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Pathogenic anti-dsDNA mAb and cross-reactivity
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Lupus nephritis (LN) remains the most common severe manifestation of systemic lupus erythematosus (SLE) characterized by the presence of autoantibodies (Abs) that are believed to play a central role in the pathogenesis of LN. Among more than 100 Abs reported in SLE, only a few display a direct glomerular binding capacity. Such antiglomerular Abs ar...
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Context 1
... a large panel of hybridoma generated from lupus- prone NZB/NZW or MRL/lpr mice with dsDNA, histone or nucleosome specificity, Mostoslavsky et al. [26] have identified that some of these hybridomas when injected intraperitoneally in Rag-1-deficient mice develop massive proteinuria with glomerular deposits. Such effects were restricted to the anti-dsDNA mAb clones since antinucleo- some mAb clones (5/5) and antihistone mAb clones (3/3) were nonpathogenic (Table 1). Pathogenic anti-dsDNA mAbs (5/7), but not the nonpathogenic ones, cross-react with α-actinin, a glomerular component. ...
Context 2
... another study by the same group, it was also reported that some of these pathogenic Abs cross-react with laminin-1 [27]. Cross- reactivity details are reported in Table 1. Glomerular α- actinin is localized at the cell surface of mesangial cells and in epithelial cells (podocytes), but α-actinin is absent from GBM [28]. ...
Citations
... LN-pathogenic anti-dsDNA monoclonal (m)Abs have been defined through their capacity to induce LN following their introduction into animal models [79,80]. One of the characteristics of these LN-pathogenic mAbs (e.g., clone R4A) is to bind non-DNA structures in renal tissues treated with DNases and related targets including α-actinin, laminin, annexin II, ribosomal P, collagen III/IV, entactin, proteoglycan heparan sulfate, and N-methyl-D-aspartate receptors (NMDAR) [81,82]. In humans, these cross-reactive anti-dsDNA/α actinin-glomerular Abs have been retrieved at LN onset with the particularity to be effective in binding kidney cells including mesangial cells, podocytes, and the renal cell line HEK [83][84][85]. ...
Lupus nephritis (LN) represents the most severe organ manifestation of systemic lupus erythematosus (SLE) in terms of morbidity and mortality. To reduce these risks, tremendous efforts have been made in the last decade to characterize the different steps of the disease and to develop biomarkers in order to better (i) unravel the pre-SLE stage (e.g., anti-nuclear antibodies and interferon signature); (ii) more timely initiation of therapy by improving early and accurate LN diagnosis (e.g., pathologic classification was revised); (iii) monitor disease activity and therapeutic response (e.g., recommendation to re-biopsy, new urinary biomarkers); (iv) prevent disease flares (e.g., serologic and urinary biomarkers); (v) mitigate the deterioration in the renal function; and (vi) reduce side effects with new therapeutic guidelines and novel therapies. However, progress is poor in terms of improvement with early death attributed to active SLE or infections, while later deaths are related to the chronicity of the disease and the use of toxic therapies. Consequently, an individualized treat-to-target strategy is mandatory, and for that, there is an unmet need to develop a set of accurate biomarkers to be used as the standard of care and adapted to each stage of the disease.
Keywords: lupus nephritis; renal biopsy; urinary markers; autoantibodies; biomarkers
... We have discovered previously that DS possesses peculiar affinity for apoptotic cells and their released autoAgs [7][8][9][10]. DS, a major component of the extracellular matrix and connective tissue, is increasingly expressed during tissue injury and accumulates in wound areas [2,11]. ...
... AutoAg-DS complexes may activate B1 cells via a dual binding mode, i.e., with autoAg binding to the variable region of the B1 cell's autoBCR and DS binding to the heavy chain of the autoBCR. Upon entering B1 cells, DS may regulate immunoglobulin (Ig) production by engaging the Ig-processing complex in the endoplasmic reticulum and the transcription factor GTF2I necessary for Ig gene expression [9,10]. AutoAg-DS affinity therefore defines a unifying biochemical and immunological property of autoAgs: any self-molecule possessing DS-affinity has a high propensity to become autoantigenic, and this has led to the identification of numerous autoAgs [8,[12][13][14]. ...
... We have consistently found that DS binds apoptotic cells regardless of cell type [7,9]. To figure out which molecules are involved in this affinity, we searched for DS-affinity proteins shared in all 6 human cell lines of this study and found 39 autoAg candidates (Fig. 9). ...
Chronic and debilitating autoimmune sequelae pose a grave concern for the post-COVID-19 pandemic era. Based on our discovery that the glycosaminoglycan dermatan sulfate (DS) displays peculiar affinity to apoptotic cells and autoantigens (autoAgs) and that DS-autoAg complexes cooperatively stimulate autoreactive B1 cell responses, we compiled a database of 751 candidate autoAgs from six human cell types. At least 657 of these have been found to be affected by SARS-CoV-2 infection based on currently available multi-omic COVID data, and at least 400 are confirmed targets of autoantibodies in a wide array of autoimmune diseases and cancer. The autoantigen-ome is significantly associated with various processes in viral infections, such as translation, protein processing, and vesicle transport. Interestingly, the coding genes of autoAgs predominantly contain multiple exons with many possible alternative splicing variants, short transcripts, and short UTR lengths. These observations and the finding that numerous autoAgs involved in RNA-splicing showed altered expression in viral infections suggest that viruses exploit alternative splicing to reprogram host cell machinery to ensure viral replication and survival. While each cell type gives rise to a unique pool of autoAgs, 39 common autoAgs associated with cell stress and apoptosis were identified from all six cell types, with several being known markers of systemic autoimmune diseases. In particular, the common autoAg UBA1 that catalyzes the first step in ubiquitination is encoded by an X-chromosome escape gene. Given its essential function in apoptotic cell clearance and that X-inactivation escape tends to increase with aging, UBA1 dysfunction can therefore predispose aging women to autoimmune disorders. In summary, we propose a model of how viral infections lead to extensive molecular alterations and host cell death, autoimmune responses facilitated by autoAg-DS complexes, and ultimately autoimmune diseases. Overall, this master autoantigen-ome provides a molecular guide for investigating the myriad of autoimmune sequalae to COVID-19 and clues to the rare but reported adverse effects of the currently available COVID vaccines.
... A common process of pathogenesis between skin and kidney was recently proposed through the comparative analysis of skin and kidney biopsies at a single-cell RNA sequencing level [11]. In addition, it has been further described that part of the Ig spectrum implicated in LBT and lupus nephritis is related to anti-chromatin Abs [22,23] and a relation also exists between anti-chromatin Abs and leukopenia [24]. Indeed, anti-chromatin Abs have been demonstrated to bind skin and kidney basement membrane structures with high affinity. ...
The lupus band test (LBT) is frequently performed for patients with lupus erythematosus (LE) but its capacity to discriminate cutaneous (C)LE from systemic (S)LE is debated, as well as its association with serum antinuclear antibodies (ANA) and complement reduction. Among 158 patients, 56 received retrospectively a diagnosis of CLE, 37 have SLE and 65 other skin disorders. Considering 29 clinical, histopathologic, LBT, and serological parameters: 5 parameters were effective in distinguishing LE from other skin disorders (e.g. skin photosensitivity, LBT positivity, basal vacuolar changes, thickening of the basement membrane, and anti-SSA-60 kDa); and 8 parameters were able to separate SLE from CLE (e.g. arthritis, lupus nephritis, hematological manifestations, Raynaud/sicca manifestations, anti-chromatin, anti-dsDNA, and low levels of C3/4). A positive LBT was further determined to be associated with systemic manifestations when associated with anti-chromatin response and complement reduction in the profile of patients evolving to a systemic form of lupus.
... According to previous reports [4,7], such an immunological trend presenting normal complemetemia, normal autoantibody levels, and Th2-dominant circumstances is recognized as a peculiar characteristic of MLN, which is considered to be connected with the peculiar developmental mechanism of MLN. Generally, the developmental mechanism for active LN can be summarized as follows: circulating ICs directly deposit into the glomerular vasculature, or autoantibodies bind to autoantigens (such as nucleosomes or C1q) which are planted into the glomerulus [2,30]. Meanwhile, unlike in active LN, the developmental mechanism of MLN is considered to involve autoantibodies that might bind to an endogenous glomerular antigen, resulting in in situ IC formation [4,28,30]. ...
... Generally, the developmental mechanism for active LN can be summarized as follows: circulating ICs directly deposit into the glomerular vasculature, or autoantibodies bind to autoantigens (such as nucleosomes or C1q) which are planted into the glomerulus [2,30]. Meanwhile, unlike in active LN, the developmental mechanism of MLN is considered to involve autoantibodies that might bind to an endogenous glomerular antigen, resulting in in situ IC formation [4,28,30]. Thus, glomerular EXT1/EXT2 might be involved in the unique developmental mechanism of MLN. However, the obvious question that arises is why are EXT1/EXT2 expressed in LN patients with a MN component if EXT1/ EXT2 are not target antigens. ...
Exostosin 1 and exostosin 2 (EXT1/EXT2) on glomerular basement membrane (GBM) were recently reported as novel putative antigens in secondary membranous nephropathy with autoimmune disease. However, the clinical significance of glomerular EXT1/EXT2 remains elusive in patients with lupus nephritis (LN). The immunofluorescence staining pattern of glomerular EXT1/EXT2 is also undetermined in membranous LN (MLN) or proliferative LN (PLN). We cross-sectionally analyzed patients with MLN (pure class V, n = 11) and PLN (class III, IV, and mixed class III/IV + V, n = 22) who underwent renal biopsies between 2010 and 2020 at Showa University Hospital. Glomerular EXT1/EXT2 expressions were evaluated by immunofluorescence. T-helper (Th) cell-related serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay. The positivity for both EXT1/EXT2 was higher in patients with MLN than PLN (90.9% vs 63.6%, P = 0.212). MLN showed global and bright granular EXT1/EXT2 expressions along GBM, while PLN showed segmental and moderate expressions on GBM. Additionally, glomerular EXT1/EXT2 positivity was not associated with the degree of proteinuria or renal function in MLN and PLN patients, but the levels of serum anti-dsDNA antibody and circulating immune complexes were lower in patients with EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Moreover, serum complement levels and IL-4/IFN-γ ratios were elevated in EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Collectively, immunofluorescence staining for glomerular EXT1/EXT2 had characteristic patterns between MLN and PLN. Glomerular EXT1/EXT2 expressions tended to be high in Th2-dominant MLN patients without severe hypocomplementemia and elevated autoantibodies. Thus, EXT1/EXT2 might be involved in the unique developmental mechanism of MLN.
... We have discovered previously that DS possesses peculiar affinity for apoptotic cells and their released autoAgs [6][7][8][9]. DS, a major component of the extracellular matrix and connective tissue, is increasingly expressed during tissue injury and accumulates in wound areas [1,10]. Because of their affinity, DS and autoAgs form macromolecular complexes which cooperatively activate autoreactive B1 cells. ...
... AutoAg-DS complexes may activate B1 cells via a dual binding mode, i.e., with autoAg binding to the variable region of the B1 cell's autoBCR and DS binding to the heavy chain of the autoBCR. Upon entering B1 cells, DS may regulate immunoglobulin (Ig) production by engaging the Ig-processing complex in the endoplasmic reticulum and the transcription factor GTF2I necessary for Ig gene expression [8,9]. AutoAg-DS affinity therefore defines a unifying biochemical and immunological property of autoAgs: any self-molecule possessing DS-affinity has a high propensity to become autoantigenic, and this has led to the identification of numerous autoAgs [7,[11][12][13]. ...
Chronic and debilitating autoimmune sequelae pose a grave concern for the post-COVID-19 pandemic era. Based on our discovery that the glycosaminoglycan dermatan sulfate (DS) displays peculiar affinity to apoptotic cells and autoantigens (autoAgs) and that DS-autoAg complexes cooperatively stimulate autoreactive B1 cell responses, we compiled a database of 751 candidate autoAgs from six human cell types. At least 657 of these have been found to be affected by SARS-CoV-2 infection based on currently available multi-omic COVID data, and at least 400 are confirmed targets of autoantibodies in a wide array of autoimmune diseases and cancer. The autoantigen-ome is significantly associated with various processes in viral infections, such as translation, protein processing, and vesicle transport. Interestingly, the coding genes of autoAgs predominantly contain multiple exons with many possible alternative splicing variants, short transcripts, and short UTR lengths. These observations and the finding that numerous autoAgs involved in RNA-splicing showed altered expression in viral infections suggest that viruses exploit alternative splicing to reprogram host cell machinery to ensure viral replication and survival. While each cell type gives rise to a unique pool of autoAgs, 39 common autoAgs associated with cell stress and apoptosis were identified from all six cell types, with several being known markers of systemic autoimmune diseases. In particular, the common autoAg UBA1 that catalyzes the first step in ubiquitination is encoded by an X-chromosome escape gene. Given its essential function in apoptotic cell clearance and that X-inactivation escape tends to increase with aging, UBA1 dysfunction can therefore predispose aging women to autoimmune disorders. In summary, we propose a model of how viral infections lead to extensive molecular alterations and host cell death, autoimmune responses facilitated by autoAg-DS complexes, and ultimately autoimmune diseases. Overall, this master autoantigen-ome provides a molecular guide for investigating the myriad of autoimmune sequalae to COVID-19 and clues to the rare but reported adverse effects of the currently available COVID vaccines.
... IC formation and deposit in the kidneys are most likely involved in the mechanism for urinary excretion of autoantibodies in SLE ( Figure 1). However, despite their importance of renal pathology in SLE, and numerous studies of autoantibodies in serum and IC deposits in kidneys [27][28][29][30][31][32], there have been Figure 1. Physiopathology of LN and urine biomarkers. ...
... IC formation and deposit in the kidneys are most likely involved in the mechanism for urinary excretion of autoantibodies in SLE ( Figure 1). However, despite their importance of renal pathology in SLE, and numerous studies of autoantibodies in serum and IC deposits in kidneys [27][28][29][30][31][32], there have been few reports of specific autoantibodies in the urine of SLE patients (Table 1). ...
The kidney is one of the main organs affected by the autoimmune disease systemic lupus erythematosus. Lupus nephritis (LN) concerns 30–60% of adult SLE patients and it is significantly associated with an increase in the morbidity and mortality. The definitive diagnosis of LN can only be achieved by histological analysis of renal biopsies, but the invasiveness of this technique is an obstacle for early diagnosis of renal involvement and a proper follow-up of LN patients under treatment. The use of urine for the discovery of non-invasive biomarkers for renal disease in SLE patients is an attractive alternative to repeated renal biopsies, as several studies have described surrogate urinary cells or analytes reflecting the inflammatory state of the kidney, and/or the severity of the disease. Herein, we review the main findings in the field of urine immune-related biomarkers for LN patients, and discuss their prognostic and diagnostic value. This manuscript is focused on the complement system, antibodies and autoantibodies, chemokines, cytokines, and leukocytes, as they are the main effectors of LN pathogenesis.
... Second, antibodies bind to an antigen (such as nucleosomes or C1q) that is "planted" into the glomerulus. Finally, autoantibodies may bind to an endogenous glomerular antigen, resulting in "in situ" immune complex formation [6]. There is a correlation between anti-dsDNA antibody levels and the development of renal disease, and anti-dsDNA antibodies have been identified in glomerular immune complexes [6][7][8][9][10]. ...
... Finally, autoantibodies may bind to an endogenous glomerular antigen, resulting in "in situ" immune complex formation [6]. There is a correlation between anti-dsDNA antibody levels and the development of renal disease, and anti-dsDNA antibodies have been identified in glomerular immune complexes [6][7][8][9][10]. However, there are additional antibodies involved in the development of LN. ...
Kidney involvement in systemic lupus erythematosus (SLE)—termed lupus nephritis (LN)—is a severe manifestation of SLE that can lead to end-stage kidney disease (ESKD). LN is characterized by immune complex deposition and inflammation in the glomerulus. We tested the hypothesis that autoantibodies targeting podocyte and glomerular cell proteins contribute to the development of immune complex formation in LN. We used Western blotting with SLE sera from patients with and without LN to identify target antigens in human glomerular and cultured human-derived podocyte membrane proteins. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified the proteins in the gel regions corresponding to reactive bands observed with sera from LN patients. We identified 102 proteins that were present in both the podocyte and glomerular samples. We identified 10 high-probability candidates, including moesin, using bioinformatic analysis. Confirmation of moesin as a target antigen was conducted using immunohistochemical analysis (IHC) of kidney biopsy tissue and enzyme-linked immunosorbent assay (ELISA) to detect circulating antibodies. By IHC, biopsies from patients with proliferative lupus nephritis (PLN, class III/IV) demonstrated significantly increased glomerular expression of moesin (p < 0.01). By ELISA, patients with proliferative LN demonstrated significantly increased antibodies against moesin (p < 0.01). This suggests that moesin is a target glomerular antigen in lupus nephritis.
... It is not difficult to see that the pathological characteristics of IMN are very abnormal. Firstly, the antigen antibody complex was deposited only under the glomerular epithelial cells, and mesangial cell proliferation was rare, indicating that the immune complex was generated by an in situ immune complex [70,71]. Recently, Liu et al. hypothesized that the autoantigen of IMN came from human lungs [72]. ...
Regulatory B cells (Breg) are widely regarded as immunomodulatory cells which play an immunosuppressive role. Breg inhibits pathological autoimmune response by secreting interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and adenosine and through other ways to prevent T cells and other immune cells from expanding. Recent studies have shown that different inflammatory environments induce different types of Breg cells, and these different Breg cells have different functions. For example, Br1 cells can secrete IgG4 to block autoantigens. Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the humoral immune response is dominant and the cellular immune response is impaired. However, only a handful of studies have been done on the role of Bregs in this regard. In this review, we provide a brief overview of the types and functions of Breg found in human body, as well as the abnormal pathological and immunological phenomena in IMN, and propose the hypothesis that Breg is activated in IMN patients and the proportion of Br1 can be increased. Our review aims at highlighting the correlation between Breg and IMN and proposes potential mechanisms, which can provide a new direction for the discovery of the pathogenesis of IMN, thus providing a new strategy for the prevention and early treatment of IMN.
... 60 Additionally, alpha-enolase may be released from neutrophil extracellular traps (NETs) during NETosis which may trigger auto-antibody formation. 54 Auto-antibodies may bind to components of the GBM directly or to nucleosomes which have become "planted antigens" bound to GBM. 42,43,61,62 Nucleosomes have a high affinity for negatively charged GBM proteins including laminin, heparan sulfate, and collagen IV. 43,44,63 Auto-antibodies binding heparan sulfate have been identified in animal models and human LN. 41,42 Although some glomerular antibodies appear to be nephritogenic, the pathogenic contribution of others remains elusive. ...
Lupus nephritis (LN) occurs in up to 60% of SLE patients, and is a leading cause of disability and death. Current treatment of LN consists of a combination of high dose corticosteroids that non-specifically decrease inflammation and cytotoxic medications that reduce auto-antibody production. That combination of therapy is associated with significant side effects while remission rates remain inadequate. Since the introduction of biologics into the pharmacological armamentarium, there has been hope for less toxic and more effective therapies for LN. Unfortunately, after multiple clinical trials, no biologic has improved efficacy over standard of care therapies for LN. This is likely, in part, due to disease heterogeneity. The utilization of biomarkers in LN may provide a way to stratify patients and guide therapeutic options. In this review, we summarize traditional and novel LN biomarkers and discuss how they may be used to diagnose, stratify, and guide therapy in patients with LN, bringing precision medicine to the forefront of LN therapy.
... The enzyme is nearly undetectable in glomeruli and loop of Henle. (Migliorini et al., 2002;Haimoto et al., 1986) Circulating α-enolase antibodies have been repeatedly detected in serum of humans with autoimmune diseases such as but not limited to rheumatoid arthritis, systemic lupus erythematosus (SLE), and mixed cryoglobulinemia (Terrier et al., 2007;Lee et al., 2003Lee et al., , 2009Pratesi et al., 2000;Hanrotel-Saliou et al., 2011). Approximately 70% of human SLE patients with detectable anti-α-enolase antibodies have active nephritis Hanrotel-Saliou et al., 2011). ...
... (Migliorini et al., 2002;Haimoto et al., 1986) Circulating α-enolase antibodies have been repeatedly detected in serum of humans with autoimmune diseases such as but not limited to rheumatoid arthritis, systemic lupus erythematosus (SLE), and mixed cryoglobulinemia (Terrier et al., 2007;Lee et al., 2003Lee et al., , 2009Pratesi et al., 2000;Hanrotel-Saliou et al., 2011). Approximately 70% of human SLE patients with detectable anti-α-enolase antibodies have active nephritis Hanrotel-Saliou et al., 2011). In people with lupus nephritis, α-enolase is overexpressed in tubules and glomeruli in comparison to healthy controls (Migliorini et al., 2002). ...
Renal α-enolase has variable expression in inflammatory and neoplastic diseases. Therefore, in order to define the distribution of α-enolase in renal tissues of cats, an immunohistochemistry assay was validated and described here. Tissues from 29 cats with IRIS Stage 2–4 CKD, 8 control cats < 2 years of age, and 4 control cats> 10 years of age were assessed. Interstitial nephritis was the predominant histopathological finding in the CKD group. The control cats < 2 years of age had moderate α-enolase immunoreactivity in tubular epithelium but staining was absent to mild in glomeruli. In contrast, α-enolase was moderate to high in tubular epithelium and glomeruli in control cats > 10 years of age. In cats with CKD, α-enolase was decreased in tubules that were degenerative or atrophic, similar to normal tubules in control groups, and moderate to high in glomeruli. When compared between the study groups, the results suggest that alpha-enolase decreases in damaged tubules and increases in the glomeruli of older cats prior to the development of detectable CKD. Further studies will be required to determine whether these findings relate to the pathogenesis or could be used in the diagnosis of feline CKD.
