Th110 - Repertoire of Anti-nuclear Antigen (ANA) Reactive B Cells in Systemic Lupus Erythematosus

Abstract Text: Objective. To gain insights into tolerance checkpoints, selection processes and developmental trajectories of autoreactive B cells, we studied the BCR sequences from thousands of anti-nuclear antigen binding (ANA)+ and ANA- B cells from individuals with systemic lupus erythematosus (SLE).
Methods. From a cohort of 13 patients with SLE, we sequenced B cell receptor (BCR) heavy chain variable regions and investigated the features of the IgH repertoire of ANA+ and ANA- B cells from naïve, memory and age-associated B cells (ABCs), and from total plasmablasts.
Results. The frequency of ANA+ B cells was similar in ABCs and naive B cells and higher in both than in memory B cells. ANA+ naïve and ANA+ ABCs used different gene segments and have longer CDR3 sequences than ANA+ memory B cells and ANA- subsets. ANA+ ABCs and memory B cells have a lower frequency of somatic hypermutation (SHM), less strong selection and less activation induced deaminase (AID) targeting WRC hotspots compared with their ANA- counterparts. Patients with active disease have a lower frequency of SHM in ANA+ ABCs and memory B cells and in ANA- ABCs.
Conclusion. Our results suggest an immune checkpoint restricting the differentiation of ANA+ naïve B cells into memory B cells and suggest that ANA+ ABCs originate from ANA+ naïve B cells, potentially through an extrafollicular (EF) pathway. The EF pathway appears to be more prominent in patients with active SLE. Further, there is a dysregulation of somatic hypermutation in ANA+ antigen-experienced B cells in SLE.