibodies to type I interferons was found in middle‐aged HIV‐infected patients with concomitant OIs (11.6% vs. 5.3% in COVID‐19 subjects; p

Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto‐antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto‐antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto‐antibodies are specific for either TG2 or TG3 with no TG2–TG3 cross reactivity. By generating monoclonal antibodies from TG3‐specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2‐specific and TG3‐specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase‐reactive populations show distinct selection of certain heavy and light chain V‐genes. Mass spectrometry analysis of TG3‐specific serum IgA corroborates preferential usage of IGHV2‐5 in combination with IGKV4‐1. Collectively, these results demonstrate parallel induction of anti‐TG2 and anti‐TG3 auto‐antibody responses involving separate B‐cell populations in DH patients. [ABSTRACT FROM AUTHOR]

Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8+ T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8+ TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs. [ABSTRACT FROM AUTHOR]

Abstract Background Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with versus without auto-Abs. Results We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2, β and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with versus without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiO2 (100% (70–100) vs. 90% (60–100), p = 0.01), but were not different in other characteristics. Mortality at day 28 was not different between patients with and without auto-Abs (18.7 vs. 23.7%, p = 0.279). In multivariable analysis, 28-day mortality was associated with age (adjusted odds ratio (aOR) = 1.06 [1.04–1.08], p

Abstract Auto-antibodies (Abs) to type I interferons (IFNs) are found in up to 25% of patients with severe COVID-19, and are implicated in disease pathogenesis. It has remained unknown, however, whether type I IFN auto-Abs are unique to COVID-19, or are also found in other types of severe respiratory illnesses. To address this, we studied a prospective cohort of 284 adults with acute respiratory failure due to causes other than COVID-19. We measured type I IFN auto-Abs by radio ligand binding assay and screened for respiratory viruses using clinical PCR and metagenomic sequencing. Three patients (1.1%) tested positive for type I IFN auto-Abs, and each had a different underlying clinical presentation. Of the 35 patients found to have viral infections, only one patient tested positive for type I IFN auto-Abs. Together, our data suggest that type I IFN auto-Abs are uncommon in critically ill patients with acute respiratory failure due to causes other than COVID-19.

To identify specific human leukocyte antigen (HLA)-Class II (DRB/DQB1/DPB1) alleles associated with systemic sclerosis (SSc) and to explore their relation with SSc autoantibodies, clinical manifestations, and disease subsets. HLA-class II alleles (DRB1/DRB3/DRB4/DRB5/DQB1) were determined by DNA typing in 80 SSc cases and 60 matched controls and HLA-DPB1 in 40 SSc patients and 30 controls by allele-specific-polymerase chain reaction with sequence-specific primers (PCR-SSP). The mean age of SSc patients was 36.9 ± 9.4 years; 76 females and 4 males (F:M 19:1) and a disease duration of 5.3 ± 3.3 years, they were 43(53.7%) limited and 37(46.2%) diffuse subtypes. SSc was significantly associated with DRB1*11, DRB1*01, DQB1*04, and DQB1*03*03 in a >4-fold manner, whereas DPB1*04 had a >7-fold increased risk compared to controls. There was a strong association between DRB1*11 (p = 0.04), DQB1*03*03 (p = 0.005), and DPB1*13 (p = 0.009) with anti-topoisomerase I (anti-topoI) whereas the frequency of DRB1*01 (p < 0.0001) was increased in patients with anti-centromere (ACA) positive SSc compared those negative (56% vs 25%; p < 0.0001). DRB1*03, DRB1*15, and DQB1*03*01 were SSc protective alleles in patients with positive ACA. Anti-topo I was associated with interstitial lung disease (ILD) (p < 0.01), whereas ACA with pulmonary arterial hypertension (PAH) (p = 0.01) and protection against ILD (p < 0.001). In addition, HLA-DRB1*03, DQB1*03*01and DPB1*03 were more frequent in patients with ILD than in patients without. Associations between specific HLA-class II alleles with certain SSc-specific autoantibodies (anti-topo I and ACA) were identified. Specific HLA associations with clinical and serological subtypes could serve as biomarkers of disease severity and progression in SSc. [ABSTRACT FROM AUTHOR]

Abstract Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto‐antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto‐antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto‐antibodies are specific for either TG2 or TG3 with no TG2–TG3 cross reactivity. By generating monoclonal antibodies from TG3‐specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2‐specific and TG3‐specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase‐reactive populations show distinct selection of certain heavy and light chain V‐genes. Mass spectrometry analysis of TG3‐specific serum IgA corroborates preferential usage of IGHV2‐5 in combination with IGKV4‐1. Collectively, these results demonstrate parallel induction of anti‐TG2 and anti‐TG3 auto‐antibody responses involving separate B‐cell populations in DH patients.

Myocarditis refers to inflammation of the myocardium caused by infectious and non-infectious process. It should be considered in any patient presenting with unexplained congestive heart failure, ventricular arrhythmias, atrial fibrillation or dilated cardiomyopathy . Prompt diagnosis and treatment is required, otherwise unrecognized myocarditis can rapidly progress to cardiogenic shock with increase in mortality and morbidity. Although various etiologies such as viruses and autoimmune phenomenon have been proposed, there are many unanswered questions regarding the underlying pathophysiology that initiate and trigger myocardial inflammation. These gaps in knowledge need to addressed by developing appropriate myocarditis disease models for understanding the interaction of initial insult, autoimmunity, and host genetics so as to develop novel therapeutic modalities that can halt the disease progression for better clinical outcomes. This review focuses on etiology, pathophysiology, symptomatology, diagnosis, treatment and directions of myocarditis. [ABSTRACT FROM AUTHOR]

Autoimmunity is a condition in which the immune system cannot recognize the self from nonself-antigens. Autoimmunity is relatively more common in females than males. The process of embryo implantation is considered the most significant restricting factor in female reproduction. The immunological system of the females may affect the success or failure of pregnancy by its effect on extremely important steps from ovulation to implantation processes, thus ensuring the importance of autoimmunity for women in sub-fertility. The association between autoimmunity and female reproduction receives increased attention nowadays. A successful conception is a result of multiple complex interactions between the developed embryo and the receptive uterus and is usually under immune-hormonal control. In certain circumstances, the female ovary can be a target of an autoimmune attack, like some organ-specific or systemic autoimmune disorders subsequently resulting in clinically significant ovarian dysfunction, implantation failure, and sub-fertility. Consequently, the effect of a specific auto-antibody on the etiology of infertility remains unknown. This review focused on auto-antibodies that may affect female fertility. [ABSTRACT FROM AUTHOR]

The presence of a certain group of auto-antibodies (AAbs) is known to correlate with the severity of COVID-19. It is, however, unknown if such AAbs are prevalent and impact COVID-19-related outcomes in lung transplant recipients (LTRs) who are immunosuppressed. We performed a retrospective study of LTRs with COVID-19 and analyzed samples before and after COVID-19 for IgG AAbs. AAbs analysis was carried out using autoimmune and coronavirus microarray and the resulting cross-sectional differences in Ab-scores and clinical variables were analyzed using Fischer’s Exact test for categorical variables and a paired t-test for continuous variables. Linear regression was used to analyze the differences in Ab-scores and COVID-19 severity. LTRs with non-severe [NS gp (n = 10)], and severe [S gp (n = 8)] COVID-19 disease were included. Ferritin and acute respiratory failure were higher in the S group (p = 0.03; p < 0.0001). Among the AAbs analyzed, interferon-related AAbs (IFN-alpha2, IFN-beta, IFN lamba, IFN-epsilon), eight interleukin-related AAbs, and several tissue-related AAbs were also found to be changed significantly from pre- to post-COVID-19 (p < 0.05). IFN-lambda (p = 0.03) and IL-22 (p = 0.002) were significantly associated with COVID-19 severity and remained significant in linear regression analysis while controlling for other variables. AAbs are common in LTRs, and certain groups of antibodies are particularly enhanced in LTRs with severe COVID-19. Preliminary observations of this study need to be confirmed by a larger sample size.

Background: Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with versus without auto-Abs. Results: We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2, β and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with versus without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiO2 (100% (70–100) vs. 90% (60–100), p = 0.01), but were not different in other characteristics. Mortality at day 28 was not different between patients with and without auto-Abs (18.7 vs. 23.7%, p = 0.279). In multivariable analysis, 28-day mortality was associated with age (adjusted odds ratio (aOR) = 1.06 [1.04–1.08], p < 0.001), SOFA score (aOR = 1.18 [1.12–1.23], p < 0.001) and immunosuppression (aOR = 1.82 [1.1–3.0], p = 0.02), but not with the presence of auto-Abs (aOR = 0.69 [0.38–1.26], p = 0.23). Conclusions: In ICU patients, auto-Abs against type I IFNs were found in at least 10% of patients with critical COVID-19 pneumonia. They were not associated with day 28 mortality. [ABSTRACT FROM AUTHOR]

Patients suffering from immune‐mediated necrotizing myopathies (IMNM) harbor, the pathognomonic myositis‐specific auto‐antibodies anti‐SRP54 or ‐HMGCR, while about one third of them do not. Activation of chaperone‐assisted autophagy was described as being part of the molecular etiology of IMNM. Endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR)‐stress accompanied by activation of the unfolded protein response (UPR) often precedes activation of the protein clearance machinery and represents a cellular defense mechanism toward restoration of proteostasis. Here, we show that ER/SR‐stress may be part of the molecular etiology of IMNM. To address this assumption, ER/SR‐stress related key players covering the three known branches (PERK‐mediated, IRE1‐mediated, and ATF6‐mediated) were investigated on both, the transcript and the protein levels utilizing 39 muscle biopsy specimens derived from IMNM‐patients. Our results demonstrate an activation of all three UPR‐branches in IMNM, which most likely precedes the activation of the protein clearance machinery. In detail, we identified increased phosphorylation of PERK and eIF2a along with increased expression and protein abundance of ATF4, all well‐documented characteristics for the activation of the UPR. Further, we identified increased general XBP1‐level, and elevated XBP1 protein levels. Additionally, our transcript studies revealed an increased ATF6‐expression, which was confirmed by immunostaining studies indicating a myonuclear translocation of the cleaved ATF6‐form toward the forced transcription of UPR‐related chaperones. In accordance with that, our data demonstrate an increase of downstream factors including ER/SR co‐chaperones and chaperones (e.g., SIL1) indicating an UPR‐activation on a broader level with no significant differences between seropositive and seronegative patients. Taken together, one might assume that UPR‐activation within muscle fibers might not only serve to restore protein homeostasis, but also enhance sarcolemmal presentation of proteins crucial for attracting immune cells. Since modulation of ER‐stress and UPR via application of chemical chaperones became a promising therapeutic treatment approach, our findings might represent the starting point for new interventional concepts. [ABSTRACT FROM AUTHOR]

Purpose: The pathogenesis of life-threatening coronavirus disease 2019 (COVID-19) pneumonia in ICU patients can involve pre-existing auto-antibodies (auto-Abs) neutralizing type I interferons (IFNs). The impact of these auto-Abs on SARS-CoV-2 clearance in the lower respiratory tract (LRT) is unclear., Methods: We performed a retrospective study in 99 ICU patients with COVID-19 pneumonia between March and May 2020. LRT SARS-CoV-2 load (intensity and duration) was analyzed according to the presence or not of circulating auto-Abs neutralizing type I IFNs., Results: Among the 99 included patients, 38 (38%) were positive for auto-Abs neutralizing type I IFNs, with 5 (5%) harboring auto-Abs neutralizing IFN-α2 at any concentration, while 33 (33%) had auto-Abs neutralizing only IFN-ω at the lower concentration. SARS-CoV-2 load in the LRT and duration of viral shedding, were similar in patients with or without auto-Abs neutralizing type I IFNs. Patients with auto-Abs had the same mortality than those without auto-Abs, despite greater occurrence of renal failure and ECMO support, and longer duration of mechanical ventilation and ICU stay., Conclusion: In summary, 5% of patients with critical COVID-19 pneumonia carried auto-Abs neutralizing IFN-α2, while about 1/3 harbored auto-Abs neutralizing low concentrations of IFN-ω. The detection of either type of auto-Abs did not impact LRT viral clearance and mortality, although it was associated with greater morbidity and a longer hospitalization. These findings suggest that similar albeit hitherto unknown mechanisms of disease drive critical COVID-19 pneumonia in patients without auto-Abs against type I IFNs., Competing Interests: Declarations. Ethics Approval and Consent to Participate: In accordance with current French law, informed written consent for demographic, physiologic and hospital-outcome data analyses was not obtained because this observational study did not modify existing diagnostic or therapeutic strategies. Nonetheless, patients and/or relatives were informed about the anonymous data collection and told that they could decline inclusion. The protocol was approved by the ethics committee of the Société de Réanimation de Langue Française (registration no. CE-SRLF-2093) and the database is registered with the Commission Nationale de l’Informatique et des Libertés (CNIL, registration no. 1950673). Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glutathione S-transferase omega-1 (GSTO1-1) is a cytosolic enzyme involved in the modulation of critical inflammatory pathways as well as in cancer progression. Auto-antibodies against GSTO1-1 were detected in the serum of patients with esophageal squamous cell carcinoma and were proposed as potential biomarkers in the early detection of the disease. Our findings show that anti-GSTO1-1 antibodies can be found in a variety of inflammatory diseases, including autoimmune rheumatoid arthritis, infectious SARS-CoV-2, and trichinellosis. Our findings strongly suggest that anti-GSTO1-1 antibodies may be a marker of tissue damage/inflammation rather than a specific tumor-associated biomarker. [ABSTRACT FROM AUTHOR]

Objective: To see the clinical and immunological profile of systemic lupus erythematosus (SLE) patients and their correlation with the central nervous system and renal involvement. Study Design: Cross-sectional study. Place and Duration of Study: Fauji Foundation Hospital Rawalpindi from Sep 2019 to Sep 2020. Methodology: One hundred forty patients were selected according to SLE ACR (American College of Rheumatology) criteria. Detailed history and examination, including dermatological examination, were done, and blood samples were taken for baseline investigations and SLE-related autoimmune profile. Statistical analysis was done using SPSS 23 to determine the correlation between skin, central nervous system and renal involvement. Results: In our study, among the lupus-specific lesions, photosensitivity was most frequent 119 (85%) finding followed by oral ulcers 114 (81.4%), alopecia 112 (80%) and malar rash 81 (57.9%). Among the immunological profile, antinuclear antibody (ANA) was the most frequent 116 (82.9%) finding, followed by anti-double stranded antibody 71 (51.7%). Hypocomplementemia and anti-Sm antibody was significantly associated with lupus nephritis (p-value <0.05). There was no correlation between skin and neuropsychiatric involvement and skin and nephritis. Conclusion: This study depicts the clinical immune profile of SLE patients in Pakistan. In our patients, autoimmune profile and complement levels could predict renal involvement. [ABSTRACT FROM AUTHOR]

Pulmonary Alveolar Proteinosis (PAP) is a rare, usually autoimmune, disease, where surfactant accumulates within alveoli due to decreased clearance, causing dyspnea and hypoxemia. The disease is even more rare in pregnancy; nevertheless, it has been reported in pregnant women and can even appear for the first time during pregnancy as an asthma-like illness. Therefore, awareness is important. Similarly to many autoimmune diseases, it can worsen during pregnancy and postpartum, causing maternal and fetal/neonatal complications. This paper offers a narrative literature review of PAP and pregnancy, while illustrating a case of a pregnant patient with known PAP who developed preeclampsia in the third trimester but had an overall fortunate maternal and neonatal outcome. [ABSTRACT FROM AUTHOR]

Anti-brush border antibody (ABBA) disease, also called anti–low-density lipoprotein receptor-related protein 2 (anti-LRP2) nephropathy, occurs due to the formation of antibodies against brush border antigens of the renal proximal convoluted tubule. We report a case of ABBA disease in a male farmer in his 30s who presented with 2 years of polyuria, dysuria, nocturia, and urinary urgency. He described a history of long-term occupational exposure to pesticides and silica, evolving into possible pneumoconiosis, and prior pulmonary tuberculosis. At presentation, he had reduced kidney function (serum creatinine 3.6 mg/dL) with hyponatremia, hypokalemia, hypophosphatemia, a normal anion gap, metabolic acidosis, and respiratory acidosis, and 2.2 g/day of urine proteinuria. The kidney biopsy was consistent with ABBA, showing amorphous immune-deposits in the tubular basement membrane and strong positivity on indirect immunofluorescence in the brush border of the proximal tubules. The trigger for production of ABBA is still unknown, but it may be associated with chronic conditions such as pulmonary tuberculosis and occupational exposures such as silica and pesticides, as seen in the patient in this report. Most cases do not respond to immunosuppression, and the prognosis is poor.

Valeria Giorgi1 1, Daniela Marotto2 2, Alberto Batticciotto3 3, Fabiola Atzeni4 4, Sara Bongiovanni1 1, Piercarlo Sarzi-Puttini1 1 1Rheumatology Unit, Internal Medicine Department, ASST Fatebenefratelli-Sacco, Milan University School of Medicine, Milan, Italy; 2Rheumatology Unit, ATS Sardegna, P. Dettori Hospital, Tempio Pausania, Italy; 3Rheumatology Unit, Internal Medicine Department, ASST Settelaghi, Ospedale Di Circolo - Fondazione Macchi, Varese, Italy; 4Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, ItalyCorrespondence: Valeria Giorgi Email vale.gio@fastwebnet.itAbstract: Medical cannabis (MC) describes the usually inhaled or ingested use of a cannabis plant or cannabis extract for medicinal purposes. The action of whole cannabis plants is extremely complex because their large number of active compounds not only bind to a plethora of different receptors but also interact with each other both synergistically and otherwise. Renewed interest in the medicinal properties of cannabis has led to increasing research into the practical uses of cannabis derivatives, and it has been found that the endocannabinoid system (particularly CB2 receptor activation) is a possible target for the treatment of inflammatory and the autoimmune diseases related to immune cell activation. However, in vivo findings still lack, creating difficulties in applying translational cannabinoid research to human immune functions. In this review, we summarized the main mechanisms of action of medical cannabis plant especially regarding the immune system and the endocannabinoid system, looking at preliminary clinical data in three most important autoimmune diseases of three different specialities: rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.Keywords: cannabis, cannabis derivatives, cannabidiol, tetrahydrocannabinol, terpenes, autoimmunity, auto-antibodies

The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis. [ABSTRACT FROM AUTHOR]

Interleukin -10 is an anti-inflammatory, T regulatory cytokine, produced by several activated immune cells and it has vital role in the suppression of the immune response via downregulation of the Th1, antigen presenting cells, and inflammatory cytokines production, as well as activation of B cell proliferation, differentiation and antibody production. Epigenetic modifications of the promoter of interleukin-10 controls its expression in the immune cells. Methylation of CG sequences within the promoter may play a crucial role in the induction of the chronic status of the SLE. Peripheral blood samples were collected from 60 patients had SLE (30 arthritis SLE and 30 nephritis SLE) and 30 apparently healthy controls. Interleukin-10 levels were assessed in the sera of the studied groups by ELISA technique, then DNA were extracted from whole blood and the methylation of interleukin promoter were analyzed by Real time-PCR technique. The serum level of interleukin-10 was significantly increased in SLE arthritis and nephritis patients' groups compared to controls (23.46 ± 20.37 pg/ml and 28.23 ± 22.83 pg/ml vs. 16.03 ± 5.70 pg/ml, respectively). Also, the results were significantly higher in hypermethylation status of arthritis and nephritis SLE patients' groups compared to the control group (29.98±23.52 and 41.52 ± 22.27 vs. 14.44 ± 3.88, respectively). As well as, a significant difference was shown in hypomethylated status of arthritis and nephritis SLE patients' groups compared to the control group (25.70 ± 13.06 and 26.51±10.5 vs. 11.79 ± 5.11, respectively). In conclusion, in this study the results of IL-10 level were increased in SLE patients, there were no significant differences between hypermethylation and hypomethylation status of the IL-10 promoter when compared between SLE patients and healthy controls. [ABSTRACT FROM AUTHOR]

RationaleAtherosclerosis is a chronic inflammatory disease of large arteries that involves an autoimmune response with autoreactive T cells and auto-antibodies recognizing Apolipoprotein B (ApoB), the core protein of low-density lipoprotein (LDL). Here, we aimed to establish a clinical association between circulating human ApoB auto-antibodies with atherosclerosis and its clinical risk factors using a novel assay to detect auto-antibodies against a pool of highly immunogenic ApoB-peptides.Methods and ResultsTo detect polyclonal IgM- and IgG-antibodies recognizing ApoB, we developed a chemiluminescent sandwich ELISA with 30 ApoB peptides selected by an in silico assay for a high binding affinity to MHC-II, which cover more than 80% of known MHC-II variants in a Caucasian population. This pre-selection of immunogenic self-peptides accounted for the high variability of human MHC-II, which is fundamental to allow T cell dependent generation of IgG antibodies. We quantified levels of ApoB-autoantibodies in a clinical cohort of 307 patients that underwent coronary angiography. Plasma anti-ApoB IgG and IgM concentrations showed no differences across healthy individuals (n = 67), patients with coronary artery disease (n = 179), and patients with an acute coronary syndrome (n = 61). However, plasma levels of anti-ApoB IgG, which are considered pro-inflammatory, were significantly increased in patients with obesity (p = 0.044) and arterial hypertension (p < 0.0001). In addition, patients diagnosed with the metabolic syndrome showed significantly elevated Anti-ApoB IgG (p = 0.002). Even when normalized for total plasma IgG, anti-ApoB IgG remained highly upregulated in hypertensive patients (p < 0.0001). We observed no association with triglycerides, total cholesterol, VLDL, or LDL plasma levels. However, total and normalized anti-ApoB IgG levels negatively correlated with HDL. In contrast, total and normalized anti-ApoB IgM, that have been suggested as anti-inflammatory, were significantly lower in diabetic patients (p = 0.012) and in patients with the metabolic syndrome (p = 0.005).ConclusionUsing a novel ELISA method to detect auto-antibodies against ApoB in humans, we show that anti-ApoB IgG associate with cardiovascular risk factors but not with the clinical appearance of atherosclerosis, suggesting that humoral immune responses against ApoB are shaped by cardiovascular risk factors but not disease status itself. This novel tool will be helpful to develop immune-based risk stratification for clinical atherosclerosis in the future.

In vivo establishment and long-term persistence of a heterogeneous memory or an adaptive NK cell pool represents a functional adaptation to human cytomegalovirus (HCMV) infection in humans. Memory NK cells are commonly identified by lack of the FcεRIγ signalling chain, variably associated to the preferential but not completely overlapping expression of the HLA-E receptor NKG2C and CD57 maturation marker. Although characterized by selective hyperresponsiveness to IgG stimulation, the impact of the CD16/antibody interaction in regulating the establishment/maintenance and size, and in determining the relative abundance of this population, is still under investigation. Memory NK cell subset ex vivo profile and in vitro responsiveness to CD16 stimulation was evaluated in HCMV+ healthy donors and in patients affected by immune thrombocytopenia (ITP), an antibody-mediated autoimmune disease. We identified the FcεRIγ− NKG2C+CD57+ memory NK cell subset, whose abundance is uniquely associated with anti-HCMV antibody levels in healthy seropositive donors, and which is significantly expanded in ITP patients. This fully mature memory subset robustly and selectively expands in vitro in response to mAb-opsonized targets or ITP-derived platelets and displays superior CD16-dependent IFNγ production. Our work identifies opsonizing antibodies as a host-dependent factor that shapes HCMV-driven memory NK cell compartment. We first demonstrate that chronic exposure to auto-antibodies contributes to the establishment/expansion of a highly specialized and unique memory NK cell subset with distinct CD16-dependent functional capabilities. We also identify the specific contribution of the lack of FcεRIγ chain in conferring to NKG2C+CD57+ memory cells a higher responsivity to CD16 engagement. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of interferon-α2 auto-antibodies (IFN-α2 Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α2 Abs transfer during convalescent plasma treatment. Methods: Sera from healthy controls, cases of COVID-19, and other respiratory illness were tested for IFN-α2 Abs by ELISA and a pseudo virus–based neutralization assay. The effects of disease severity, sex, and age on the risk of having neutralizing IFN-α2 Abs were determined. Longitudinal analyses were performed to determine association between IFN-α2 Abs and survival and viral load and whether serum IFN-α2 Abs appeared after convalescent plasma transfusion. Results: IFN-α2 neutralizing sera were found only in COVID-19 patients, with proportions increasing with disease severity and age. In the acute stage of COVID-19, all sera from patients with ELISA-detected IFN-α2 Abs (13/164, 7.9%) neutralized levels of IFN-α2 exceeding physiological concentrations found in human plasma and this was associated with delayed viral clearance. Convalescent plasma donors that were anti-IFN-α2 ELISA positive (3/118, 2.5%) did not neutralize the same levels of IFN-α2. Neutralizing serum IFN-α2 Abs were associated with delayed viral clearance from the respiratory tract. Conclusions: IFN-α2 Abs were detected by ELISA and neutralization assay in COVID-19 patients, but not in ICU patients with other respiratory illnesses. The presence of neutralizing IFN-α2 Abs in critically ill COVID-19 is associated with delayed viral clearance. IFN-α2 Abs in COVID-19 convalescent plasma donors were not neutralizing in the conditions tested. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a severe pulmonary disease, which is one of the major complications in COVID-19 patients. Dysregulation of the immune system and imbalances in cytokine release and immune cell activation are involved in SARS-CoV-2 infection. Here, the inflammatory, antigen, and auto-immune profile of patients presenting COVID-19-associated severe ARDS has been analyzed using functional proteomics approaches. Both, innate and humoral responses have been characterized through acute-phase protein network and auto-antibody signature. Severity and sepsis by SARS-CoV-2 emerged to be correlated with auto-immune profiles of patients and define their clinical progression, which could provide novel perspectives in therapeutics development and biomarkers of COVID-19 patients. Humoral response in COVID-19 patients' profile separates with significant differences patients with or without ARDS. Furthermore, we found that this profile can be correlated with COVID-19 severity and results more common in elderly patients. [ABSTRACT FROM AUTHOR]