Fecal immunoglobulin A (IgA) and its subclasses in systemic lupus erythematosus patients are nuclear antigen reactive and this feature correlates with gut permeability marker levels

Gudi, Radhika; Kamen, Diane L.; Vasu, Chenthamarakshan

doi:10.1016/j.clim.2022.109107

Cited by 8 publications

(7 citation statements)

References 18 publications

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“…Recent reports, including ours, have shown that higher gut inflammation and permeability markers, calprotectin and zonulin (pre‐Hp2), are produced by SLE patients compared to healthy controls [51–53]. However, it is not known if these features are a consequence of the disease activities or occur prior to clinical stage disease.…”

Section: Discussionmentioning

confidence: 93%

Intestinal permeability and inflammatory features of juvenile age correlate with the eventual systemic autoimmunity in lupus‐prone female SWR × NZB F1 (SNF1) mice

Gudi,

Johnson,

Gaudreau

et al. 2023

Immunology

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The incidence of systemic lupus erythematosus (SLE) is about nine times higher in women than in men, and the underlying mechanisms that contribute to this gender bias are not fully understood. Previously, using lupus‐prone (SWR × NZB)F1 (SNF1) mice, we have shown that the intestinal immune system could play a role in the initiation and progression of disease in SLE, and depletion of gut microbiota produces more pronounced disease protection in females than in males. Here, we show that the gut permeability features of lupus‐prone female SNF1 mice at juvenile ages directly correlate with the expression levels of pro‐inflammatory factors, faecal IgA abundance and nAg reactivity and the eventual systemic autoantibody levels and proteinuria onset. Furthermore, we observed that the disease protection achieved in female SNF1 mice upon depletion of gut microbiota correlates with the diminished gut inflammatory protein levels, intestinal permeability and circulating microbial DNA levels. However, faecal microbiota transplant from juvenile male and females did not result in modulation of gut inflammatory features or permeability. Overall, these observations suggest that the early onset of intestinal inflammation, systemic autoantibody production and clinical stage disease in lupus‐prone females is linked to higher gut permeability in them starting at as early as juvenile age. While the higher gut permeability in juvenile lupus‐prone females is dependent on the presence of gut microbes, it appears to be independent of the composition of gut microbiota.

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Section: Discussionmentioning

confidence: 93%

Intestinal permeability and inflammatory features of juvenile age correlate with the eventual systemic autoimmunity in lupus‐prone female SWR × NZB F1 (SNF1) mice

Gudi,

Johnson,

Gaudreau

et al. 2023

Immunology

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“…Our study aimed to better understand how IgA isotype autoantibodies contribute to SLE pathology. Our rationale for exploring IgA isotype autoantibodies in SLE was based on recent insights including the presence of IgA autoantibodies in SLE ( 13 – 15 , 17 , 18 , 47 ), evidence that IgA can be pathogenic in rheumatoid arthritis ( 48 , 49 ), and an increasing appreciation of the ability of IgA to facilitate proinflammatory immune responses when bound to viral and bacterial pathogens or in antitumor responses ( 29 , 30 ). Glomerular IgA staining in addition to IgG, IgM, C1q, and C3, the so-called “full house” immunofluorescence, is an almost uniform finding in all classes of lupus nephritis ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…IgA is almost uniformly present in lupus nephritis glomeruli, in addition to IgG, IgM, C3, and C1q, and is used for diagnosis ( 16 ). Elevated amounts of IgA ANAs have also been found in the saliva and fecal samples of individuals with SLE ( 17 , 18 ). In addition, one study found an increase in IgA isotype B cell clones in individuals with SLE compared with healthy controls (HCs) and those with other immune-mediated diseases ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Lupus IgA1 autoantibodies synergize with IgG to enhance plasmacytoid dendritic cell responses to RNA-containing immune complexes

Waterman,

Dufort,

Posso

et al. 2024

Sci. Transl. Med.

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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.

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“…Higher gut permeability and microbial translocation have been implicated in the development of autoimmunity, and recent studies have shown that faecal IgA to nuclear antigens can precede the development of disease in lupus-prone mice [56,57 ▪▪ ]. Similarly, Gudi et al [58 ▪▪ ] identified elevated faecal IgA antibodies to dsDNA, nucleohistone and ANAs (collectively, nuclear antigens) in patients with established SLE. Faecal IgA abundance and reactivity to nuclear antigens (particularly IgA1) correlated with levels of the gut permeability marker zonulin, suggesting that the epithelial barrier function of proximal gut is compromised in SLE.…”

Section: New Insight Into Old Autoantibodies In Systemic Lupus Erythe...mentioning

confidence: 99%

An update on autoantibodies in systemic lupus erythematosus

Gómez-Bañuelos

Fava

Andrade

2022

Current Opinion in Rheumatology

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Purpose of reviewAutoantibodies are cornerstone biomarkers in systemic lupus erythematosus (SLE), an autoimmune disease characterized by autoantibody-mediated tissue damage. Autoantibodies can inform about disease susceptibility, clinical course, outcomes and the cause of SLE. Identifying pathogenic autoantibodies in SLE, however, remains a significant challenge. This review summarizes recent advances in the field of autoantibodies in SLE.Recent findingsHigh-throughput technologies and innovative hypothesis have been applied to identify autoantibodies linked to pathogenic pathways in SLE. This work has led to the discovery of functional autoantibodies targeting key components is SLE pathogenesis (e.g. DNase1L3, cytokines, extracellular immunoregulatory receptors), as well as the identification of endogenous retroelements and interferon-induced proteins as sources of autoantigens in SLE. Others have reinvigorated the study of mitochondria, which has antigenic parallels with bacteria, as a trigger of autoantibodies in SLE, and identified faecal IgA to nuclear antigens as potential biomarkers linking gut permeability and microbial translocation in SLE pathogenesis. Recent studies showed that levels of autoantibodies against dsDNA, C1q, chromatin, Sm and ribosomal P may serve as biomarkers of proliferative lupus nephritis, and identified novel autoantibodies to several unique species of Ro52 overexpressed by SLE neutrophils.SummaryAutoantibodies hold promise as biomarkers of pathogenic mechanisms in SLE.

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Fecal immunoglobulin A (IgA) and its subclasses in systemic lupus erythematosus patients are nuclear antigen reactive and this feature correlates with gut permeability marker levels

Cited by 8 publications

References 18 publications

Intestinal permeability and inflammatory features of juvenile age correlate with the eventual systemic autoimmunity in lupus‐prone female SWR × NZB F1 (SNF1) mice

Intestinal permeability and inflammatory features of juvenile age correlate with the eventual systemic autoimmunity in lupus‐prone female SWR × NZB F1 (SNF1) mice

Lupus IgA1 autoantibodies synergize with IgG to enhance plasmacytoid dendritic cell responses to RNA-containing immune complexes

An update on autoantibodies in systemic lupus erythematosus

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