Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus

Tipton, Christopher; Fucile, Christopher; Darce, Jaime; Chida, Asiya Seema; Ichikawa, Travis; Gregoretti, Ivan V.; Schieferl, Sandra M; Hom, Jennifer; Jenks, Scott A.; Feldman, Ron J.; Mehr, Ramit; Wei, Chungwen; Lee, F Eun-Hyung; Cheung, Wan Cheung; Rosenberg, Alexander F.; Sanz, Iñaki

doi:10.1038/ni.3175

Cited by 425 publications

(568 citation statements)

References 51 publications

(86 reference statements)

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“…In addition to a direct migration of AQP4 autoantibody‐secreting plasmablasts into the CNS compartment, we observed connections between CSF Ig peptides and peripheral blood memory, DN memory, and naïve VH transcripts indicating that additional maturation and differentiation of peripheral blood B cells into ASCs likely occurs within the CNS. Interestingly, a high degree of connectivity was observed between ASCs and activated naïve B cells in active systemic lupus erythematosus patients 12. Our data suggest that naïve B cells may also be actively recruited into the enhanced ASC response associated with NMOSD clinical relapse 16.…”

Section: Discussionmentioning

confidence: 65%

“…The stringency for CDR3 identity was chosen based on prior analysis of NMOSD CSF plasmablast clones1 that showed significant intraclonal CDR3 sequence variability. A similar approach was taken in the analysis of antibody‐secreting cell populations in systemic lupus erythematosus (SLE) 12. Lineage analysis (rooted B‐cell lineage trees) was performed using IgTree,13 kindly provided by Prof. Ramit Mehr.…”

Section: Methodsmentioning

confidence: 99%

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CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Kowarik

Astling

Gasperi

et al. 2017

Ann Clin Transl Neurol

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ObjectivesNeuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system (CNS) targeted against aquaporin‐4 (AQP4). The origin and trafficking of AQP4‐specific B cells in NMOSD remains unknown.MethodsPeripheral (n = 7) and splenic B cells (n = 1) recovered from seven NMOSD patients were sorted into plasmablasts, naïve, memory, and CD27‐IgD‐ double negative (DN) B cells, and variable heavy chain (VH) transcriptome sequences were generated by deep sequencing. Peripheral blood (PB) VH repertoires were compared to the same patient's single‐cell cerebrospinal fluid (CSF) plasmablast (PB) VH transcriptome, CSF immunoglobulin (Ig) proteome, and serum Ig proteome. Recombinant antibodies were generated from paired CSF heavy‐ and light chains and tested for AQP4 reactivity.ResultsApproximately 9% of the CSF VH sequences aligned with PB memory B cells, DN B cells, and plasmablast VH sequences. AQP4‐specific VH sequences were observed in each peripheral B‐cell compartment. Lineage analysis of clonally related VH sequences indicates that CSF AQP4‐specific B cells are closely related to an expanded population of DN B cells that may undergo antigen‐specific B‐cell maturation within the CNS. CSF and serum Ig proteomes overlapped with the VH sequences from each B‐cell compartment; the majority of matches occurring between the PB VH sequences and serum Ig proteome.InterpretationDuring an acute NMOSD relapse, a dynamic exchange of B cells occurs between the periphery and CNS with AQP4‐specific CSF B cells emerging from postgerminal center memory B cells and plasmablasts. Expansion of the PB DN B‐cell compartment may be a potential biomarker of NMOSD activity.

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Section: Discussionmentioning

confidence: 65%

Section: Methodsmentioning

confidence: 99%

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Kowarik

Astling

Gasperi

et al. 2017

Ann Clin Transl Neurol

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“…This has been observed in multiple studies, suggesting differences in B‐cell selection and antigen‐specific B‐cell clonal expansion. All the BCR sequencing studies to date have shown an enrichment of IGHV4 gene family usages,17, 23, 35, 36 specifically IGHV4‐34 17, 36. IGHV4‐34 was the dominant serum autoantibody IGHV gene 17.…”

Section: Slementioning

confidence: 99%

“…This is characterized by polyclonal (multiple) B‐cell expansions 36. This is possibly secondary to increased numbers of plasmablasts.…”

Section: Slementioning

confidence: 99%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

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SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

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“…IGHV5‐51 is associated with Celiac disease 128129, 130, 131130 but it also has a unique framework 1 region that can bind to human red blood cell antigens I and i when in its germline form,132 these antigens can therefore be considered to be superantigens.…”

Section: Gene Use Analysismentioning

confidence: 99%

Immunoglobulin gene analysis as a tool for investigating human immune responses

Dunn-Walters

Townsend

Sinclair

et al. 2018

Immunological Reviews

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SummaryThe human immunoglobulin repertoire is a hugely diverse set of sequences that are formed by processes of gene rearrangement, heavy and light chain gene assortment, class switching and somatic hypermutation. Early B cell development produces diverse IgM and IgD B cell receptors on the B cell surface, resulting in a repertoire that can bind many foreign antigens but which has had self‐reactive B cells removed. Later antigen‐dependent development processes adjust the antigen affinity of the receptor by somatic hypermutation. The effector mechanism of the antibody is also adjusted, by switching the class of the antibody from IgM to one of seven other classes depending on the required function. There are many instances in human biology where positive and negative selection forces can act to shape the immunoglobulin repertoire and therefore repertoire analysis can provide useful information on infection control, vaccination efficacy, autoimmune diseases, and cancer. It can also be used to identify antigen‐specific sequences that may be of use in therapeutics. The juxtaposition of lymphocyte development and numerical evaluation of immune repertoires has resulted in the growth of a new sub‐speciality in immunology where immunologists and computer scientists/physicists collaborate to assess immune repertoires and develop models of immune action.

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Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus

Cited by 425 publications

References 51 publications

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Antibody repertoire analysis in polygenic autoimmune diseases

Immunoglobulin gene analysis as a tool for investigating human immune responses

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