Understanding B‐cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B‐cell immunomics approach

Tipton, Christopher; Hom, Jennifer; Fucile, Christopher; Rosenberg, Alexander F.; Sanz, Iñaki

doi:10.1111/imr.12660

Cited by 54 publications

(37 citation statements)

References 72 publications

(126 reference statements)

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“…Rather, the physiochemical properties of naturally occurring self-reactive antibodies, which are well described in SLE, are likely to account for their promiscuous binding characteristics. 20 Limitations of this study include a modest cohort size and no examination of native glial or vascular reactivities, where the latter in particular may account for complement deposition observed in NPSLE brain tissue. 21 In addition, we studied only one cytokine and used rodent hippocampal neurons, which in culture may not express key surface antigens for human NPSLE.…”

Section: Discussionmentioning

confidence: 99%

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus

Varley

Andersson

Grant

et al. 2020

Annals of Neurology

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This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N‐methyl‐D‐aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal‐surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020;88:1244–1250

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Section: Discussionmentioning

confidence: 99%

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus

Varley

Andersson

Grant

et al. 2020

Annals of Neurology

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“…Another hallmark of the SLE repertoire is defective tolerance resulting in increased frequencies of disease-specific IgHV4-34 B cells and VH4-34-encoded 9G4-idiotype autoantibodies. These antibodies display intrinsic autoreactivity against a variety of self-antigens (nucleic acids and blood-group antigens among others), which is mediated by a hydrophobic patch encoded in the germline framework 1 (FR1) 30 . In healthy individuals, elimination of the FR1 patch through somatic mutation allows the expression of non-autoreactive, protective IgHV4-34 antibodies (clonal redemption) 31 .…”

Section: Germline Clonotypes Dominate the Covid-19 Asc Repertoirementioning

confidence: 99%

Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

et al. 2020

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A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.

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“…In addition to intrinsic B cell abnormalities, alteration of the functional status of other cells involved in regulating antibody production may also contribute to the development of autoimmunity. In this regard, abnormal GC reactions in autoimmune tissues, 82 disturbances of regulatory T cells, 2 increased TFH, 68 abnormalities of CD4+ 83 and CD8+ T cells 84 85 with diminished T cell responses have been reported. As precise understanding of potential abnormalities underlying B cell dysfunction in SLE has critical importance for improved therapeutic outcome, 86 the operative mechanisms remain to be fully delineated.…”

Section: Diminished Bcr and Tlr9 Signaling In Human Sle B Cellsmentioning

confidence: 99%

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

et al. 2020

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Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton’s tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically.

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Understanding B‐cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B‐cell immunomics approach

Cited by 54 publications

References 72 publications

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus

Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

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