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

ABSTRACT: Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies.

SUBMITTER: Tipton CM

PROVIDER: S-EPMC4512288 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Tipton Christopher M CM Fucile Christopher F CF Darce Jaime J Chida Asiya A Ichikawa Travis T Gregoretti Ivan I Schieferl Sandra S Hom Jennifer J Jenks Scott S Feldman Ron J RJ Mehr Ramit R Wei Chungwen C Lee F Eun-Hyung FE Cheung Wan Cheung WC Rosenberg Alexander F AF Sanz Iñaki I

Nature immunology 20150525 7

Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consis ...[more]

PMID: 26006014

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Project description:The diagnosis of Systemic Lupus Erythematosus (SLE) is challenging due to its heterogeneous clinical presentation and lack of robust biomarkers for laboratory testing to distinguish it from other autoimmune or infectious diseases. Current diagnostic criterion relies on a combination of clinical examination and laboratory tests, and it does not readily distinguish between those with active clinical disease from those that are clinically quiescent. Several groups have attempted to apply emerging high throughput profiling technologies to diagnose SLE. Despite showing promising diagnostic potential, many of them are expensive and technically challenging for routine clinical uses. Here we report a pilot study of applying a technically simple and highly customisable leukocyte capture antibody microarray to profile healthy (n=24) and SLE patients (n=60) of various disease activities. Our analysis reveals a set of surface antigen biomarkers that have significant association with SLE. In addition, we present a computational method to calculate a score from the entire microarray profile to obtain a score that correlate most reliably with SLE disease activity. Although the current version of our microarray alone does not match the discriminatory power of the standard laboratory tests (serum dsDNA, complements C3 and C4), the combination of the two yields a test with significantly increased discriminatory ability than what can be achieved individually. This work paves the way for a customised SLE-specific antibody microarray for accurate diagnosis and monitoring of SLE that can be readily translated to routine clinical use. Blood samples were collected from 60 patients of Systemic Lupus Erythematosus (SLE) of different disease activity (11 active, 16 semi-active, and 33 inactive), and compared it with blood samples from 24 healthy blood donors. For each subject, we extracted PBMCs and apply them to a leukocyte capture antibody microarray. The microarray was then scaned by a DotScan™ slide reader (Medsaic; Eveleigh, NSW, Australia). The number of immobilized cells was proportional to the light scattered at each antibody spot. Binding of PBMCs to each antibody dot was monitored by light scatter and averaged between the duplicate spots on each slide. We then performed statistical analysis to identify CD antigen markers that are associated with SLE, as well as determining the potential diagnostic ability of this microarray for SLE.

Dataset Information

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

Publications

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

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