Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a...

Area of Science:

• Immunology
• Rheumatology
• Genetics

Background:

• Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease affecting synovial joints.
• RA is traditionally classified into seropositive (SP-RA) and seronegative (SN-RA) forms.
• A severe, destructive form of SN-RA, termed CND-RA, requires differentiation from other RA subtypes.

Purpose of the Study:

• To identify distinct biological characteristics of CND-RA compared to SP-RA and other SN-RA.
• To investigate the role of cytotoxic CD8+ lymphocytes in autoimmune arthritis, specifically in CND-RA.
• To establish CND-RA as an independent subset of RA.

Main Methods:

• Comparative analysis of T-cell receptor beta (TCRβ) repertoire, cytokine levels, and autoantibody repertoires in CND-RA, SP-RA, and SN-RA patients versus healthy controls.
• Whole-exome sequencing (WES) and single-cell RNA-sequencing (sc-RNA-seq) to analyze somatic mutations and gene expression in CD8+ lymphocytes.
• Assessment of IgG repertoire recognition of endogenous proteins.

Main Results:

• CND-RA patients exhibit a unique TCRβ signature in CD8+ lymphocytes.
• Elevated levels of the bone-resorption cytokine TNFSF14 were observed in CND-RA patients.
• CND-RA patients' IgG repertoires recognized fewer endogenous proteins compared to SP-RA patients.
• WES identified a stable mutation profile with a cytotoxic gene expression signature in clonally expanded CD8+ T-cells from an index CND-RA patient.

Conclusions:

• CND-RA represents a distinct and aggressive subset of rheumatoid arthritis.
• The identified TCRβ signature in CD8+ lymphocytes is specific to CND-RA.
• Understanding RA heterogeneity, particularly within SN-RA, is crucial for developing targeted therapies for treatment-resistant patients.