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Background: IgA nephropathy is thought to be an autoimmune disease wherein galactose-deficient IgA1 (Gd-IgA1) is recognized by IgG autoantibodies, resulting in formation and renal accumulation of nephritogenic immune complexes. Although this hypothesis is supported by recent findings that, in renal immunodeposits of IgA nephropathy patients, IgG is enriched for Gd-IgA1-specific autoantibodies, experimental proof is still lacking., Methods: IgG isolated from sera of IgA nephropathy patients or produced as a recombinant IgG (rIgG) was mixed with human Gd-IgA1 to form immune complexes. IgG from healthy individuals served as a control. Nude and SCID mice were injected with human IgG and Gd-IgA1, in immune complexes or individually, and their presence in kidneys was ascertained by immunofluorescence. Pathologic changes in the glomeruli were evaluated by quantitative morphometry and exploratory transcriptomic profiling was performed by RNA-Seq., Results: Immunodeficient mice injected with Gd-IgA1 mixed with IgG autoantibodies from patients with IgA nephropathy, but not Gd-IgA1 mixed with IgG from healthy individuals, displayed IgA, IgG, and mouse complement C3 glomerular deposits and mesangioproliferative glomerular injury with hematuria and proteinuria. Un-complexed Gd-IgA1 or IgG did not induce pathological changes. Moreover, Gd-IgA1-rIgG immune complexes injected into immunodeficient mice induced histopathological changes characteristic of human disease. Exploratory transcriptome profiling of mouse kidney tissues indicated that these immune complexes altered gene expression of multiple pathways, in concordance with the changes observed in kidney biopsies of patients with IgA nephropathy., Conclusions: This study provides the first in vivo evidence for a pathogenic role of IgG autoantibodies specific for Gd-IgA1 in the pathogenesis of IgA nephropathy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Consistently with their diagnostic and prognostic value, autoantibodies specific for systemic sclerosis (SSc) embedded in immune complexes (ICs) elicited a pro-inflammatory and pro-fibrotic cascade in healthy skin fibroblasts, engaging Toll-like receptors (TLRs) via their nucleic acid components. The objective of this study was to investigate the pathogenicity of SSc-ICs in endothelial cells., Methods: ICs were purified from the sera of SSc patients bearing different autoantibody specificities (antibodies against DNA topoisomerase I, centromeric proteins, RNA polymerase, and Th/To), patients with systemic lupus erythematosus (SLE) and primary anti-phospholipid syndrome (PAPS), or healthy controls (NHS) using polyethylene glycol precipitation. Human umbilical vein endothelial cells (HUVECs) were incubated with ICs, positive and negative controls. mRNA levels of endothelin-1 (et-1), collagenIα1 (colIα1), interferon (IFN)-α, and IFN-β were investigated by real-time PCR; et-1 and il-6 mRNA levels were assessed after pre-treatment with bafilomycin. ICAM-1 expression was evaluated by cell ELISA; secretion of IL-6, IL-8, and transforming growth factor (TGF)-β1 in culture supernatants was measured by ELISA. The expression of Fcγ receptors (CD64, CD32, and CD16) was assessed in endothelial cells at FACS analysis. Intracellular signaling pathways culminating with NFκB, p38MAPK, SAPK-JNK, and Akt were assessed by Western blotting. Healthy skin fibroblasts were stimulated with supernatants from HUVECs incubated with ICs, and TGF-β1 secretion and mRNA levels of colIα1 and matrix metalloproteinase (mmp)-1, protein expression of α smooth muscle actin (α-SMA), and IL-6 were evaluated by Western blotting; et-1 mRNA levels were assessed in fibroblasts pre-treated with IL-6 and TGF-β inhibitors and stimulated with ATA-ICs., Results: All SSc stimulated IL-6 secretion; ACA-ICs and anti-Th/To-ICs increased ICAM-1 expression; all SSc-ICs but anti-Th/To-ICs augmented IL-8 levels; all SSc-ICs but ACA-ICs and ARA-ICs upregulated et-1, and all SSc-ICs but ARA-ICs affected TGF-β1 secretion. colIα1, IFN-α, and IFN-β mRNA levels were not affected by any SSc-IC. FcγRII (CD32) and FcγRIII (CD16) were not detectable on HUVECs, while FcγRI (CD64) was minimally expressed. A differential modulation of tlr expression was observed: tlr2, tlr3, and tlr4 were upregulated by ATA-ICs and ACA-ICs, while anti-Th/To-ICs resulted in tlr9 upregulation. Pre-treatment with bafilomycin did not affect the upregulation of et-1 and il-6 induced by ATA-ICs, ACA-ICs, and anti-Th/To-ICs; a 23% reduction in both genes was reported for ARA-ICs. All SSc-ICs activated p38MAPK and Akt, and all SSc-ICs but ARA-ICs yielded the activation of NFκB; ATA-ICs and ACA-ICs increased the activation rate of both subunits of SAPK-JNK. When healthy skin fibroblasts were stimulated with supernatants from HUVECs incubated with SSc-ICs, TGF-β1 secretion, colIα1, α-SMA, and IL-6 expression levels were significantly modulated. Pre-treatment with IL-6 and TGF-β inhibitors prevented et-1 upregulation induced by ATA-ICs by 85% and 77%, respectively., Conclusions: These data provide the first demonstration of the pathogenicity of ICs from scleroderma patients with different autoantibodies on the endothelium. Endothelial activation induced by SSc-ICs ultimately led to a pro-fibrotic phenotype in healthy skin fibroblasts.

We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-α2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA ( p < 0.001), anti-Smith antigen (Sm) ( p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) ( p < 0.001), anti-Sm-U1RNP complex ( p = 0.028), and anti-ribosomal P ( p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-α2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Systemic lupus erythematosus (SLE) is a chronic multi-system inflammatory disease associated with autoantibody formation. Clinical management of lupus is associated with multiple adverse events. Resveratrol is a phytoalexin with several pharmacological properties. This study aimed to evaluate the combinatorial effect of resveratrol (25 mg/kg and 50 mg/kg) and its bio-enhancer piperine (1/10th dose of resveratrol) on pristane-induced SLE murine model. Mice were injected with 0.5 ml of pristane and after 2 months they were orally dosed with resveratrol combinations for 4 months. Determined by indirect immunofluorescence, resveratrol was unable to abrogate autoantibody formation. The increased IFN-α, IL-6 and TNF-α was mitigated by low dose of resveratrol and piperine (RP-1). None of the doses regulated the increase in nitric oxide. Lipogranulomas associated with injected pristane were not observed after RP-1 and high dose of resveratrol (Res-2) treatment. Lupus mice witnessed IgG and IgM immune complexes by direct immunofluorescence assay and associated histopathological observations in kidneys, liver, lung, spleen and skin. None of the treatment regimens were able to regulate the manifestations observed in spleen and skin. RP-1 and Res-2 proved beneficial in kidney, liver and lungs and were able to ameliorate lupus associated manifestations. Renal manifestations (proteinuria and decreased creatinine in urine) were successfully mitigated by RP-1 and Res-2 and high dose combination of resveratrol and piperine. Oxidative stress (reactive oxygen species by flowcytometry and catalase, superoxide dismutase, glutathione peroxidase, reduced glutathione and lipid peroxidation by biochemical analysis) was evident by pristane injection. These were regulated by different doses of resveratrol alone and in combination with piperine. Hence, resveratrol when used in combination with piperine successfully reduces some measures of morbidity with little or no effect on mortality associated with lupus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by immune complexes. Because these complexes contain mitochondrial components, we assessed the presence of antibodies to whole mitochondria (wMITO) using an ELISA in which mitochondria from mouse liver are bound to microtiter plates pre-coated with poly-l-lysine. Studies with this ELISA demonstrated that SLE plasmas contain abundant anti-wMITO activity. While digestion with DNase 1 did not affect anti-wMITO activity, adsorption of plasma on DNA affinity columns could reduce binding activity. Assay for anti-mitochondrial antibodies (AMA) by immunofluorescence and an ELISA with the M2 antigen (2-oxo-acid dehydrogenase protein complex) showed a low frequency of positivity, indicating that AMA and anti-wMITO are distinct specificities. In the study of 204 patients with SLE, the levels of anti-wMITO were higher in active SLE and correlated with levels of anti-DNA. These findings suggest that anti-wMITO can form immune complexes with mitochondria which may drive pathogenesis., (Published by Elsevier Inc.)

Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG-rheumatoid factor (IgG-RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG-RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG-RF production by plasma cells and regulates autoimmune-mediated bone loss. Fra1 deficiency in B cells (Fra1 ΔBcell ) led to increased IgG1-producing bone marrow plasma cells, enhanced IgG-RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG-RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T-cell-dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast-mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG-RF production and autoimmune-mediated bone loss. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Background: In systemic sclerosis (SSc), autoantibodies provide the most accurate tool to predict the disease subset and pattern of organ involvement. Scleroderma autoantibodies target nucleic acids or DNA/RNA-binding proteins, thus SSc immune complexes (ICs) can embed nucleic acids. Our working hypothesis envisaged that ICs containing scleroderma-specific autoantibodies might elicit proinflammatory and profibrotic effects in skin fibroblasts., Methods: Fibroblasts were isolated from skin biopsies obtained from healthy subjects and patients with diffuse cutaneous SSc (dcSSc). ICs were purified by polyethylene-glycol precipitation from sera of SSc patients bearing different autoantibodies. ICs from patients with systemic lupus erythematosus (SLE) and primary anti-phospholipid syndrome (PAPS) and from normal healthy subjects (NHS) were used as controls. After incubation with ICs, fibroblasts were evaluated for ICAM-1 expression, interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-2, tumor growth factor (TGF)-β1 and Pro-CollagenIα1 secretion, collagen (col)Iα1, mmp-1, toll-like receptor (tlr)2, tlr3, tlr4, tlr7, tlr8, tlr9, interferon (ifn)-α, ifn-β and endothelin-1 mRNA, and NFκB, p38MAPK and SAPK-JNK activation rate. Experiments were also performed after pretreatment with DNase I/RNase and NFκB/p38MAPK inhibitors., Results: The antigenic reactivity for each SSc-IC mirrored the corresponding serum autoantibody specificity, while no positivity was observed in NHS-ICs or sera. SSc-ICs but not NHS-ICs increased ICAM-1 expression, stimulated IL-6, IL-8, MMP-2, MCP-1, TGF-β1 and Pro-CollagenIα1 secretion, upregulated et-1, ifn-α, ifn-β, tlr2, tlr3 and tlr4, and activated NFκB, p38MAPK and SAPK-JNK. tlr9 was significantly upregulated by ARA-ICs, mmp-1 was significantly induced by ACA-ICs whereas colIα1 was not modulated by any SSc-ICs. SLE-ICs and PAPS-ICs significantly upregulated MMP-2 and activated NFκB, p38MAPK and SAPK-JNK. SLE-ICs and PAPS-ICs did not affect colIα1, mmp-1 and Pro-CollagenIα1. DNase I and RNase treatment significantly reduced the upregulation of study mediators induced by SSc-ICs. Pretreatment with NFκB/p38MAPK inhibitors suggested that response to anti-Th/To-ICs was preferentially mediated by p38MAPK whereas ATA-ICs, ACA-ICs and ARA-ICs engaged both mediators. In dcSSc fibroblasts, stimulation with SSc-ICs and NHS-ICs upregulated IL-6 and IL-8., Conclusions: These data provide the first demonstration of the proinflammatory and profibrotic effects of SSc-ICs on fibroblasts, suggesting the potential pathogenicity of SSc autoantibodies. These effects might be mediated by Toll-like receptors via the interaction with nucleic acid fragments embedded in SSc-ICs.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is often difficult to diagnose and distinguish from other diseases, because no NPSLE-specific antibodies have been identified. We developed a novel proteomic strategy for identifying and profiling antigens in immune complexes in the cerebrospinal fluid (CSF), and applied this strategy to 26 NPSLE patients. As controls, we also included 25 SLE patients without neuropsychiatric manifestations (SLE), 15 with relapsing remitting multiple sclerosis (MS) and 10 with normal pressure hydrocephalus (NPH). We identified immune complexes of suprabasin (SBSN) in the CSF of the NPSLE group. The titer of anti-SBSN antibodies was significantly higher in the CSF of the NPSLE group compared to those of the SLE, MS and NPH groups. Microarray data showed that the senescence and autophagy pathways were significantly changed in astrocytes exposed to anti-SBSN antibodies. Our findings indicate that SBSN could be a novel autoantibody for the evaluation of suspected NPSLE., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Primary renal tubulointerstitial disease resulting from proximal tubule antigen-specific antibodies and immune complex formation has not been well characterized in humans. We report a cohort of patients with a distinct, underappreciated kidney disease characterized by kidney antibrush border antibodies and renal failure (ABBA disease). We identified ten patients with ABBA disease who had a combination of proximal tubule damage, IgG-positive immune deposits in the tubular basement membrane, and circulating antibodies reactive with normal human kidney proximal tubular brush border. All but one of the patients also had segmental glomerular deposits on renal biopsy specimen. Patients with ABBA disease were elderly and presented with AKI and subnephrotic proteinuria. Serum from all patients but not controls recognized a high molecular weight protein in renal tubular protein extracts that we identified as LDL receptor-related protein 2 (LRP2), also known as megalin, by immunoprecipitation and mass spectrometry. Immunostaining revealed that LRP2 specifically colocalized with IgG in the tubular immune deposits on the ABBA biopsy specimen but not the control specimen analyzed. Finally, ABBA serum samples but not control samples showed reactivity against recombinantly expressed N-terminal LRP2 fragments on Western blots and immunoprecipitated the recombinantly expressed N-terminal region of LRP2. This case series details the clinicopathologic findings of patients with ABBA disease and shows that the antigenic target of these autoantibodies is LRP2. Future studies are needed to determine the disease prevalence, stimulus for ABBA, and optimal treatment., (Copyright © 2018 by the American Society of Nephrology.)

Immune complexes (IC) containing predominantly malondialdehyde-LDL and the corresponding autoantibodies (MDA-LDL IC) predict acute cardiovascular events, while IC rich in oxidized LDL (oxLDL IC) predict cardiovascular disease progression. Our objective was to determine mechanisms that could explain these prognostic differences. We compared the effects of the interaction of oxLDL, MDA-LDL and the corresponding IC with human macrophages focusing on apoptosis, metalloproteinases, and proinflammatory cytokines. MDA-LDL IC induced higher degrees of apoptosis, higher levels of caspase-3 expression, and increased expression and release of MMP-1 and TNF compared to MDA-LDL, oxLDL, and oxLDL IC. The pro-apoptotic effects of MDA-LDL IC were inhibited by blocking TNFR 1 or FcγRI. Blocking FcγRI abrogated the induction and expression of MMPs and proinflammatory cytokines by MDA-LDL IC. In conclusion, the interaction of MDA-LDL IC with FcγRI triggers macrophage apoptosis and increased expression and release of TNF and MMP-1, which can lead to the rupture of unstable plaques., (Copyright © 2017. Published by Elsevier Inc.)

Background: Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy due to the development of autoantibodies against the VWF-cleaving protease ADAMTS13. ADAMTS13-specific circulating immune complexes (CICs) have been described in patients with acquired TTP, but their clinical relevance remained to be established. The aim of this study was to assess the association between ADAMTS13-specific CICs and ADAMTS13-related measurements, clinical and laboratory markers of disease severity, and occurrence of TTP relapse, in autoimmune TTP patients., Material and Methods: We measured ADAMTS13-specific CICs in 51 patients with severe ADAMTS13 deficiency and anti-ADAMTS13 autoantibodies, at the first episode of acquired TTP. The associations between ADAMTS13-specific CICs and the variables of interest were assessed by linear, logistic and Cox proportional hazard regression models, where appropriate., Results: The prevalence of ADAMTS13-specific CICs in patients experiencing the first TTP episode was 39% (95% confidence intervals [CI]: 26-52%). ADAMTS13-specific CICs were not associated neither with laboratory markers of disease severity, nor with patterns of clinical presentation. Conversely, among 45 survivors, a positive association was found between the presence of ADAMTS13-specific CICs and the risk of recurrence within 2years after the first TTP episode (adjusted hazard ratio, 3.4 [95% CI: 0.9 to 13.5])., Conclusions: ADAMTS13-specific CICs seem to be able to predict the recurrence of acute TTP episodes in the first 2years after disease onset. Therefore, their measurement might be used as a tool to stratify the risk of disease relapse, with potential influence on surveillance and therapeutic choices during remission phase., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Autoantibodies against galactose-deficient IgA1 drive formation of pathogenic immune complexes in IgA nephropathy. IgG autoantibodies against galactose-deficient IgA1 in patients with IgA nephropathy have a specific amino-acid sequence, Y 1 CS 3 , in the complementarity-determining region 3 of the heavy chain variable region compared with a Y 1 CA 3 sequence in similar isotype-matched IgG from healthy controls. We previously found that the S 3 residue is critical for binding galactose-deficient IgA1. To determine whether this difference is due to a rare germline sequence, we amplified and sequenced the corresponding germline variable region genes from peripheral blood mononuclear cells of seven patients with IgA nephropathy and six healthy controls from whom we had cloned single-cell lines secreting monoclonal IgG specific for galactose-deficient IgA1. Sanger DNA sequencing revealed that complementarity-determining region 3 in the variable region of the germline genes encoded the Y 1 C(A/V) 3 amino-acid sequence. Thus, the A/V>S substitution in the complementarity-determining region 3 of anti-galactose-deficient-IgA1 autoantibodies of the patients with IgA nephropathy is not a rare germline gene variant. Modeling analyses indicated that the S 3 hydroxyl group spans the complementarity-determining region 3 loop stem, stabilizing the adjacent β-sheet and stem structure, important features for effective binding to galactose-deficient IgA1. Understanding processes leading to production of the autoantibodies may offer new approaches to treat IgA nephropathy., (Copyright © 2016 by the American Society of Nephrology.)

A deficiency in ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type-1 repeats, member 13) is associated with thrombotic thrombocytopenic purpura (TTP). Congenital TTP is caused by a defect in the ADAMTS13 gene resulting in decreased or absent enzyme activity; acquired TTP results from autoantibodies that either inhibit the activity or increase the clearance of ADAMTS13. Despite major progress in recent years in our understanding of the disease, many aspects around the pathophysiology of TTP are still unclear. Newer studies expanded the TTP field from ADAMTS13 and inhibitory antibodies to immune complexes, cloned autoantibodies, and a possible involvement of other proteases. Additionally, several new treatment strategies supplementing plasma-exchange and infusion are under investigation for a better and more specific treatment of TTP patients. In this review, we discuss the recent insights in TTP pathophysiology and describe upcoming therapeutic opportunities.

Introduction: Patients with persistent high levels of serum vitamin B12 were often referred to Hematology departments. In this study, characteristic of patients with serum vitamin B12 levels higher than 2500 pmol/L (high B12) were studied., Methods: Prevalence of high B12 was evaluated during a 10-month period. Samples with high B12 were incubated with polyethylene glycol (PEG) and a new measurement of vitamin B12 was carried out using the supernatant. As a pilot study, 26 frozen samples with high B12 were evaluated for changes in vitamin B12 after PEG. Moreover, a prospective study was carried out during three consecutive months. Size exclusion chromatography was employed to demonstrate the presence of immune complexes (ICs) with plasma vitamin B12-binding proteins in some serum samples with high B12., Results: Prevalence of high B12 was 1.3%. Results from 26 frozen samples and from a prospective study (28 cases) showed that undergoing vitamin B12 treatment was the main cause of high B12. However, ICs were detected in 10 frozen samples and in seven cases (25%) of the prospective study, respectively. Serum vitamin B12 decreased to normal values after precipitation with PEG, and size exclusion chromatography confirmed ICs. An association with autoimmune or hematological disorders was observed., Conclusions: In patients with repeatedly high B12 levels, ICs were detected in approximately 25% of samples. Precipitation with PEG is an easy method to confirm the presence of ICs and to evaluate serum vitamin B12 levels in these patients., (© 2013 John Wiley & Sons Ltd.)

Induction of autoantibodies (autoAbs) targeting disease drivers / mediators is emerging as a potential immunotherapeutic strategy. Auto-immune complex (IC)-retaining follicular dendritic cells (FDCs) critically regulate pathogenic autoAb production in autoreactive germinal centers (GCs); however, their ability to induce potentially therapeutic autoAbs has not been explored. We hypothesized that deliberate display of clinically targeted antigens (Ags) in the form of ICs on FDC membranes induces target-specific autoreactive GCs and autoAbs that may be exploited therapeutically. To test our hypothesis, three therapeutically relevant Ags: TNF-α, HER2/neu and IgE, were investigated. Our results indicated that TNF-α-, HER2/neu- and IgE-specific autoAbs associated with strong GC reactions were induced by TNF-α-, HER2/neu- and IgE-IC retention on FDCs. Moreover, the induced anti-TNF-α autoAbs neutralized mouse and human TNF-α with half maximal Inhibitory Concentration (IC₅₀) of 7.1 and 1.6 nM respectively. In addition, we demonstrated that FDC-induced Ab production could be non-specifically inhibited by the IgG-specific Endo-S that accessed the light zones of GCs and interfered with FDC-IC retention. In conclusion, the ability of FDCs to productively present autoAgs raises the potential for a novel immunotherapeutic platform targeting mediators of autoimmune disorders, allergic diseases, and Ab responsive cancers.

Simple Summary: Cytokines are substances important in the regulation of the immune system. The cytokine interleukin-6 (IL-6) is important for the normal function of the immune system and also plays a pathogenic role in multiple diseases such as chronic inflammation, autoimmunity cancer, sepsis, and cardiovascular disease. A new immunoregulatory mechanism is described. Proteolytic degradation of serum albumin generates immunoregulatory neo-structures, one of which has the capacity to induce IL-6, Il-6-inducing factor, IL-6IF. The serum concentration of this factor is significantly increased in advanced stages of colon cancer and is associated with cancer-specific survival of the patients. IL-6IF is immunogenic, resulting in the production of autoantibodies with the capacity to inhibit IL-6IF-induced IL-6 synthesis. The specificity of these autoantibodies, using the single B-cell technique, enables the production of human monoclonal antibodies, which therapeutically can be used to specifically inhibit pathological IL-6 production, leaving IL-6 for the normal function of the immune system intact. Background: Interleukin-6 is dysregulated in multiple pathological conditions, e.g., cancer and inflammatory diseases. Aim: To investigate new mechanisms for the regulation of pathological IL-6 production. Methods: PBMCs (peripheral blood mononuclear cells) stimulated by cancer serum factors or specific peptides produce interleukin-6 (IL-6). Immunoregulatory albumin neo-structures and peptides were identified with 2D gel electrophoresis and MALDI-TOF-MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) analyses. Il-6 and albumin neo-structures were determined by ELISA (enzyme-linked immunosorbent assay). Results: Conformational changes in normal serum albumin by proteolytic degradation generates an IL-6-inducing neo-structure, IL-6-inducing factor (IL-6IF). This neo-structure is immunogenic which results in the production of autoantibodies. IL-6 production induced by IL-6IF and cancer patient sera is inhibited by specific antibodies. The serum concentration of IL-6IF is significantly higher in advanced cancer stages, and its presence is significantly correlated with the survival of the patients. Conclusions: A new mechanism for the induction IL-6 synthesis is presented. Based on this mechanism, the pathological IL-6 production related to enhanced proteolytic activity can be diagnosed and selectively inhibited by specific antibodies. Such antibodies were identified and purified. Thus, the neo-structure, inducing pathological IL-6 production, associated with a reduced survival of cancer patients, can be selectively removed by the therapeutic administration of antibodies leaving the function of IL-6 needed for the normal activity of the immune system intact. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex multi-organ autoimmune disease marked by the production of autoantibodies against nuclear structures, formation of immune complexes, and chronic inflammation triggered by their tissular deposition. SLE is characterized by alternating periods of relapse and remission and each flare has the potential to cause new organ damage related to either the disease process or the medication toxicity. Despite remarkable progress across its multiple domains, SLE is still an area with many unmet needs, calling for innovative and practical solutions. The efforts of the drug development programme in lupus have led to considerable growth in the last decade, owing to the approval of belimumab, anifrolumab, and voclosporin. The increasing understanding of the pathogenesis of the disease has enabled the exploration of novel therapeutic strategies. New discoveries in the intricate cytokine kaleidoscope of lupus have made the concept of targeted therapy an attractive and promising research focus. JAK inhibitors are oral targeted therapies approved for a wide variety of diseases across the Rheumatology, Gastroenterology, Dermatology, and Haematology fields. Multiple JAKis are currently being investigated in SLE. This paper aims to summarize existing data coming from both clinical trials and case reports regarding the use of JAK inhibitors in SLE. [ABSTRACT FROM AUTHOR]

Introduction: Despite progress in our understanding of disease pathogenesis for systemic autoimmune rheumatic diseases (SARD), these diseases are still associated with high morbidity, disability, and mortality. Much of the strongest evidence to date implicating environmental factors in the development of autoimmunity has been based on well-established, large, longitudinal prospective cohort studies. Methods: Herein, we review the current state of knowledge on known environmental factors associated with the development of SARD and potential areas for future research. Results: The risk attributable to any particular environmental factor ranges from 10-200%, but exposures are likely synergistic in altering the immune system in a complex interplay of epigenetics, hormonal factors, and the microbiome leading to systemic inflammation and eventual organ damage. To reduce or forestall the progression of autoimmunity, a better understanding of disease pathogenesis is still needed. Conclusion: Owing to the complexity and multifactorial nature of autoimmune disease, machine learning, a type of artificial intelligence, is increasingly utilized as an approach to analyzing large datasets. Future studies that identify patients who are at high risk of developing autoimmune diseases for prevention trials are needed. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a complex autoimmune disorder characterized by a spectrum of hypersensitivity reactions, encompassing Type II, Type III, and Type IV responses. Firstly, RA is marked by Type II hypersensitivity reactions driven by autoantibodies, such as rheumatoid factor (RF) and anti-(cyclic) citrullinated protein antibodies (ACPAs). These autoantibodies serve not only as serological markers for RA but also actively participate in inflammation, bone erosion, and clinical outcomes, with concurrent activation of the complement system involving C1q, C3, and C5 components specifically linked to RA progression and bone damage. Secondly, RA exhibits traits of Type III hypersensitivity, marked by the formation of immune complexes inciting inflammatory reactions. Immunoglobulin G (IgG) autoantibodies like RF and ACPA play pivotal roles in immune complex formation and the ensuing inflammatory responses. RA also demonstrates Type IV hypersensitivity propelled by CD4+ T cells, encompassing T helper 1 (Th1) and Th17 subsets. Th1 cells release interferon (IFN)-γ, promoting proinflammatory cytokines, while Th17 cells secrete IL-17, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF), contributing to synovial inflammation, bone and cartilage damage, and angiogenesis. RA concurrently exhibits features of Type II, Type III, and Type IV hypersensitivity. It is crucial to comprehend the presence and complex interplay of hypersensitivity responses and specific immune cell subsets in RA to create precise and efficient therapeutic approaches for the management of this incapacitating autoimmune condition. Thus, in this review, we aim to provide a comprehensive overview of the hypersensitivity features of RA.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of large amounts of autoantibodies and immune complex formation. Because of their atypical clinical symptoms, SLE patients with digestive system involvement may not be recognized or treated precisely and extensively. Clinicians should pay close attention to SLE with digestive system involvement, as these conditions can easily worsen the condition and possibly endanger the patient's life. In this review we summarized the pathogenesis, pathological characteristics, clinical manifestations, diagnosis, and therapies for digestive system involvement in SLE. [ABSTRACT FROM AUTHOR]

Long COVID, a name often given to the persistent symptoms following acute SARS-CoV-2 infection, poses a multifaceted challenge for health. This review explores the intrinsic relationship between comorbidities and autoimmune responses in shaping the trajectory of long COVID. Autoantibodies have emerged as significant players in COVID-19 pathophysiology, with implications for disease severity and progression. Studies show immune dysregulation persisting months after infection, marked by activated innate immune cells and high cytokine levels. The presence of autoantibodies against various autoantigens suggests their potential as comorbid factors in long COVID. Additionally, the formation of immune complexes may lead to severe disease progression, highlighting the urgency for early detection and intervention. Furthermore, long COVID is highly linked to cardiovascular complications and neurological symptoms, posing challenges in diagnosis and management. Multidisciplinary approaches, including vaccination, tailored rehabilitation, and pharmacological interventions, are used for mitigating long COVID's burden. However, numerous challenges persist, from evolving diagnostic criteria to addressing the psychosocial impact and predicting disease outcomes. Leveraging AI-based applications holds promise in enhancing patient management and improving our understanding of long COVID. As research continues to unfold, unravelling the complexities of long COVID remains paramount for effective intervention and patient care. [ABSTRACT FROM AUTHOR]

Since entering the stage 25 years ago as a highly specific serological biomarker for rheumatoid arthritis, anti-citrullinated protein antibodies (ACPAs) have been a topic of extensive research. This hallmark B cell response arises years before disease onset, displays interpatient autoantigen variability, and is associated with poor clinical outcomes. Technological and scientific advances have revealed broad clonal diversity and intriguing features including high levels of somatic hypermutation, variable-domain N-linked glycosylation, hapten-like peptide interactions, and clone-specific multireactivity to citrullinated, carbamylated and acetylated epitopes. ACPAs have been found in different isotypes and subclasses, in both circulation and tissue, and are secreted by both plasmablasts and long-lived plasma cells. Notably, although some disease-promoting features have been reported, results now demonstrate that certain monoclonal ACPAs therapeutically block arthritis and inflammation in mouse models. A wealth of functional studies using patient-derived polyclonal and monoclonal antibodies have provided evidence for pathogenic and protective effects of ACPAs in the context of arthritis. To understand the roles of ACPAs, one needs to consider their immunological properties by incorporating different facets such as rheumatoid arthritis B cell biology, environmental triggers and chronic antigen exposure. The emerging picture points to a complex role of citrulline-reactive autoantibodies, in which the diversity and dynamics of antibody clones could determine clinical progression and manifestations. In this Review, the authors provide an overview of the immunological, clinical and pathophysiological features of anti-citrullinated protein antibodies in rheumatoid arthritis, highlighting the latest findings regarding the complex contribution of anti-citrullinated protein antibodies to the disease. Key points: Citrulline B cell responses are diverse but share important features that might be linked to rheumatoid arthritis-associated B cell dysregulation as well as environmental triggers, antigen exposure and the evolution of chronic immune reactions. Anti-citrullinated protein antibodies (ACPAs) are extensively multireactive towards citrullinated, carbamylated and acetylated proteins, have high somatic hypermutation, and carry N-linked glycosylations in the variable regions. More than 100 patient-derived human monoclonal ACPAs have been generated from different B cell compartments and patients, providing invaluable insights into citrulline autoimmunity and antibody function. Although disease-causative autoantigens are presently unknown, ACPAs can target different synovial cells and are likely to form pathogenic immune complexes. Results from studies using human monoclonal ACPAs reveal that some clones can completely block arthritis and inflammation in mouse models, while showing moderate pathogenic properties in other settings. Different ACPA clones with different immunological features and antigen-binding patterns might mediate disease-promoting effects or have protective roles. [ABSTRACT FROM AUTHOR]

Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, FcαR, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-α responses in vitro. pDC responses to these ICs required both FcαR and FcγRIIa, showing synergy between these Fc receptors. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcαR than pDCs from healthy control individuals. Although pDC FcαR expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-α, up-regulated pDC FcαR expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis. Editor's summary: Autoantibodies to nuclear antigens contribute to pathology in systemic lupus erythematosus (SLE). However, it is not understood how different isotypes of these antibodies contribute to disease. Here, Waterman et al. characterized circulating immunoglobulin A1 (IgA1) autoantibodies in individuals with SLE, showing that they reacted against many of the same self-antigens as their immunoglobulin G (IgG) counterparts, including against Smith ribonuclear proteins. The authors further showed that interferon-α (IFN-α)–producing plasmacytoid dendritic cells expressed the IgA1 receptor, Fc α receptor (FcαR), and that IgA1-containing immune complexes could drive IFN-α production by these cells in vitro. The authors showed that these responses required the presence of both IgA1 and IgG. Last, the authors showed that, in 18 individuals with SLE, interferon-stimulated gene expression positively correlated with the amount of FcαR in whole blood. Together, these results suggest that targeting FcαR could be a potential therapeutic for SLE treatment. —Brandon Berry [ABSTRACT FROM AUTHOR]

Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila. IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1KI-CD89tg) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins—a risk locus for IgA nephropathy—inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease. Editor's summary: How the gut microbiome affects immunoglobulin A (IgA) nephropathy is not fully understood. Gleeson et al. investigated this interaction in patients with and without IgA nephropathy and in mice to show that Akkermansia muciniphila, a species of mucin-degrading bacteria, contributed to autoimmune kidney disease. Human IgA subclass 1 was deglycosylated by A. muciniphila and could travel from the mouse gut to the kidney glomeruli via the circulation. Mice expressing human IgA1 and human Fc α receptor I developed IgA nephropathy when colonized by A. muciniphila. In humans, increased amounts of α-defensin 6 were associated with decreased A. muciniphila in control individuals, but this correlation was lost in patients with IgA nephropathy. After incubation with A. muciniphila, human IgA1 was recognized by autoantibodies in sera of patients with IgA nephropathy. This study demonstrates that A. muciniphila contributes to IgA nephropathy pathogenesis. —Brandon Berry [ABSTRACT FROM AUTHOR]

The function of immune complexes in rheumatoid arthritis (RA) is related to their composition and size. Using dynamic light scattering (DLS), we investigated the link between the RA circulating immune complex (CIC) particles' size and the CIC immunoglobulin level. In this study, 30 RA patients and 30 healthy individuals were included. IgA, IgG, and IgM were found in all analyzed CICs, but more IgA and IgG were found in RA than in control CICs. In both control and RA CICs, DLS detected 50 particles that differed in size and clustered around two size groups: with a 7.5–164 nm radius and with a 342–1718 nm radius. An increased level of IgA in RA CICs, compared to control ones, was associated with more than 50% of CIC particles. In RA, compared to the control, a higher number of CICs with 28.2 nm, 531 nm, 712 nm, and 1718 nm particles and a lower number of CICs with 78.8 nm particles were detected. This particle distribution pattern did not reflect the changes in the CIC immunoglobulin level. Thus, RA elevated CIC IgA was linked with all these particles (except the 1718 nm particle), the IgM increase was linked with 43.8 nm and 712 nm particles, and the IgG increase was linked with the 712 nm particle only. This study provides the very first data on the association between CIC particles' size, CIC immunoglobulin level, and RA. It opens the possibility that the size of CICs determined by DLS can be used as a criterion in RA diagnosis or monitoring after a large-scale study confirmation. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an idiopathic chronic autoimmune disease that can affect any organ in the body, including the neurological system. Multiple factors, such as environmental (infections), genetic (many HLA alleles including DR2 and DR3, and genes including C4), and immunological influences on self-antigens, such as nuclear antigens, lead to the formation of multiple autoantibodies that cause deleterious damage to bodily tissues and organs. The production of autoantibodies, such as anti-dsDNA, anti-SS(A), anti-SS(B), anti-Smith, and anti-neuronal DNA are characteristic features of this disease. This autoimmune disease results from a failure of the mechanisms responsible for maintaining self-tolerance in T cells, B cells, or both. Immune complexes, circulating antibodies, cytokines, and autoreactive T lymphocytes are responsible for tissue injury in this autoimmune disease. The diagnosis of SLE is a rheumatological challenge despite the availability of clinical criteria. NPSLE was previously referred to as lupus cerebritis or lupus sclerosis. However, these terms are no longer recommended because there is no definitive pathological cause for the neuropsychiatric manifestations of SLE. Currently, the treatment options are primarily based on symptomatic presentations. These include the use of antipsychotics, antidepressants, and anxiolytic medications for the treatment of psychiatric and mood disorders. Antiepileptic drugs to treat seizures, and immunosuppressants (e.g., corticosteroids, azathioprine, and mycophenolate mofetil), are directed against inflammatory responses along with non-pharmacological interventions. [ABSTRACT FROM AUTHOR]

Autoantibodies directed against complement component C1q are commonly associated with autoimmune diseases, especially systemic lupus erythematosus. Importantly, these anti-C1q autoantibodies are specific for ligand-bound, solid-phase C1q and do not bind to fluid-phase C1q. In patients with anti-C1q, C1q levels are in the normal range, and the autoantibodies are thus not depleting. To study these human anti-C1q autoantibodies at the molecular level, we isolated C1q-reactive B cells and recombinantly produced nine monoclonal antibodies (mAbs) from four different healthy individuals. The isolated mAbs were of the IgG isotype, contained extensively mutated variable domains, and showed high affinity to the collagen-like region of C1q. The anti-C1q mAbs exclusively bound solid-phase C1q in complex with its natural ligands, including immobilized or antigen-bound IgG, IgM or CRP, and necrotic cells. Competition experiments reveal that at least 2 epitopes, also targeted by anti-C1q antibodies in sera from SLE patients, are recognized. Electron microscopy with hexameric IgG-C1q immune complexes demonstrated that multiple mAbs can interact with a single C1q molecule and identified the region of C1q targeted by these mAbs. The opsonization of immune complexes with anti-C1q greatly enhanced Fc-receptor-mediated phagocytosis but did not increase complement activation. We conclude that human anti-C1q autoantibodies specifically bind neo-epitopes on solid-phase C1q, which results in an increase in Fc-receptor-mediated effector functions that may potentially contribute to autoimmune disease immunopathology. [ABSTRACT FROM AUTHOR]

Routine immunofluorescence microscopy of glomerular immunodeposits in IgA nephropathy shows IgA, C3, and lambda light chains, and sometimes IgG, IgM, and kappa light chains. However, a previous study using high-resolution confocal microscopy showed IgG in all IgA nephropathy cases, likely representing autoantibodies specific for galactose-deficient IgA1. Here, we used high-resolution confocal microscopy to examine the composition of glomerular immunodeposits and colocalization of kappa and lambda light chains with IgA or IgG heavy chains in kidney-biopsy samples from twenty patients with IgA nephropathy, seventeen without IgG, and nine with no or trace kappa light chains by routine immunofluorescence microscopy. IgG was detected in all biopsies by high-resolution confocal microscopy. Single-optical-plane images showed similar colocalization of IgG heavy chains with kappa and lambda light chains. Colocalization of IgA heavy chains was greater with lambda light chains than with kappa light chains. Colocalization of IgG heavy chain with kappa light chains was higher than with lambda light chains in biopsies with endocapillary hypercellularity and crescents, i.e., biopsies with active lesions. We confirmed the utility of high-resolution confocal microscopy to detect components of glomerular immunodeposits not apparent on routine immunofluorescence microscopy and for colocalization of different components, potentially clarifying the pathogenesis of IgA nephropathy. [ABSTRACT FROM AUTHOR]

• Transfer of RA antibody (B09) to mice induces pain without joint inflammation. • B09 is retained in the dorsal root ganglia where it binds satellite glia cells. • Fcγ receptors are critical for B09 antibody-induced pain-like behavior development. • B09 alters the transcriptional profile of satellite glia and neurons in the DRG. Joint pain is one of the most debilitating symptoms of rheumatoid arthritis (RA) and patients frequently rate improvements in pain management as their priority. RA is hallmarked by the presence of anti-modified protein autoantibodies (AMPA) against post-translationally modified citrullinated, carbamylated and acetylated proteins. It has been suggested that autoantibody-mediated processes represent distinct mechanisms contributing to pain in RA. In this study, we investigated the pronociceptive properties of monoclonal AMPA 1325:01B09 (B09 mAb) derived from the plasma cell of an RA patient. We found that B09 mAb induces pain-like behavior in mice that is not associated with any visual, histological or transcriptional signs of inflammation in the joints, and not alleviated by non-steroidal anti-inflammatory drugs (NSAIDs). Instead, we found that B09 mAb is retained in dorsal root ganglia (DRG) and alters the expression of several satellite glia cell (SGC), neuron and macrophage-related factors in DRGs. Using mice that lack activating FcγRs, we uncovered that FcγRs are critical for the development of B09-induced pain-like behavior, and partially drive the transcriptional changes in the DRGs. Finally, we observed that B09 mAb binds SGC in vitro and in combination with external stimuli like ATP enhances transcriptional changes and protein release of pronociceptive factors from SGCs. We propose that certain RA antibodies bind epitopes in the DRG, here on SGCs, form immune complexes and activate resident macrophages via FcγR cross-linking. Our work supports the growing notion that autoantibodies can alter nociceptor signaling via mechanisms that are at large independent of local inflammatory processes in the joint. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is the most common glomerular autoimmune disease and has severe long‐term consequences for patients, with 40% of the patients eventually progressing to end‐stage renal disease. Despite the severity, no causal treatment is currently available. While the pathogenesis of IgAN is complex, disease severity is linked to autoantibodies against the gd‐IgA1 epitope, a stretch in the hinge region of IgA1 that lacks O‐glycans and is found in the characteristic immune complexes deposited in the kidneys of IgAN patients. One elegant, causal approach would be to remove the anti‐gd‐IgA1 autoantibodies and consequently reduce the immune complex burden on the kidneys. The administration of synthetic polymers that present autoantigens in a multivalent manner have been established as promising therapeutic strategies in other autoimmune diseases and may be applied to IgAN. We here present an improved protocol for the synthesis of the gd‐IgA1 epitope, its successful coupling to a poly‐L‐lysine polymer and proof‐of‐concept experiments that the polymer‐bound synthetic glycopeptide is able to capture the IgAN autoantibodies, making this approach a promising way forward for developing a targeted treatment option for IgAN patients. [ABSTRACT FROM AUTHOR]

Introduction: The combined presence of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GADA) and to the islet-specific cation efflux transporter ZnT8 (ZnT8A) in serum is the best predictive sign of the loss of immune tolerance and the clinical manifestation of autoimmune diabetes mellitus (DM). The screening of GADA and ZnT8A could help to reach to a correct diagnosis and to start an early and adequate treatment. The aim of the study was to develop an immunoassay for the simultaneous detection of these autoantibodies using a chimera molecule that includes the immunodominant regions of ZnT8 and GAD65, expressed by baculovirus-insect cells system. Materials and Methods: ZnT8/GAD65 was expressed using the Bac to Bac™ baculovirus expression system. The recombinant chimera was purified by an His6-tag and identified by SDS-PAGE and western blot analysis, and by an indirect ELISA using specific antibodies against ZnT8 and GAD65. A fraction of ZnT8/ GAD65 was biotinylated. A bridge ELISA (b-ELISA) was developed using ZnT8/ GAD65 immobilized in polystyrene microplates, human sera samples from healthy individuals (n = 51) and diabetic patients (n = 49) were then incubated, and afterwards ZnT8/GAD65-biotin was added. Immune complexes were revealed with Streptavidin-Horseradish Peroxidase. Results were calculated as specific absorbance and expressed as standard deviation scores: SDs. Results: ZnT8/GAD65 was efficiently produced, yielding 30 mg/L culture medium, 80% pure. This recombinant chimera retains the immunoreactive conformation of the epitopes that are recognized by their specific antibodies, so it was used for the development of a high sensitivity (75.51%) and specificity (98.04%) b-ELISA for the detection of ZnT8A and/or GADA, in a one-step screening assay. The ROC curves demonstrated that this method had high accuracy to distinguish between samples from healthy individuals and diabetic patients (AUC = 0.9488); the cut-off value was stablished at 2 SDs. Conclusions: This immunoassay is useful either to confirm autoimmune diabetes or for detection in routine screening of individuals at risk of autoimmune DM. As DM is a slow progress disease, remaining asymptomatic for a long preclinical period, serological testing is of importance to establish a preventive treatment. [ABSTRACT FROM AUTHOR]

Mast cells are multifunctional immune cells with complex roles in tissue homeostasis and disease. Cardiac mast cells (HCMCs) are strategically located within the human myocardium, in atherosclerotic plaques, in proximity to nerves, and in the aortic valve. HCMCs express the high-affinity receptor (FcεRI) for IgE and can be activated by anti-IgE and anti-FcεRI. Autoantibodies to IgE and/or FcεRI have been found in the serum of patients with a variety of immune disorders. We have compared the effects of different preparations of IgG anti-IgE obtained from patients with atopic dermatitis (AD) with rabbit IgG anti-IgE on the release of preformed (histamine and tryptase) and lipid mediators [prostaglandin D2 (PGD2) and cysteinyl leukotriene C4 (LTC4)] from HCMCs. Functional human IgG anti-IgE from one out of six AD donors and rabbit IgG anti-IgE induced the release of preformed (histamine, tryptase) and de novo synthesized mediators (PGD2 and LTC4) from HCMCs. Human IgG anti-IgE was more potent than rabbit IgG anti-IgE in inducing proinflammatory mediators from HCMCs. Human monoclonal IgE was a competitive antagonist of both human and rabbit IgG anti-IgE. Although functional anti-IgE autoantibodies rarely occur in patients with AD, when present, they can powerfully activate the release of proinflammatory and vasoactive mediators from HCMCs. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and it is characterized by mesangial IgA deposition. Asymptomatic hematuria with various degrees of proteinuria is the most common clinical presentation and up to 20%–40% of patients develop end-stage kidney disease within 20 years after disease onset. The pathogenesis of IgAN involves four sequential processes known as the "four-hit hypothesis" which starts with the production of a galactose-deficient IgA1 (gd-IgA1), followed by the formation of anti-gd-IgA1 IgG or IgA1 autoantibodies and immune complexes that ultimately deposit in the glomerular mesangium, leading to inflammation and injury. Although several key questions about the production of gd-IgA1 and the formation of anti-gd-IgA1 antibodies remain unanswered, a growing body of evidence is shedding light on the innate and adaptive immune mechanisms involved in this complex pathogenic process. Herein, we will focus on these mechanisms that, along with genetic and environmental factors, are thought to play a key role in disease pathogenesis. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA–anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) nephropathy is the most common type of glomerulonephritis worldwide characterized by excessive serum levels of glycosylated which triggers the generation of glycan-specific IgG and IgA autoantibodies. This pathological condition results in the formation of circulatory IgA immune complexes, which are essential for the development of glomerular inflammation, especially IgA nephropathy. The serum galactosylated IgA1, IgG, and IgA autoantibodies are suggested as the biomarkers of IgA nephropathy since IgA antibodies are early markers for disease activity too. Serum IgA antibodies emerged as the early COVID-19-specific antibody response about two days after initial symptoms of COVID-19 in comparison with IgG and IgM antibody concentrations, which appeared after five days. IgA nephropathy is frequently presented as microscopic or macroscopic hematuria and proteinuria with a male predominance. COVID-19 infection can include several organs aside from the lungs, such as kidneys through different mechanisms. It is demonstrated in most cases that short-lasting symptoms such as gross hematuria resolve either spontaneously or following a short course of steroids. This review summarized the reported cases of relapses or denovo reported cases of relapses or de-novo IgA nephropathy and IgA vasculitis following COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a genetically predisposed, female-predominant disease, characterized by multiple organ damage, that in its most severe forms can be life-threatening. The pathogenesis of SLE is complex and involves cells of both innate and adaptive immunity. The distinguishing feature of SLE is the production of autoantibodies, with the formation of immune complexes that precipitate at the vascular level, causing organ damage. Although progress in understanding the pathogenesis of SLE has been slower than in other rheumatic diseases, new knowledge has recently led to the development of effective targeted therapies, that hold out hope for personalized therapy. However, the new drugs available to date are still an adjunct to conventional therapy, which is known to be toxic in the short and long term. The purpose of this review is to summarize recent advances in understanding the pathogenesis of the disease and discuss the results obtained from the use of new targeted drugs, with a look at future therapies that may be used in the absence of the current standard of care or may even cure this serious systemic autoimmune disease. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune factor X (FX or F10) deficiency (AiF10D) is an extremely rare acquired haemorrhagic disorder characterized by a severe reduction in FX activity due to autoantibodies against FX. Aim: Anti‐FX autoantibodies were investigated in four patients with suspected AiF10D, and their properties were analysed. Methods and results: Anti‐FX auto antibodies in plasma were detected by ELISA with three of four cases. One case of anti‐FX autoantibody negativity was later diagnosed as AL‐amyloidosis. IgG1 and IgG3 coexisted in all anti‐FX autoantibodies of the three patients with AiF10D (cases X1, X2, and X3). Western blot analysis showed that the antibodies were bound to the FX light chain for cases X2 and X3, but the binding was weak for case X1. When the fusion proteins of a secretory luciferase with full‐length FX or its γ‐carboxylated glutamic acid (Gla) domain were added to the plasma of the three patients, both fusion proteins were immunoprecipitated as antigen‐antibody complexes. Contrarily, the latter fusion protein produced in the presence of warfarin demonstrated a decrease in the collection rate, suggesting that their autoantibodies recognized the light chain and regions containing Gla residues. Since all three patients were essentially negative for FX inhibitors, it was concluded that the anti‐FX autoantibodies for these cases were predominantly non‐neutralizing. The concentration of the FX antigen also significantly reduced in these patients, suggesting that anti‐FX autoantibodies promote the clearance of FX. Conclusion: Immunological anti‐FX autoantibody detection is highly recommended to ensure that AiF10D cases are not overlooked, and to start necessary immunosuppressive therapies. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes on tissues. Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematological disorder that rarely develops in SLE, mainly caused by inhibitory or clearing autoantibody against ADAMTS13. Although B cells play critical roles in the pathogenesis of two diseases, the role of B-cell depletion therapy using rituximab (RTX), a chimeric monoclonal antibody targeting CD20, in the management of TTP associated with SLE remains unclear. We present a 27-year-old woman who manifested TTP and nephritis simultaneously at diagnosis of SLE. This patient successfully responded to high-dose glucocorticoids combined with plasma exchange, and early administration of RTX-induced sustained remission of TTP without relapse over 16 months. This literature review in light of our case demonstrates relationship between early intervention with RTX and better treatment response despite the degree of ADAMTS13 activity. Moreover, we discuss the clinical features in TTP associated with SLE, risk factors for the development of TTP in SLE, and possible outcomes based on RTX dose. It is important to consider upfront RTX as a promising treatment strategy for SLE-associated secondary TTP to improve short-term response and long-term prognosis. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematous (SLE) is a chronic autoimmune disease characterized by the deposition of immune complexes in various tissues and thus multisystem affection. The autoantibody profile can be utilized as a significant prognostic indicator for clinicians. Alpha-enolase is a multifunctional protein, which after inflammation, is expressed in cell membranes of eukaryotic cells, such as monocytes, T lymphocytes, B lymphocytes, neuronal cells, and endothelial cells. Objective: The aim of the current study was to evaluate serum level of Anti-a-enolase Ab in adult systemic lupus erythematous patient and its association with lupus activity. Patients and Methods: This was a case control study which included 105 SLE patients who recruited from the outpatient Rheumatology and Rehabilitation Clinic at Mansoura University Hospital. Participants were divided into three groups; group 1 (35 participants) which includes adult patients diagnosed as SLE, group 2 (35 participant) which includes adult patient diagnosed as lupus nephritis and group 3 (35 participants) which includes age- and sex-matched healthy volunteers (control group). Results: The current study demonstrated that SLE with LN showed the highest levels, followed by SLE without LN and lastly the healthy individuals. The anti-a-enolase antibody level showed significant positive correlations with renal biopsy grade, SLICC RENAL, SLEDAI-2K, R-SLEDAI. The serum level of anti-a-enolase antibody could discriminate between SLE cases and control subjects with high accuracy AUC (AUC=0.997). At best cut off value (=0.894), sensitivity was 98.6%, specificity was 97.1%, PPV was 98.6%, NPV was 97.2% and accuracy was 98.1%. Conclusion: The current study demonstrated that, serum Anti-a-enolase Ab seemed to be significantly correlated with SLE as well as with diseases activity particularly LN. Additionally, it could be used as a reliable predictor in the differentiation between SLE and healthy persons, also in differentiating SLE cases with LN from those without LN. [ABSTRACT FROM AUTHOR]

Dysfunctional eating patterns include alterations in experiencing and expressing hunger, appetite, and satiety, which may lead to eating disorders or obesity in the long term. Alterations in hormones such as ghrelin have been suggested to influence emotional eating in women with obesity. Ghrelin-reactive autoantibodies (autoAbs) are present both in healthy individuals and those with eating disorders and have been suggested to protect the hormone from degradation and preserve its functional activity. This study aimed to evaluate the relationship between IgG ghrelin-reactive autoAbs with dysfunctional eating patterns, subjective perception of stress, and body composition parameters in young women. This cross-sectional study included 82 women (age 21±2 years) classified according to body fat percentage. Dysfunctional eating patterns were measured with the Spanish version of the Three-factor Eating Questionnaire-R18, and perceived stress was measured with the Spanish version of the Perceived Stress Scale – 10. A validated in-house enzyme-linked immunosorbent assay was performed to measure IgG ghrelin-reactive autoAbs in its free, total, and immune complex fractions. Free IgG ghrelin-reactive autoAbs were positively correlated with weight, BMI, body fat percentage, waist, and hip circumference in women with very high body fat percentage. In this group, a negative correlation was observed between ghrelin immune complexes and uncontrolled eating. This exploratory research shows that IgG ghrelin-reactive autoAbs have a potential role in altered body composition parameters and appetite expression, such as uncontrolled eating in women with very high body fat. Further studies are required to clarify the role of IgG autoAbs in eating behavior. [ABSTRACT FROM AUTHOR]

Working model. [Display omitted] • The expression of HER2/ErbB2, a member of the EGFR family that was found increased in kidneys of patients and mice with lupus nephritis, is specifically augmented by treatment with type I Interferons in murine kidney. • EGFR-ErbB2 (HER2) dual kinase inhibitor lapatinib, administered before but not after renal disease onset, lowered autoantibody levels and lessened immune complex deposition in the kidney in lupus prone mice. • However, lapatinib increased kidney disease severity, with higher proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells, hinting at its mechanism on tissue damage in vivo. • Our work provides a cautionary warning for the possible use of lapatinib in patients with SLE and suggests further investigation using single EGFR inhibitors. Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis. [ABSTRACT FROM AUTHOR]

The article discusses the role of autoantibodies in lupus nephritis, focusing on anti-C1q and anti-double-stranded (dsDNA) antibodies. The study suggests a significant association between elevated levels of these antibodies and proliferative lupus nephritis, indicating their potential role in the disease pathology. Furthermore, the research highlights the importance of understanding the underlying mechanisms of these antibodies and their impact on treatment response. The study also emphasizes the need for further exploration into different autoantibody combinations and their effects on disease progression, as well as the importance of standardizing testing methods for clinical decision-making. [Extracted from the article]

Neutrophil extracellular traps (NETs) are involved in systemic lupus erythematosus (SLE). We sought to cluster SLE patients based on serum NET levels. Serum NET levels were higher in SLE patients than healthy controls. Frequencies of pleuritis and myositis were increased in patients with high serum NET levels. Serum NET levels negatively correlated with anti–double stranded DNA (anti-dsDNA) antibody titers and C1q-binding immune complexes, but positively correlated with C-reactive protein (CRP) and monocyte counts. Neutrophil transcriptome analysis demonstrated no difference in NET-associated signatures, irrespective of serum NET levels, suggesting anti-dsDNA antibody-mediated clearance of NETs. In serum, NET levels were significantly correlated with myeloid cell-derived inflammatory molecules. Serum NET-based cluster analysis revealed 3 groups of patients based on serum NET and CRP levels, anti-dsDNA antibody titers, and monocyte count. Monocytes were consistently activated following NET-containing immune complex (NET-IC) stimulation. In conclusion, SLE patients with high serum NET levels had lower anti-dsDNA antibody titers and higher inflammatory responses. NET-IC-stimulated monocytes might associate with an inflammatory response characterized by elevated CRP levels. These findings can apply to precision medicine, as inflammatory processes, rather than antibody-dependent processes, can be targeted in specific subpopulations of SLE patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia exacerbates autoimmune response and accelerates the progression of several autoimmune disorders, but the mechanistic basis is not well understood. We recently demonstrated that hypercholesterolemia is associated with increased serum extracellular DNA levels secondary to a defect in DNase‐mediated clearance of DNA. In this study, we tested whether the impaired DNase response plays a causal role in enhancing anti‐nuclear antibody levels and renal immune complex deposition in an Apoe−/− mouse model of hypercholesterolemia. We demonstrate that hypercholesterolemic mice have enhanced anti‐ds‐DNA and anti‐nucleosome antibody levels which is associated with increased immune complex deposition in the renal glomerulus. Importantly, treatment with DNase1 led to a decrease in both the autoantibody levels as well as renal pathology. Additionally, we show that humans with hypercholesterolemia have decreased systemic DNase activity and increased anti‐nuclear antibodies. In this context, our data suggest that recombinant DNase1 may be an attractive therapeutic strategy to lower autoimmune response and disease progression in patients with autoimmune disorders associated with concomitant hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is an immune kidney disease characterized by glomerular subepithelial immune complexes (ICs) containing antigen, IgG, and products of complement activation. Whereas proteinuria is caused by complement-mediated podocyte injury, the pathways of complement activation remain controversial due to the predominance of IgG4 in ICs, an IgG subclass considered unable to activate complement. THSD7A, a transmembrane protein expressed on podocytes, is the target autoantigen in ~3% of cases of primary MN. In this study, we analyzed sera from 16 patients with THSD7A-associated MN with regard to the anti-THSD7A IgG subclasses and their ability to fix complement in vitro. The serum concentration of anti-THSD7A IgG varied over two orders of magnitude (1.3-243 mg/mL). As a relative proportion of all IgG anti-THSD7A, IgG4 was by far the most abundant subclass (median 79%), followed by IgG1 (median 11%). IgG4 was the dominant subclass of anti-THSD7A antibodies in 14 sera, while IgG1 was dominant in one and co-dominant in another. One quarter of MN sera additionally contained low levels of anti-THSD7A IgA1. ICs formed by predominantly IgG4 anti-THSD7A autoantibodies with immobilized THSD7A were relatively weak activators of complement in vitro, compared to human IgG1 and IgG3 mAbs used as positive control. Complement deposition on THSD7A ICs was dose-dependent and occurred to a significant extent only at relatively high concentration of anti-THSD7A IgG. C3b fixation by THSD7A ICs was completely abolished in factor B-depleted sera, partially inhibited in C4-depleted sera, unchanged in C1q-depleted sera, and also occurred in Mg-EGTA buffer. These results imply that THSD7A ICs predominantly containing IgG4 activate complement at high IgG4 density, which strictly requires a functional alternative pathway, whereas the classical and lectin pathways are dispensable. These findings advance our understanding of how IgG4 antibodies activate complement. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a hyperactive immune system with multiple abnormalities in B-cell proliferation, antibody production, T-cell regulation, and immune complex (IC) formation. In humans, Immunoglobulin (Ig) G is found in four subclasses. IgG1-IgG4, which are distinguished by both structural and biological differences. Fab-arm Exchange (FAE), specific biases in the IgG4 response repertoire, and a decreased capacity to induce effector functions mediated by interactions in the fragment crystallizable (Fc) region are just a few of the distinctive characteristics of IgG4. The recent finding of the presence of double-stranded DNA (dsDNA) and antinuclear antibody (ANA)-IgG4 has raised attention to this IgG subclass and its possible role in SLE. IgG4 was previously believed to just have anti-inflammatory effects by inhibiting immune responses, but recent studies have shown that these antibodies can also play a role in the onset and development of some clinical disorders. To consider the clinical effects of IgG4 presence, it is necessary to discuss its characteristics, which could underlie the potential role it can play in SLE. Therefore, this study aimed to comprehensively review the role of IgG4 in SLE to elucidate the collective incidence of high IgG4 levels reported in some SLE patients. [ABSTRACT FROM AUTHOR]

Lymphoma is a chronic inflammatory disease in which the immune system is highly affected. Increased oxidative stress is one of the common conditions of cancer and affects macromolecules. Histone modifications affect the chromatin structure and functions. In this study, histone H1 (His-H1) protein was modified by reactive oxygen species (ROS), and structural and chemical changes were studied. Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients were selected, and oxidative stress markers, inflammatory cytokines, and serum autoantibodies were analyzed using biochemical and immunological assays. Furthermore, the formation of antigen-antibody immune complexes was assessed by the Langmuir plot. ROS-modified His-H1 (ROS-His-H1) showed substantial structural perturbation in protein (UV-hyperchromicity and increased intrinsic fluorescence) compared to the native His-H1 protein. A possible explanation for the changes is suggested by the exposure of the aromatic chromophore to the solvent. In-depth structural analysis by circular dichroism (CD) exhibited major changes in α-helix (−21.43%) and turns (+33%), reflecting changes in the secondary structure of histone H1 protein after ROS exposure. ELISA and competitive ELISA findings revealed high recognitions of serum autoantibodies to ROS-His-H1 from NHL, followed by HL subjects. Healthy controls showed negligible binding. Non-modified His-H1 did not show any binding with serum samples from either cohort. High apparent association constants (ACCs) were calculated for ROS-His-H1 using purified IgGs from NHL (1.46 × 10–6 M) compared to HL (1.33 × 10–6 M) patients. Non-modified His-H1 exhibited a hundred times less ACC for NHL (2.38 × 10–8 M) and HL (2.46 × 10–8 M) patients. Thus, ROS modifications of histone H1 cause structural changes and expose cryptic neo-epitopes on the protein against which autoantibodies were generated. These perturbations might affect the histone DNA interaction dynamics and potentially be correlated with gene dysregulation. These subtle molecular changes with an immune imbalance might further aggravate the disease. [ABSTRACT FROM AUTHOR]