Autoreactive Antibodies Research Articles

Humoral Immunity against SARS-CoV-2 and the Impact on COVID-19 Pathogenesis.

It has been more than a year since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged. Many studies have provided insights into the various aspects of the immune response in coronavirus disease 2019 (COVID-19). Especially for antibody treatment and vaccine development, humoral immunity to SARS-CoV-2 has been studied extensively, though there is still much that is unknown and controversial. Here, we introduce key discoveries on the humoral immune responses in COVID-19, including the immune dynamics of antibody responses and correlations with disease severity, neutralizing antibodies and their cross-reactivity, how long the antibody and memory B-cell responses last, aberrant autoreactive antibodies generated in COVID-19 patients, and the efficacy of currently available therapeutic antibodies and vaccines against circulating SARS-CoV-2 variants, and highlight gaps in the current knowledge.

Diverse functional autoantibodies in patients with COVID-19.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1-6. Although pathological innate immune activation is well-documented in severe disease1, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172patients with COVID-19 and 22healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.

Clinical experience of plasmapheresis for neuromyelitis optica patients in Mexico

BackgroundNeuromyelitis optica spectrum disorders (NMOSDs) are a group of chronic immune-mediated demyelinating diseases of the central nervous system. Their pathophysiology dependent on humoral mediated responses caused by autoreactive IgG antibodies against aquaporin-4 water channels (AQP4-IgG) or myelin oligodendrocyte glycoprotein (MOG-IgG). Plasma exchange (PLEX) has proved to be a beneficial therapy in patients with severe relapses. We present the largest series of Latin American patients treated with PLEX for acute NMOSDs relapses. MethodsA retrospective study was conducted. Selection included patients diagnosed with NMOSDs who received PLEX between 2010-2019, irrespective of their AQP4-IgG serostatus. All patients received 5 grams of IV methylprednisolone. PLEX therapy could be initiated simultaneously or after IV steroids. Baseline and post-PLEX therapy Expanded Disability Status Scale (EDSS) was measured to identify acute response to therapy. Comparison between responders and non-responders was also conducted. Subgroup analysis stratified response by serostatus, type of clinical relapse and time to PLEX. ResultsA total of 89 patients were included. Mean age at onset was 38 ± 12.97 years. 49 (55.1%) patients were AQP4-IgG seropositive. Most patients had unilateral optic neuritis (34.8%) or longitudinally extensive transverse myelitis (33.7%). Mean time from onset to PLEX initiation was 20.9 ± 18.1 days. Response rate was 39.3% and mean decline in EDSS was 0.7 ± 0.9 (p <0.001). Decline in EDSS and response rate were independent of serostatus, type of clinical relapse or time to PLEX initiation. ConclusionPLEX appears to be an effective therapy for NMOSDs relapses even in limited resources setting where treatment initiation may be delayed. The benefit seems to be independent of the type of clinical relapse and AQP4 IgG serostatus.

Recombinant Fragment of the Extracellular Domain of Human Desmoglein 3 Fused with the Fc-Fragment of Human IgG1 Selectively Adsorbs Autoreactive Antibodies from the Sera of Pemphigus Patients.

Using the recombinant second fragment of the extracellular domain (EC2) of human desmoglein type 3 (Dsg3) as an affinity ligand, an immunosorbent was obtained that selectively binds autoreactive antibodies to this domain from the immune sera of patients with pemphigus. The EC2 protein was obtained in the form of a fusion protein with the Fc-fragment of human IgG1. The production was carried out in CHO cells using the method of transient expression.

SOCS1 mimetics attenuate autoimmune pathology in a murine model of lupus

Abstract Autoimmune diseases are driven, in large part, by the aberrant activation of lymphocytes which mediate a dysregulated cytokine milieu and produce pathogenic, auto-reactive antibodies. Notably, many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS-1) is an inducible, intracellular protein known to regulate IFN-γ signaling through dampening of the JAK/STAT signaling cascade. We have previously shown that a peptide mimicking the kinase inhibitory region of SOCS1 (SOCS1-KIR) inhibited IFN-γ signaling and inflammation-driven disease progression. Using Fas deficient MRL/lpr mice, which spontaneously develop a lupus-like disease, we tested the hypothesis that SOCS1-KIR administration would alter lymphocyte phenotype and modulate lupus-associated pathologies. SOCS1-KIR administration reduced severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of germinal center B cells. Together, these data show that SOCS1-KIR treatment altered lymphocyte phenotype and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

Evaluation of differential autoantibody profiles in gut and brain tissues in children with Autism Spectrum Disorder (ASD).

Abstract Autoimmunity is a comorbidity often associated with autism spectrum disorder (ASD), and a better understanding of immune dysbiosis and autism is crucial to identify differential ASD phenotypes and develop better biomarkers. We aimed to study autoantibody (aAb) reactivity to gut and brain tissues to find aAb profiles in children with autism that could serve to identify ASD subpopulations with biomarker potential. Methods: We used plasma from typically developing children (TD; n=149) and children diagnosed with ASD (n=208). To assess aAb reactivity, we probed plasma brain and gut tissues by Western blot. Results: While we found reactivity against brain (28% ASD and 32% TD), and gut (15% ASD and 11% TD) in both groups, we observed reactivity to antigens in defined molecular weight ranges in the gut tissue recognized by aAbs from the ASD subjects and not the TD samples. Further, some individuals had aAb reactivity to both brain and gut (8.6% ASD and 8% TD). These data are consistent with our previous studies against cerebellum tissue, where we reported aAb reactivity in both groups (ASD and TD), but some autoantibodies were differentially reactive in the ASD population. Conclusion: We identified aAbs reactive to brain and gut antigens in both TD and ASD children, with differential recognition of plasma from children with ASD to proteins in the gut extract. We are currently working on identification of the differentially recognized proteins in the gut tissue. Further, we can link our findings to the clinical data of these children, including reported GI issues. Such aAbs have the potential to serve as predictors of a subgroup of ASD individuals or facilitate a better understanding of the different sub-phenotypes of ASD based on differential aAb profiles.

Soluble syndecan I (CD138) released by MRL/Lpr T cells enhances APRIL-mediated lupus B cell survival and differentiation

Abstract High level of soluble serum syndecan-1 (CD138), a heparan sulfate–bearing proteoglycan, in systemic lupus erythematosus (SLE) patients correlates with disease activity and lupus nephritis. Mechanisms responsible for the increase in serum CD138 and the immunopathological function of serum CD138 in lupus development remain poorly understood. In this study, recapitulating the findings in SLE patients, we found a sharp increase in serum CD138 levels parallel to the progression of disease in MRL/Lpr (lupus prone) mice. Although TCRβ+CD138+ T cells expand with age in MRL/Lpr mice, TCRβ+CD138− cells are the likely source of circulating CD138 as the transfer of TCRβ+CD138− cells, but not TCRβ+CD138+ cells, led to an increase in serum CD138 in the recipient mice. We found that CD138 expressed on lupus T cells was resistant to cleavage by MMP9 and collagenase, but it was very sensitive to trypsin. We also found high levels of trypsin production by TCRβ+CD138− cells. Suggesting a role for trypsin expressed by these cells in the elevated serum CD138 in lupus mice, trypsin produced by TCRβ+CD138− cells effectively cleaved CD138 from T cells. Interestingly, soluble CD138 was able to bind APRIL and enhance APRIL-mediated ERK activation and B cell differentiation. The ability of CD138 to potentiate APRIL-induced B cell differentiation was dependent on TACI expression, as the synergistic effect of APRIL and CD138 on plasma cell formation was strongly ablated on TACI deficient B cells. These findings reveal a role for soluble CD138 in B cell differentiation and autoreactive antibody production in MRL/Lpr mice. Understanding the mechanisms by which soluble CD138 is produced and how it functions may reveal novel druggable targets for lupus disease.

Human monoclonal autoantibodies in autoimmune basal ganglia encephalitis target dopamine receptors and act as drug agonists

Abstract Neuropsychiatric diseases in autoimmune basal ganglia encephalitis (BGE) are associated with anti-neuronal autoantibodies which target the basal ganglia. BGE includes the group A streptococcal sequelae Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). In SC, autoantibodies against dopamine receptors 1 and 2 (D1R and D2R) are elevated, and IgG in SC sera and cerebrospinal fluid (CSF) induce excessive dopaminergic D2R signaling and dopamine release. D1R autoantibody reactivity targeting the basal ganglia is not defined. Here we demonstrate specific IgG targeting of D1R in multiple neuropsychiatric PANDAS cohorts by serum, CSF, and human-derived mAbs. Anti-D1R human mAbs and serum autoantibodies induced D1R second messenger signaling in a dose-dependent manner. The results suggest that D1R autoantibodies enhanced antibody-mediated IgG signaling activity in the presence of the neurotransmitter dopamine. D1R autoantibodies sensitized D1R and exacerbated endogenous dopamine signaling in disease. Agonistic D1R signaling was inhibited by synthetic D1R peptide epitopes derived from human D1R extracellular loops which identified the immunodominant epitopes and antibody specificity. Taken together, D2R autoantibodies in BGE lead to excessive dopamine release and chorea, while D1R autoantibodies act like dopamine on receptors leading to allosteric enhancement and neuropsychiatric disease. Collectively, our novel findings suggest dopamine receptor autoantibodies in basal ganglia disorders act like drugs and mediate hyperactive dopaminergic receptor signaling.

Autoimmunity, IgE and FcεRI-bearing cells.

Antibody-mediated autoimmune diseases (AAID) involve several isotypes of autoreactive antibodies. In a growing number of AAID, autoreactive IgE are present with a significant prevalence and are often associated with the presence of IgG anti-IgE and/or anti-FcεRIα (high affinity IgE receptor α chain). FcεRI-bearing cells, such as basophils or mast cells, are key players in some of these AAID. Recent advances in the pathophysiology of these diseases led to the passed or current development of anti-IgE strategies that showed very potent effects in some of them. The present review centralizes the information on the relevance of autoreactive IgE and FcεRI-bearing cells in the pathophysiology of different AAID and the ones where the anti-IgE therapeutic strategy shows or may show some benefits for the patients.

EVIDENCE OF ANTI-DOUBLE STRANDED DNA ANTIBODIES AND C-REACTIVE PROTEIN IN EGYPTIAN PATIENTS WITH HIGH ANTI-SCHISTOSOMA MANSONI ANTIBODY TITER

Schistosomiasis is one of the major public health diseases that induced a diversity of immunologicreactions. Significant association between autoreactive antibodies and autoimmune disorderswas suggested. This study investigated the presence of anti-double stranded DNA (anti-dsDNA) antibodies and inflammatory biomarker, C-reactive protein (CRP) in 89 Egyptian patients,with Schistosoma mansoni clinical evidence and high anti-Schistosoma antibody titer. Theresults showed positive serum anti-ds DNA antibodies in 11/89(12.4%) of them, without significanceto age, sex or anti-Schistosoma antibody titers. CRP was positive in 20/89(22.5%) of patients,with significant correlation with anti-ds DNA antibodies (P=0.000).

Analysis of Autoantibodies against Promyelocytic Leukemia Nuclear Body Components and Biochemical Parameters in Sera of Patients with Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by immune-mediated destruction of intrahepatic bile ducts and the presence of specific antibodies. The aim of the study was to examine the diagnostic significance of antibodies against promyelocytic leukemia nuclear body (PML NB) components such as Sp100, Sp140, and PML in a cohort of PBC patients and compare the results with biochemical and histological parameters. Serum samples were collected from 93 PBC patients. Anti-Sp100 and anti-PML antibodies were assessed using commercially available kits, anti-Sp140 using developed “in-house” ELISA test. Anti-Sp140, anti-Sp100, and anti-PML antibodies were present in 25 (27%), 37 (40%), and 29 (31%) PBC patients, respectively. Anti-PML NB positive patients also showed increased concentration of bilirubin and alkaline phosphatase (p < 0.05). In the group with the presence of at least two types of these antibodies, more frequent deaths or transplantations were observed. A correlation between the presence of antibodies and histological grade (OR = 2.55 p = 0.039) was established. Patients with bilirubin > 1.1 mg/dL at the time of diagnosis had a significantly shorter time of survival than patients with bilirubin ≤ 1.1 mg/dL (HR 5.7; 95% C.I., 2.7, 12.3; p < 0.001). Our data confirm very high specificity of anti-PML NB antibodies, which can expand the laboratory diagnostic capabilities of PBC. We found an association between positive reactivity of autoantibodies directed against components of PML nuclear bodies and higher concentrations of bilirubin and alkaline phosphatase, but the main prognostic marker of survival remains serum bilirubin.

COVID-19 and male fertility: Taking stock of one year after the outbreak began.

The aim of this review is to summarize, following a timeline, the current knowledge regarding the effects of the Sars-cov2 virus on male fertility, researching the pathological and clinical results of the studies published in the last year. A systematic research was performed on the major international online databases; Thirty-five articles were selected. A statistically significant reduction in testosterone levels and sperm quality in subjects with COVID-19 has been highlighted in several papers; however, in many cases the tests have been conducted in patients with active disease and long-term consequences are still not known. Some studies have confirmed the presence of the virus in the testis in a low percentage of patients; viral presence in sperm has only been found in one study. Testicular discomfort, which could indicate viral orchitis, was highlighted in several works, with an incidence of up to 19% percent of patients. The presence of inflammatory lymphocytic infiltrates, IgG and inflammatory cytokines have been documented in several works; pathological signs of inflammation were found in 60.9% of testicular biopsies performed in one study. The entry of the virus into the testis cells, both stromal and seminal cells appeared to be Angiotensin Converting Enzyme-2 (ACE2) mediated, as it also occurs in other tissues. DNA fragmentation, reactive oxygen species (ROS) formation, autoantibody production and ACE2 mediated effect have all been hypothesized as cause of cellular damage. The results on effects of COVID-19 infection on the male reproductive system are currently insufficient as they are based on a small number of patients and therefore are often contradictory.Certain mechanisms of testicular damage are still to be assessed, as any risk categories like age, ethnicity, or others. As for the transmission of the virus through sperm, there is insufficient evidence to ensure that this cannot happen.

Functional Autoreactive Anti-β2 Adrenergic Antibodies May Contribute to Insulin Resistance Profile in Patients with Chronic Chagas Disease.

Potential activation of β2 adrenergic receptors (β2AR) by specific autoreactive antibodies (Abs) that arise during the host reaction to Trypanosoma cruzi, could contribute to the elevated prevalence of metabolic disturbances described in patients with chronic Chagas disease (CCD). This study aimed to determine the prevalence of anti-β2AR Abs in patients with CCD, as well as the correlation of these Abs with the presence of glucose and lipid metabolism disturbances, in order to explore their association with an insulin resistance profile. Additionally, we tested the functional effects of anti-β2AR Abs employing an in vitro bioassay with neuroendocrine cells expressing β2AR. A clinical and metabolic evaluation including an OGTT was performed in 80 CCD patients and 40 controls. Anti-β2AR Abs were measured by an in-house-developed ELISA, and the β2 adrenergic activity of affinity-purified IgG fractions from patient’ sera were assayed in CRE-Luc and POMCLuc transfected AtT-20 cells. A higher proportion of dysglycemia (72.5% vs. 37.5%; p = 0.001) was observed in the CCD group, accompanied by increased HOMA2-IR (p = 0.019), especially in subjects with Abs (+). Anti-β2AR Abs reactivity (7.01 (2.39–20.5); p = 0.0004) and age >50 years (3.83 (1.30–11.25); p = 0.014) resulted as relevant for IR prediction (AUC: 0.786). Concordantly, Abs (+) CCD patients showed elevated metabolic risk scores and an increased prevalence of atherogenic dyslipidemia (p = 0.040), as compared to Abs (−) patients and controls. On functional bioassays, Abs exerted specific and dose-dependent β2-agonist effects. Our findings suggest that anti-β2AR Abs may induce the activation of β2AR in other tissues besides the heart; furthermore, we show that in patients with CCD these Abs are associated with an insulin resistance profile and atherogenic dyslipidemia, providing biological plausibility to the hypothesis that adrenergic activation by anti-β2AR Abs could contribute to the pathogenesis of metabolic disturbances described in CCD patients, increasing their cardiovascular risk.

A Novel Natural Autoantibody Targeted Complement Inhibitor Protects against Lung Transplant Ischemia Reperfusion Injury

Purpose Chronic obstructive pulmonary disease is characterized by chronic inflammation and severe lung parenchyma damage that is in part driven by autoimmunity. Lung specific autoreactive antibodies (AAb) are indicative of disease progression and severity. The purpose of this study was to elucidate how pre-existing AAb contribute to ischemia reperfusion injury (IRI) and graft rejection following lung transplant (LTx). We hypothesize that pre-existing AAb bind cryptic antigens exposed during IRI which exacerbates lung graft injury in a complement (C)-dependent pathway. Methods We generated a clinically relevant cigarette smoke (CS)-induced mouse model that exhibits increased serum AAb compared to non-smoke exposed age-matched (NS) controls. We analyzed the impact of a full pre-existing AAb repertoire by creating an orthotopic syngeneic left lung LTx model in which we transplanted the left lungs from age-matched donor mice into NS and CS mice. Furthermore, we developed a novel bifunctional inhibitor that blocks IgM binding and inhibits complement. Results CS exposure significantly increased graft injury and immune infiltration 48 hours after LTx. Syngeneic LTx into Rag−/- mice reconstituted with serum from NS and CS mice demonstrated that AAb present in CS are responsible for the observed graft injury. Immunofluorescent staining showed that IgM/IgG binding was increased in CS recipients and colocalized with C3d deposition. These data suggested that AAb-mediated graft injury may occur via the C pathway. To elucidate the role of C in AAb-mediated graft injury, we treated CS LTx recipients with a novel bifunctional C inhibitor, C2scFv-Crry, that blocks IgM binding and C activation. C2scFv-Crry treatment following LTx dramatically reduced acute graft injury and immune infiltration, and significantly decreased de novo AAb production compared to CS control LTx mice. Conclusion Ultimately, these data reveal that CS induces pre-existing AAb production that exacerbate IRI following LTx in a C-dependent manner. Furthermore, we demonstrate the efficacy of a novel C inhibitor in reducing IRI and acute graft injury.

The emerging role of autoreactive antibodies in inflammatory skin diseases.

Linked article: A. Lamberts et al. J Eur Acad Dermatol Venereol 2021; 35: 973–980. https://doi.org/10.1111/jdv.16996.

Gut Microbiota Perturbation in IgA Deficiency Is Influenced by IgA-Autoantibody Status

IgA exerts its primary function at mucosal surfaces, where it binds microbial antigens to regulate bacterial growth and epithelial attachment. One third of individuals with IgA deficiency (IgAD) suffers from recurrent mucosal infections, possibly related to an altered microbiota. We aimed to delineate the impact of IgAD and the IgA-autoantibody status on the composition and functional capacity of the gut microbiota. We performed a paired, lifestyle-balanced analysis of the effect of IgA on the gut microbiota composition and functionality based on fecal samples from individuals with IgAD and IgA-sufficient household members (n= 100), involving quantitative shotgun metagenomics, species-centric functional annotation of gut bacteria, and strain-level analyses. We supplemented the data set with 32 individuals with IgAD and examined the influence of IgA-autoantibody status on the composition and functionality of the gut microbiota. The gut microbiota of individuals with IgAD exhibited decreased richness and diversity and was enriched for bacterial species encoding pathogen-related functions including multidrug and antimicrobial peptide resistance, virulence factors, and type III and VI secretion systems. These functional changes were largely attributed to Escherichia coli but were independent of E coli strain variations and most prominent in individuals with IgAD with IgA-specific autoreactive antibodies. The microbiota of individuals with IgAD is enriched for species holding increased proinflammatory potential, thereby potentially decreasing the resistance to gut barrier-perturbing events. This phenotype is especially pronounced in individuals with IgAD with IgA-specific autoreactive antibodies, thus warranting a screening for IgA-specific autoreactive antibodies in IgAD to identify patients with IgAD with increased risk for gastrointestinal implications.

79664 Complement Driven Auto-Reactive Antibodies in Lung Transplantation

ABSTRACT IMPACT: Our work unveils a novel mechanism of ischemia repurfusion injury driven by pre-existing autoimmunity following lung transplant and a potential therapeutic strategy for blocking complement-dependent injury thereby reducing risk of lung transplant rejection. OBJECTIVES/GOALS: Our goal was to determine if pre-existing autoimmune autoantibodies, such as those resulting from cigarette smoke (CS), contribute to graft rejection in lung transplantation (LTx) and if autoreactive-mediated graft injury is complement-dependent. METHODS/STUDY POPULATION: For in vivo experiments, we utilized our emphysema mouse model. Briefly, eight-week-old C57BL/6J mice are exposed to 3R4F reference cigarette smoke 5 hours per day, 5 days a week for 6 months. Upon completion, cigarette smoked (CS) mice and control (NS) mice received syngeneic orthotopic left-lung transplant from age-matched C57BL/6J donors. To determine if pre-existing autoreactivity mediated graft injury was complement-dependent we treated CS-LTx mice with a novel, bifunctional complement inhibitor. Autoantibody levels were measured by ELISA and lung injury was assessed by blinded histopathological analyses. Complement inhibition was verified by immunofluorescence. RESULTS/ANTICIPATED RESULTS: We found that CS-exposure leads to production of autoreactive antibodies towards extracellular matrix (ECM) components and contributes to graft injury. Interestingly, LTx into CS exposed mice further increased de-novo ECM autoantibody development. Lastly, treatment with our novel, bifunctional complement inhibitor blocked autoantibody spreading and significantly reduced graft rejection. DISCUSSION/SIGNIFICANCE OF FINDINGS: These data demonstrate that smoking induces pre-LTx autoreactivity to ECM proteins that promotes graft injury following LTx. Furthermore, complement inhibition reduces autoantibody production and protects the graft from injury.

NewsCAP: Autoantibody reactivity implicated in 'long' COVID-19.

NewsCAP: Autoantibody reactivity implicated in 'long' COVID-19.

The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

Anti-SARS-CoV-2 Antibodies Within IVIg Preparations: Cross-Reactivities With Seasonal Coronaviruses, Natural Autoimmunity, and Therapeutic Implications

Introduction: Cross-reactivity to SARS-CoV-2 antigenic peptides has been detected on T-cells from pre-pandemic donors due to recognition of conserved protein fragments within members of the coronavirus's family. Further, preexisting antibodies recognizing SARS-CoV-2 with conserved epitopes in the spike region have been now seen in uninfected individuals. High-dose Intravenous Immunoglobulin (IVIg), derived from thousands of healthy donors, contains natural IgG antibodies against various antigens which can be detected both within the IVIg preparations and in the serum of IVIg-receiving patients. Whether IVIg preparations from pre-pandemic donors also contain antibodies against pre-pandemic coronaviruses or autoreactive antibodies that cross-react with SARS-CoV-2 antigenic epitopes, is unknown.Methods: 13 samples from 5 commercial IVIg preparations from pre-pandemic donors (HyQvia (Baxalta Innovations GmbH); Privigen (CSL Behring); Intratect (Biotest AG); IgVena (Kedrion S.p.A); and Flebogamma (Grifols S.A.) were blindly screened using a semi-quantitative FDA-approved and validated enzyme-linked immunosorbent assay (ELISA) (Euroimmun, Lubeck, Germany).Results: Nine of thirteen preparations (69.2%), all from two different manufactures, were antibody-positive based on the defined cut-off positivity (index of sample OD to calibrator OD > 1.1). From one manufacturer, 7/7 lots (100%) and from another 2/3 lots (67%), tested positive for cross-reacting antibodies. 7/9 of the positive preparations (77%) had titers as seen in asymptomatically infected individuals or recent COVID19-recovered patients, while 2/9 (23%) had higher titers, comparable to those seen in patients with active symptomatic COVID-19 infection (index > 2.2).Conclusion: Pre-pandemic IVIg donors have either natural autoantibodies or pre-pandemic cross-reactive antibodies against antigenic protein fragments conserved among the “common cold” - related coronaviruses. The findings are important in: (a) assessing true anti-SARS-CoV-2-IgG seroprevalence avoiding false positivity in IVIg-receiving patients; (b) exploring potential protective benefits in patients with immune-mediated conditions and immunodeficiencies receiving acute or chronic maintenance IVIg therapy, and (c) validating data from a recent controlled study that showed significantly lower in-hospital mortality in the IVIg- treated group.