T Cell-Dependent Affinity Maturation and Innate Immune Pathways Differentially Drive Autoreactive B Cell Responses in Rheumatoid Arthritis

Autor: Sarah Kongpachith, Andrew McDavid, Jacob Glanville, William H. Robinson, Chia-Hsin Ju, Raphael Gottardo, Nithya Lingampalli, Daniel R. Lu
Rok vydání: 2018
Předmět:
Male
musculoskeletal diseases
0301 basic medicine
medicine.drug_class
T-Lymphocytes
T cell
Immunology
Antibody Affinity
Autoimmunity
medicine.disease_cause
Monoclonal antibody
Autoantigens
Anti-Citrullinated Protein Antibodies
Arthritis
Rheumatoid
Affinity maturation
03 medical and health sciences
Rheumatology
Rheumatoid Factor
medicine
Humans
Immunology and Allergy
skin and connective tissue diseases
B cell
Aged
Aged
80 and over
B-Lymphocytes
Innate immune system
biology
Sequence Analysis
RNA
Chemistry
High-Throughput Nucleotide Sequencing
Middle Aged
Immunoglobulin Class Switching
Molecular biology
Immunity
Innate
Self Tolerance
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
Immunoglobulin class switching
Case-Control Studies
biology.protein
Female
Single-Cell Analysis
Antibody
Immunologic Memory
Zdroj: Arthritis & Rheumatology. 70:1732-1744
ISSN: 2326-5191
Popis: Objective Rheumatoid arthritis (RA) is characterized by the activation of B cells that produce anti-citrullinated protein antibodies (ACPAs) and rheumatoid factors (RFs), but the mechanisms by which tolerance is broken in these B cells remain incompletely understood. We undertook this study to investigate whether ACPA+ and RF+ B cells break tolerance through distinct molecular mechanisms. Methods We developed antigen-tetramers to isolate ACPA+ and RF+ B cells and performed single-cell RNA sequencing on 2,349 B cells from 6 RA patients and 1 healthy donor to analyze their immunoglobulin repertoires and transcriptional programs. Prominent immunoglobulins were expressed as monoclonal antibodies and tested for autoantigen reactivity. Results ACPA+ and RF+ B cells were enriched in the peripheral blood of RA patients relative to healthy controls. Characterization of patient-derived monoclonal antibodies confirmed ACPA and RF targeting of tetramer-specific B cells at both antigen-inexperienced and affinity-matured B cell stages. ACPA+ B cells used more class-switched isotypes and exhibited more somatic hypermutations relative to RF+ B cells, and these differences were accompanied by down-regulation of CD72 and up-regulation of genes that promote class-switching and T cell-dependent responses. In contrast, RF+ B cells expressed transcriptional programs that stimulate rapid memory reactivation through multiple innate immune pathways. Coexpression analysis revealed that ACPA+ and RF+ B cell-enriched genes belong to distinct transcriptional regulatory networks. Conclusion Our findings suggest that ACPA+ and RF+ B cells are imprinted with distinct transcriptional programs, which suggests that these autoantibodies associated with increased inflammation in RA arise from 2 different molecular mechanisms.
Databáze: OpenAIRE
Externí odkaz: