Self-reactive Antibodies Research Articles

Immunomodulatory and anti-inflammatory properties of immunoglobulin G antibodies.

Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti-microbial antibody isotype due to their long half-life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self-reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self-tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre-clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc-domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation.

Astrocytic stress response is induced by exposure to astrocyte-binding antibodies expressed by plasmablasts from pediatric patients with acute transverse myelitis

BackgroundPediatric acute transverse myelitis (ATM) accounts for 20–30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease.MethodsWe compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response.ResultsWe found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis.ConclusionsDiscordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.

Efficacy of lymphatic pump treatment in conjunction with methotrexate on rats with adjuvant-induced arthritis

Abstract Rheumatoid Arthritis (RA) is an autoimmune disease targeting synovial joints in which self-reactive T cells release cytokines and B cells produce self-reactive antibodies resulting in an inflammatory response. Lymphatic pump treatment (LPT) promotes lymphatic flow resulting in a flushing out of the immune-complexes and cytokines. A rat mode on RA (AIA) was used to determine whether LPT in conjunction with the anti-rheumatic drug, methotrexate (MTX), enhanced its therapeutic impact on RA. A preventative study was performed in which MTX was given along with LPT (3 times a day for 7 days) . Ankles were assessed daily for signs of inflammation. Flow cytometry was performed on spleen and popliteal lymph nodes (PLN) to determine changes in leukocyte populations. Cytokine levels were determined on ankle lysates. The study showed that MTX treatment delayed the onset of arthritis. MTX reduced the spleen weights (p<0.05). LPT also reduced spleen weights but did not enhance the MTX reduction. LPT reduced PLN weights compared to MTX. MTX resulted in higher numbers of CD4+ T cells and lower numbers of CD8+ T cells and B cells in spleens. PLNs treated with MTX had reduced lymphocyte numbers. MTX treatment reduced CINC-1 and TNFa levels (p<0.05). LPT also reduced CINC-1 levels. In conclusion, MTX treatments delayed arthritis formation in AIA rats while LPT affected both spleen and PLN weights. Thus, the addition of LPT to RA treatment showed potential benefits without negative effects.

Unveiling the intricacies of COVID-19: Autoimmunity, multi-organ manifestations and the role of autoantibodies.

COVID-19 is a severe infectious disease caused by a SARS-CoV-2 infection. It has caused a global pandemic and can lead to acute respiratory distress syndrome (ARDS). Beyond the respiratory system, the disease manifests in multiple organs, producing a spectrum of clinical symptoms. A pivotal factor in the disease's progression is autoimmunity, which intensifies its severity and contributes to multi-organ injuries. The intricate interaction between the virus' spike protein and human proteins may engender the generation of autoreactive antibodies through molecular mimicry. This can further convolute the immune response, with the potential to escalate into overt autoimmunity. There is also emerging evidence to suggest that COVID-19 vaccinations might elicit analogous autoimmune responses. Advanced technologies have pinpointed self-reactive antibodies that target diverse organs or immune-modulatory proteins. The interplay between autoantibody levels and multi-organ manifestations underscores the importance of regular monitoring of serum antibodies and proinflammatory markers. A combination of immunosuppressive treatments and antiviral therapy is crucial for managing COVID-19-associated autoimmune diseases. The review will focus on the generation of autoantibodies in the context of COVID-19 and their impact on organ health.

Epigenetic Control of B Cell Autoimmunity By Jmjd1c

Emerging evidence underscores the importance of e pigenetic modifications in controlling B-cell development and function. While Jmjd1c, a member of the l ysine - specific histone demethylase 3 subfamily, is known to regulate the self-renewal of normal hematopoietic stem cells and leukemia stem cells, its impact on B cell biology is unknown. To explore Jmjd1c's role in B cells, we developed B-cell-specific Jmjd1c-deficient mice through crossbreeding Jmjd1c “floxed” mice with B cell-specific Mb1-Cre mice. The absence of Jmjd1c did not impact B-cell development, but it did lead to significant alterations in basal B cell antibody production. Specifically, we observed skewed isotypes from IgG2c and IgG3 to IgG1 and IgG2b. Additionally, Jmjd1c deficiency affected antigen-specific immune responses upon T-dependent and T-independent antigen challenges, implying a crucial role of Jmjd1c in B cell function. Furthermore, auto-antibody array assays revealed increased self-reactive antibody production in Jmjd1c-deficient animals, indicating the role of Jmjd1c in regulating self-reactive B cells. At a cellular level, Jmjd1c-deficient B cells showed elevated expression of CD86, a canonical marker of B cell activation. Moreover, these B cells exhibited increased BCR-induced cell proliferation, suggesting hyperactivity to antigens, including self-antigens. Notably, Jmjd1c deficiency induced systemic autoimmune disorder in a BM12-induced systemic lupus erythematosus (SLE) animal model, resulting in amplified auto-antibody production and CD86 expression. To investigate the underlying molecular mechanisms, RNA sequencing analysis demonstrated upregulation of B cell receptor signaling related genes, NF-κB pathway signature genes, and cell cycle-related genes in Jmjd1c-deficient B cells upon anti-IgM stimulation, consistent with their hyperresponsiveness. Of particular interest, we observed upregulation of genes encoding the 26S proteasome complex, a pivotal regulator of diverse cellular processes including NF-κB pathway activation and self-antigen presentation. To explore the epigenetic aspect of these genes, we employed CUT&Tag sequencing and found that Jmjd1c deficiency correlated with increased levels of H3K36me1, a marker of active chromatin and gene transcription. Moreover, the H3K36me1 levels of B cell receptor signaling related genes, NF-κB pathway signature genes, and cell cycle-related genes were significantly augmented in Jmjd1c-deficient B cells upon anti-IgM stimulation. Notably, 26S proteasome subunit genes that were upregulated in Jmjd1c-deficient B cells exhibited higher H3K36me1 modification at the promoter regions. Collectively, our study provides valuable insights into the epigenetic control of B cell autoimmunity through the regulation of H3K36 mono-methylation by Jmjd1c. This mechanism plays a critical role in B cell activation and function, including the regulation of key genes such as those encoding the 26S proteasome complex.

Complex subsets but redundant clonality after B cells egress from spontaneous germinal centers.

Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here, we used fate-mapping reporter mice and single-cell transcriptomics coupled to antibody repertoire analysis to characterize the post-germinal center (GC) B cell compartment in a new mouse model of autoimmunity. Antibody-secreting cells (ASCs) and memory B cells (MemBs) from spontaneous GCs grouped into multiple subclusters. ASCs matured into two terminal clusters, with distinct secretion, antibody repertoire and metabolic profiles. MemBs contained FCRL5+ and CD23+ subsets, with different in vivo localization in the spleen. GC-derived FCRL5+ MemBs share transcriptomic and repertoire properties with atypical B cells found in aging and infection and localize to the marginal zone, suggesting a similar contribution to recall responses. While transcriptomically diverse, ASC and MemB subsets maintained an underlying clonal redundancy. Therefore, self-reactive clones could escape subset-targeting therapy by perpetuation of self-reactivity in distinct subsets.

The axis of complement C1 and nucleolus in antinuclear autoimmunity.

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. In speckled regions, the major ANA targets Sm/RNP and SSA/Ro contain snRNAs that confer autoimmunogenecity to Sm/RNP and SSA/Ro antigens. Recently, three GAR/RGG-containing alarmins have been identified in the nucleolus that helps explain its high autoimmunogenicity. Interestingly, C1q binds to the nucleoli exposed by necrotic cells to cause protease C1r and C1s activation. C1s cleaves HMGB1 to inactive its alarmin activity. C1 proteases also degrade many nucleolar autoantigens including nucleolin, a major GAR/RGG-containing autoantigen and alarmin. It appears that the different nuclear regions are intrinsically autoimmunogenic by containing autoantigens and alarmins. However, the extracellular complement C1 complex function to dampen nuclear autoimmunogenecity by degrading these nuclear proteins.

Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse.

In mature B cells, activation-induced deaminase reshapes Ig genes through somatic hypermutation and class switch recombination of the Ig heavy chain (IgH) locus under control of its 3' cis-regulatory region (3'RR). The 3'RR is itself transcribed and can undergo "locus suicide recombination" (LSR), then deleting the constant gene cluster and terminating IgH expression. The relative contribution of LSR to B cell negative selection remains to be determined. Here, we set up a knock-in mouse reporter model for LSR events with the aim to get clearer insights into the circumstances triggering LSR. In order to explore the consequences of LSR defects, we reciprocally explored the presence of autoantibodies in various mutant mouse lines in which LSR was perturbed by the lack of Sµ or of the 3'RR. Evaluation of LSR events in a dedicated reporter mouse model showed their occurrence in various conditions of B cell activation, notably in antigen-experienced B cells Studies of mice with LSR defects evidenced increased amounts of self-reactive antibodies. While the activation pathways associated with LSR are diverse, in vivo as well as in vitro, this study suggests that LSR may contribute to the elimination of self-reactive B cells.

Vaccination prior to SARS-CoV-2 infection reduces autoreactive antibody induction

Abstract SARS-CoV-2 infection leads to diverse outcomes ranging from asymptomatic infection to death. Several studies reported elevated autoreactive antibodies in SARS-CoV-2-infected individuals compared to healthy controls, suggesting SARS-CoV-2 infection promotes autoantibodies, which could increase the risk of autoimmunity. However, it is not known whether autoreactive antibodies observed after infection were present in individuals prior to infection. Further, the prevalence, duration, and vaccine impact on autoreactive antibodies are unresolved. Since elevated autoreactive antibodies precede the onset of autoimmune disease, it is important to investigate the impact of SARS-CoV-2 infection on self-reactive antibodies. We established a longitudinal study to collect baseline PBMC and plasma samples from participants at enrollment, beforeSARS-CoV-2 infection or vaccination. Participants were screened weekly by nasal swab PCR to detect asymptomatic infection. Additional samples were collected after confirmed SARS-CoV-2 infection and assessed for autoreactive antibodies predictive of various autoimmune disorders. Preliminary analysis showed that a subset of individuals exhibited an increase in autoreactive antibodies following infection, while other individuals unexpectedly displayed decreased levels. Notably, individuals infected after vaccination displayed fewer changes in autoreactive antibodies compared to infection prior to vaccination. Our data suggest that SARS-CoV-2 infection increases specific autoreactive antibody levels but does not induce a widespread increase in all autoreactive antibodies. Moreover, SARS-CoV-2 vaccination prior to infection reduced autoantibody induction. Supported by grants from NIH CEIRS HHSN272201400006C and Household Respiratory Virus SARS-CoV-2 Transmission and Immunity Sub-Study (HRTS) 3U01AI144616-02S1

Impact of Lymphatic Pump Treatment and Methotrexate on Inflammation, Cytokine Production, and Leukocyte Infiltration in a Rat Model of Rheumatoid Arthritis

Abstract Rheumatoid Arthritis in autoimmune disease afflicting synovial joints leading to chronic joint damage. While the specific mechanisms have not been fully identified, the immune system and inflammatory factors are actively involved. T cells release cytokines and chemokines, such as TNF-alpha, IL-1 and IL-6, CINC-1 and CINC-2, and B cells produce self-reactive antibodies including rheumatoid factor and anti-citrullinated protein antibodies. All these factors result in a pronounced and aggressive inflammatory response within the joints. Lymphatic pump treatment (LPT) promotes lymphatic flow within the body, causing a flushing out of the immune-complexes and pro-inflammatory cells. Using a rat AIA model, the goal was to determine if LPT in conjunction with methotrexate had a greater impact on rheumatoid arthritis symptoms than methotrexate alone. A 21-day AIA rat study was performed using LPT and methotrexate treatments on days 14–21. Ankle circumference and articular index scores were recorded daily as a measurement of inflammation. ELISAs of arthritic ankles homogenates and serum were used to analyze cytokine, chemokine, and autoantibody concentrations. Immune cell infiltration into the ankles was determined using immunohistochemistry. We found that LPT with methotrexate treatment did not significantly alter ankle circumference, articular index scores, immune cell infiltration, cytokine, chemokine, or antibody concentrations compared to methotrexate alone. Overall, methotrexate combined with LPT treatments on days 14–21 did not significantly alter disease progression, however, it is possible that earlier LPT treatment may have a more significant impact on disease progression. College of Graduate Studies Biomedical Sciences program at Midwestern University, Downers Grove, IL.

Characterization of a spontaneously occurring self-reactive antibody against sperm in mice

We previously established a spontaneously occurring monoclonal antibody, namely Ts3, that was reactive to sperm from an aged male mouse. The present study investigated the characteristic properties and reproductive functions of Ts3. Immunofluorescent staining revealed that Ts3 reacted to epididymal sperm, and the corresponding antigen was located in the midpiece and principal piece. Immunohistochemistry revealed positive reactions in the germ cells and Sertoli cells in the testis, the epithelial cells in the epididymis and vas deferens. Through western blotting with two-dimensional electrophoresis, we demonstrated that Ts3 reacted with four spots, which were around Mr ∼25,000–60,000 and pI 5–6. MALDI-TOF/TOF mass spectrometry identified outer dense fiber 2 (ODF2) as a candidate for Ts3. ODF2 is a cytoskeletal structural component located in the midpiece and principal piece of the flagella of mammalian sperm. This was validated with the result of immunofluorescent staining, suggesting that ODF2 was the main target antigen for Ts3. Sperm immobilization test showed that Ts3 possessed sperm immobilizing activity. Furthermore, Ts3 impaired early embryo development but not in vitro fertilization. These results suggest that ODF2 plays an important role in both sperm function and early embryonic development.

OA2-3 - Characterization of a spontaneously-occurring self-reactive antibody against sperm in mice

OA2-3 - Characterization of a spontaneously-occurring self-reactive antibody against sperm in mice

Some Trace Elements and Oxidative Stress Status in Patients with Chronic Rheumatoid Arthritis

Background Rheumatoid arthritis (R.A.) is a complex polygenic, au- toimmune inflammatory disease. It was disturbing that almost 1-2% of people depended on that geographic spreading worldwide. R.A. can result from the interaction of genetic, environmental, and autoimmunity. It is characterized by non-organ-specific self-reactive antibody production and chronic synovitis leading to the damage of cartilage and bone. Objectives To evaluate the sera of trace elements and oxidative stress levels in patients detected with chronic rheumatoid arthritis. Determination of some trace elements such as copper, zinc, and iron in the sera of patients.Patients and Method A case-control study was done on the Iraqi population from Al-Najaf, an Iraqi city. Blood samples were collected from 135 volunteers from September 2021 to February 2022 from Al-Sadder Medical City (Al-Najaf). The 180 volunteers in our study were divided into two groups patient group consisting of 90 individuals ages range: (20–70 years), male and female, and a control group consisting of 45 individuals. Blood was drawn from the patients to measure the copper, zinc, and iron concentration level using the Colorimetric method technique.Results The average zinc concentration was lower in the patient’s group than in the reference category. The average copper concentration was more significant in the patient’s group than in the reference category. In addi- tion, the average Zn/Cu ratio was lower in the patient’s group compared to the reference category. There was no statistical variation in average serum iron between patients and the reference category. However, the average Zn/Fe ratio was lower in the patient’s group compared to the reference category control group.Conclusion Lower levels of zinc and a higher level of copper suggest a role for those trace elements on that pathogen of R.A.

PREMEDICATION REGIMEN FOR THE PREVENTION OF ADVERSE REACTIONS ASSOCIATED WITH THERAPEUTIC PLASMA EXCHANGE

<h3>Introduction</h3> Therapeutic plasma exchange (TPE) is an essential treatment for various conditions as it removes plasma containing self-reactive antibodies and proteins, replacing them with isosmotic fluid. Among the commonly encountered complications, hypersensitivity reactions, including urticaria, pruritus and anaphylaxis have been reported to occur in 3-12% of patients. Information regarding effective prophylactic management to prevent these reactions is lacking. We present a case where hypersensitivity reactions to TPE were prevented using an iodinated contrast premedication protocol. <h3>Case Description</h3> A 25-year-old male patient with a history of ESRD status post deceased donor transplant with mixed rejection was evaluated for an adverse reaction during TPE. He had previously received nine treatments, six months prior which were well-tolerated. During the first of eight TPEs, the patient developed urticaria, eyelid edema and dyspnea. Given the reaction, he was pre-medicated for subsequent TPEs with methylprednisolone 40mg IV, 5 hours and 1 hour prior to TPE and diphenhydramine 50mg IV 1 hour prior to TPE. Future TPEs were well-tolerated with the premedication regimen with the exception of mild hives during his sixth session. <h3>Discussion</h3> Although TPE hypersensitivity reactions have been commonly reported, an effective method of premedication has yet to be established. We aim to bring awareness of a premedication regimen prior to TPE using a 5 hour and 1 hour IV protocol in patients with hypersensitivity reactions related to the procedure.

Breaking the Paradigm: Selection of Self-Reactive Natural Antibodies.

Abstract This Pillars of Immunology article is a commentary on “Positive Selection of Natural Autoreactive B Cells,” a pivotal article written by K. Hayakawa, M. Asano, S. A. Shinton, M. Gui, D. Allman, C. L. Stewart, J. Silver, and R. R. Hardy, and published in Science, in 1999. https://doi.org/10.1126/science.285.5424.113.

Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies.

Systemic lupus erythematosus (SLE) mainly affects females at reproductive age, which has been associated with hormones, such as prolactin (PRL). Different studies suggest that PRL exacerbates the clinical manifestations of SLE both in patients and in mouse models (e.g., the MRL/lpr strain), increasing the production of autoantibodies, which can be deposited as immune complexes and trigger inflammation and damage to different tissues. The objective of this work was to explore the potential mechanisms by which PRL increases the concentration of self-reactive antibodies in the MRL/lpr SLE model. To this end, we determined the role of PRL on the activation and proliferation of germinal center B cells (B-GCs) and their differentiation into antibody-secreting cells (ASCs). We show that the absolute number and percentage of B-GCs were significantly increased by PRL in vivo or upon in vitro treatment with anti-IgM and anti-CD40 antibodies and PRL. The augmented B-GC numbers correlated with enhanced proliferation, but we did not observe enhanced expression of CD80 and CD86 activation markers or the BCL6 transcription factor, arguing against a more effective differentiation. Nevertheless, we observed enhanced phosphorylation of STAT1, secretion of IL-6, expression of IRF4, numbers of ASCs, and levels of IgG3 antibodies directed against dsDNA. Altogether, these results support the hypothesis that a PRL-mediated expansion of B-GCs yields more self-reactive ASCs, potentially explaining the pathogenic immune complexes that steadily lead to tissue damage during SLE.

OP-17 - Characterization of spontaneously-occurring self-reactive antibody to sperm and its effects on in-vitro fertilization

Anti-sperm antibodies detected in humans possibly cause infertility. The mechanism of antibody production and the corresponding antigen are still unknown. Previously, we established a monoclonal antibody (named Ts3) reactive to sperm from an aged male mouse without any immunization. This study aims to identify the target self-antigen of Ts3 and to examine its effects on in-vitro fertilization. To examine the localization of the Ts3 recognizing antigen, mouse epididymal sperm were collected for immunofluorescent staining. The sperm proteins were extracted for two-dimensional electrophoresis and western blot analysis. Positive spots were subjected to mass spectrometry (MS). To determine influence on sperm motility, sperm immobilization test (SIT) with Ts3 was carried out. Further, the effects of Ts3 on mouse in-vitro fertilization and the developmental capacity of preimplantation embryos were investigated. Ts3 reacted to the midpiece and principal piece of mouse sperm. The detected molecular weight of the antigen to Ts3 was around 37 kDa, and the molecule was identified as outer dense fiber protein 2 (ODF2) by MS. In SIT, Ts3 was suggested to have harmful effect on sperm motility. Ts3 inhibited embryo development but not fertilization in mouse. Immunofluorescent staining of mouse preimplantation embryo showed Ts3 reacted to the membrane of the embryo and the areas of cellular contact. This study showed that Ts3, a spontaneously-occurring self-reactive antibody to sperm, recognized ODF2 as a targeted antigen. Although Ts3 did not inhibit fertilization, it impaired the sperm motility and the development of preimplantation embryo. Therefore, ODF2 antigen may be a pathogenic factor in infertility.

Dysregulated naive B cells and de novo autoreactivity in severe COVID-19

Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2–5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6–10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14–18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10–15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.

γδ Tcells license immature B cells to produce a broad range of polyreactive antibodies.

Immature autoreactive B cells are present in all healthy individuals, but it is unclear which signals are required for their maturation into antibody-producing cells. Inducible depletion of γδ Tcells show that direct interaction between γδ Tcells and immature B cells in the spleen support an "innate" transition to mature B cells with a broad range of antigen specificities. IL-4 production of γδ Tcells and cell-to-cell contact via CD30L support B cell maturation and induce genes of the unfolded protein response and mTORC1 signaling. Eight days after invivo depletion of γδ Tcells, increased numbers of B cells are already stuck in the transitional phase and express increased levels of IgD and CD21. Absence of γδ Tcells leads also to reduced levels of serum anti-nuclear autoantibodies, making γδ Tcells an attractive target to treat autoimmunity.

Antibodies as biomarkers for cancer risk: a systematic review.

Increasing evidence has linked the humoral immune response with the development of various cancers. Therefore, there is growing interest in investigating the predictive value of antibodies to assess overall and tissue site-specific cancer risk. Given the large amount of antibody types and the broad scope of the search (i.e. cancer risk), the primary aim of this systematic review was to present an overview of the most researched antibodies (i.e. immunoglobulin (Ig) isotypes (IgG, IgM, IgA, and IgE), tumour and self-antigen-reactive antibodies, infection-related antibodies) in relation to overall and site-specific cancer risk. We identified various antibody types that have been associated with the risk of cancer. While no significant associations were found for IgM serum levels, studies found an inconsistent association among IgE, IgA, and IgG serum levels in relation to cancer risk. When evaluating antibodies against infectious agents, most studies reported a positive link with specific cancers known to be associated with the specific agent recognized by serum antibodies (i.e. helicobacter pylori and gastric cancer, hepatitis B virus and hepatocellular carcinoma, and human papillomavirus and cervical cancer). Several reports identified autoantibodies, as single biomarkers (e.g. anti-p53, anti-MUC1, and anti-CA125) but especially in panels of multiple autoantibodies, to have potential as diagnostic biomarkers for specific cancer types. Overall, there is emerging evidence associating certain antibodies to cancer risk, especially immunoglobulin isotypes, tumour-associated antigen-specific, and self-reactive antibodies. Further experimental studies are necessary to assess the efficacy of specific antibodies as markers for the early diagnosis of cancer.