Autoreactive antibodies control blood glucose by regulating insulin homeostasis

Amendt, Timm; Allies, Gabriele; Nicolò, Antonella; Ayoubi, Omar El; Young, Marc; Röszer, Tamás; Setz, Corinna; Warnatz, Klaus; Jumaa, Hassan

doi:10.1073/pnas.2115695119

Cited by 11 publications

(12 citation statements)

References 75 publications

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“…A loss of complementary anti-idiotypic antibodies has been observed also in other autoimmune diseases ( 33 , 78 , 79 ). On the other hand, the role of IgM in autoimmunity may be more complex as in the so called adaptive tolerance ( 80 ) where high affinity memory IgM controls autoimmunity to insulin but our findings seem less related to this mechanism.…”

Section: Discussioncontrasting

confidence: 68%

Restriction of the Global IgM Repertoire in Antiphospholipid Syndrome

et al. 2022

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The typical anti-phospholipid antibodies (APLA) in the anti-phospholipid syndrome (APS) are reactive with the phospholipid-binding protein β2GPI as well as a growing list of other protein targets. The relation of APLA to natural antibodies and the fuzzy set of autoantigens involved provoked us to study the changes in the IgM repertoire in APS. To this end, peptides selected by serum IgM from a 7-residue linear peptide phage display library (PDL) were deep sequenced. The analysis was aided by a novel formal representation of the Igome (the mimotope set reflecting the IgM specificities) in the form of a sequence graph. The study involved women with APLA and habitual abortions (n=24) compared to age-matched clinically healthy pregnant women (n=20). Their pooled Igomes (297 028 mimotope sequences) were compared also to the global public repertoire Igome of pooled donor plasma IgM (n=2 796 484) and a set of 7-mer sequences found in the J regions of human immunoglobulins (n=4 433 252). The pooled Igome was represented as a graph connecting the sequences as similar as the mimotopes of the same monoclonal antibody. The criterion was based on previously published data. In the resulting graph, identifiable clusters of vertices were considered related to the footprints of overlapping antibody cross-reactivities. A subgraph based on the clusters with a significant differential expression of APS patients’ mimotopes contained predominantly specificities underrepresented in APS. The differentially expressed IgM footprints showed also an increased cross-reactivity with immunoglobulin J regions. The specificities underexpressed in APS had a higher correlation with public specificities than those overexpressed. The APS associated specificities were strongly related also to the human peptidome with 1 072 mimotope sequences found in 7 519 human proteins. These regions were characterized by low complexity. Thus, the IgM repertoire of the APS patients was found to be characterized by a significant reduction of certain public specificities found in the healthy controls with targets representing low complexity linear self-epitopes homologous to human antibody J regions.

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Section: Discussioncontrasting

confidence: 68%

Restriction of the Global IgM Repertoire in Antiphospholipid Syndrome

et al. 2022

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“…Accordingly, in addition to the role of natural antibodies in early antimicrobial host defense, they facilitate nonimmunogenic clearance of apoptotic cells, removal of self-antigens, and inhibit responses induced by IgG autoantibodies [ 51 , 52 , 53 ]. In this context, it is of note that autoreactive IgM antibodies that recognize insulin were very recently shown to act as key regulators of blood glucose and metabolism [ 54 ]. These antibodies control the concentration of insulin in blood: whereas low-affinity anti-insulin IgM neutralizes insulin and leads to increased blood glucose, high-affinity anti-insulin IgM protects insulin neutralization by anti-insulin IgG.…”

Section: Activation Of Self-reactive B Cells Under Physiological Cond...mentioning

confidence: 99%

Aberrant B Cell Signaling in Autoimmune Diseases

Corneth

Neys

Hendriks

2022

Cells

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Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells.

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“…Furthermore, anti-lipid immunoglobulins are an important mechanism for clearing atherogenic oxidized lipids [ 95 ] . Interestingly, auto-reactive anti-insulin immunoglobulins are present in humans despite normal glucose levels and actually contribute to glucose homeostasis by both eliminating and protecting insulin depending on the immunoglobulin class [ 96 ] . Thus, greater understanding into crucial regulatory mechanisms driving obesity-associated B-cell cytokine production and unique antibody profile is needed to innovate targeted therapeutic approaches.…”

Section: Micrornas Are Crucial Regulators Of B Cell Biology and B-cel...mentioning

confidence: 99%

MicroRNA-regulated B cells in obesity

Matz¹,

Qu²,

Karlinsey³

et al. 2022

Immunometabolism

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Obesity is a prevalent health risk by inducing chronic, low-grade inflammation and insulin resistance, in part from adipose tissue inflammation perpetuated by activated B cells and other resident immune cells. However, regulatory mechanisms controlling B-cell actions in adipose tissue remain poorly understood, limiting therapeutic innovations. MicroRNAs are potent regulators of immune cell dynamics through fine-tuning a network of downstream genes in multiple signaling pathways. In particular, miR-150 is crucial to B-cell development and suppresses obesity-associated inflammation via regulating adipose tissue B-cell function. Herein, we review the effect of microRNAs on B-cell development, activation, and function and highlight miR-150-regulated B-cell actions during obesity which modulate systemic inflammation and insulin resistance. In this way, we hope to promote translational discoveries that mitigate obesity-induced health risks by targeting microRNA-regulated B-cell actions.

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Autoreactive antibodies control blood glucose by regulating insulin homeostasis

Cited by 11 publications

References 75 publications

Restriction of the Global IgM Repertoire in Antiphospholipid Syndrome

Restriction of the Global IgM Repertoire in Antiphospholipid Syndrome

Aberrant B Cell Signaling in Autoimmune Diseases

MicroRNA-regulated B cells in obesity

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