Sialic Acid Ligand Binding of CD22 and Siglec-G Determines Distinct B Cell Functions but Is Dispensable for B Cell Tolerance Induction

Özgör, Lamia; Meyer, Sarah J; Korn, Marina A; Terörde, Klara; Nitschke, Lars

doi:10.4049/jimmunol.1800296

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…Through in-depth B-cell phenotyping, we observed higher expression of HLA-DR across B-cell populations in seropositive RA consistent with more activated B cells. We could also detect higher levels of CD22, which is a co-receptor of the BCR with a reactivity to α2,6-linked sialic acids 32 (reviewed in 33 ), in several IgM + B-cell populations in ACPA + RA. While CD22 is negative regulator of BCR, its roles on different B cell subset is complex and expression can be increased on activated B cell after certain stimuli.…”

Section: Discussionmentioning

confidence: 87%

Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance

Wang

Lloyd

Melas

et al. 2019

Sci Rep

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B cells are postulated to be central in seropositive rheumatoid arthritis (RA). Here, we use exploratory mass cytometry (n = 23) and next-generation sequencing (n = 19) to study B-cell repertoire shifts in RA patients. Expression of several B-cell markers were significantly different in ACPA+ RA compared to healthy controls, including an increase in HLA-DR across subsets, CD22 in clusters of IgM+ B cells and CD11c in IgA+ memory. Moreover, both IgA+ and IgG+ double negative (IgD− CD27−) CD11c+ B cells were increased in ACPA+ RA, and there was a trend for elevation in a CXCR5/CCR6high transitional B-cell cluster. In the RA BCR repertoire, there were significant differences in subclass distribution and, notably, the frequency of VH with low somatic hypermutation (SHM) was strikingly higher, especially in IgG1 (p < 0.0001). Furthermore, both ACPA+ and ACPA− RA patients had significantly higher total serum IgA and IgM compared to controls, based on serology of larger cohorts (n = 3494 IgA; n = 397 IgM). The observed elevated Ig-levels, distortion in IgM+ B cells, increase in double negative B cells, change in B-cell markers, and elevation of unmutated IgG+ B cells suggests defects in B-cell tolerance in RA. This may represent an underlying cause of increased polyreactivity and autoimmunity in RA.

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Section: Discussionmentioning

confidence: 87%

Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance

Wang

Lloyd

Melas

et al. 2019

Sci Rep

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“…Interestingly, α2-6 sialic acid is absent in pSS B cells and barely present in SLE, whereas α-fucose is reduced only in SLE B cells. In-depth characterisations have revealed that memory B cells are remarkably altered, and these glycosylation changes could explain the positive selection of autoreactive B cells ( 49 , 53 ), and the increased activation of BCR caused by the absence of CD22 sialic acid ligands ( 39 , 52 , 54 ). In contrast to pSS B cells, SLE B cells exhibit Gal-GlcNAc/Gal-GalNAc terminal patterns, suggesting a lack of terminal glycosylation.…”

Section: Discussionmentioning

confidence: 99%

Abnormal B cell glycosylation in autoimmunity: A new potential treatment strategy

Morel

Pochard²,

Echchih³

et al. 2022

Front. Immunol.

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Systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) are two autoimmune diseases characterised by the production of pathogenic autoreactive antibodies. Their aetiology is poorly understood. Nevertheless, they have been shown to involve several factors, such as infections and epigenetic mechanisms. They also likely involve a physiological process known as glycosylation. Both SLE T cell markers and pSS-associated autoantibodies exhibit abnormal glycosylation. Such dysregulation suggests that defective glycosylation may also occur in B cells, thereby modifying their behaviour and reactivity. This study aimed to investigate B cell subset glycosylation in SLE, pSS and healthy donors and to extend the glycan profile to serum proteins and immunoglobulins. We used optimised lectin-based tests to demonstrate specific glycosylation profiles on B cell subsets that were specifically altered in both diseases. Compared to the healthy donor B cells, the SLE B cells exhibited hypofucosylation, whereas only the pSS B cells exhibited hyposialylation. Additionally, the SLE B lymphocytes had more galactose linked to N-acetylglucosamine or N-acetylgalactosamine (Gal-GlcNAc/Gal-GalNAc) residues on their cell surface markers. Interestingly, some similar alterations were observed in serum proteins, including immunoglobulins. These findings indicate that any perturbation of the natural glycosylation process in B cells could result in the development of pathogenic autoantibodies. The B cell glycoprofile can be established as a preferred biomarker for characterising pathologies and adapted therapeutics can be used for patients if there is a correlation between the extent of these alterations and the severity of the autoimmune diseases.

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“…On the other hand, CD22 −/− × Siglec-G −/− mice produce aberrant levels of autoantibodies and show signs of overt autoimmunity, as documented by kidney damage, that is over and above the milder autoimmunity observed in Siglec-G −/− mice [21]. In more recent work by Nitschke and co-workers, a CD22 and Siglec-G double knock-in mouse was created with mutations at the critical arginine in both Siglecs, which allowed them to investigate the impact of abolishing sialic acid binding on B cells in immune tolerance [92]. Interestingly, these double mutant mice did not display the same autoimmunity as CD22 −/− × Siglec-G −/− mice [51].…”

Section: Roles Of Glycan Ligands In Controlling Cd22 As a Bcr Inhibitmentioning

confidence: 99%

Coordinated roles for glycans in regulating the inhibitory function of CD22 on B cells

2019

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CD22 is an inhibitory B cell co-receptor that recognizes sialic acid-containing glycoconjugates as ligands. Interactions with its glycan ligands are key to regulating the ability of CD22 to modulate B cell function, the most widely explored of which is antagonizing B cell receptor (BCR) signaling. Most importantly, interactions of CD22 with ligands on the same cell (cis) control the organization of CD22 on the cell surface, which minimizes co-localization with the BCR. In contrast with the modest ability of CD22 to intrinsically dampen BCR signaling, glycan ligands presented on another cell (trans) along with an antigen drawn CD22 and the BCR together within an immunological synapse, strongly inhibiting BCR signaling. New concepts are emerging for how CD22 controls B cell function, such as changes in glycosylation at different stages of B cell differentiation, specifically on GC B cells. Related to these changes, new players, such galectin-9, have been discovered that regulate cell surface nanoclusters of CD22. Roles of glycan ligands in controlling CD22 are the primary focus of this review as we highlight the ability of CD22 to modulate B cell function.

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Sialic Acid Ligand Binding of CD22 and Siglec-G Determines Distinct B Cell Functions but Is Dispensable for B Cell Tolerance Induction

Cited by 12 publications

References 44 publications

Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance

Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance

Abnormal B cell glycosylation in autoimmunity: A new potential treatment strategy

Coordinated roles for glycans in regulating the inhibitory function of CD22 on B cells

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