Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies

Abstract

A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B-cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B-cell tolerance defects are primary to autoimmune diseases and may result from altered B-cell receptor signaling and dysregulated T-cell/regulatory T-cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self-antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27^- CD21^-/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self-antigens.

Keywords: B-cell development; autoantibodies; autoimmune disease; immune tolerance checkpoint.

Figure 1.. Central B cell tolerance is compromised in patients with autoimmune disease and healthy donors carrying the 1858T PTPN22 polymorphism.

Frequencies of polyreactive new emigrant/transitional B cells in patients with type 1 diabetes (T1D), rheumatoid arthritis (RA), pediatric systemic lupus erythematosus (SLE), Sjögren’s syndrome (SjS), myasthenia gravis (MG), neuromyelitis optica spectrum disease (NMOSD), multiple sclerosis (MS) and healthy donors (HD) with either heterozygous (C/T) or homozygous (T/T) PTPN22 polymorphism were compared to the frequencies derived from a cohort of healthy donors who did not carry the 1858T PTPN22 risk allele. Proportions of polyreactive antibodies expressed by new emigrant/transitional B cells were plotted for each subject group along with the mean and standard deviation for each subject group. Statistical differences are shown when significant (****, p < 0.0001; ***, p < or = to 0.001; **, p < or = to 0.01).

Figure 2.. The peripheral B cell tolerance checkpoint is compromised in patients with autoimmune disease and healthy donors carrying the 1858T PTPN22 polymorphism.

Frequencies of (A) polyreactive and (B) autoreactive (HEp-2 reactive) mature naïve B cells in seven distinct autoimmune diseases and healthy donors with either heterozygous (C/T) or homozygous (T/T) PTPN22 polymorphism were compared to the frequencies derived from a cohort of healthy donors who did not carry the 1858T PTPN22 risk allele. Proportions of (A) polyreactive antibodies or (B) autoreactive antibodies reactive toward a human epithelial type 2 (HEp-2) cell lysate expressed by mature naïve B cells were plotted for each subject group along with the mean and standard deviation for each subject group. Statistical differences are shown when significant (****, p < 0.0001; ***, p < or = to 0.001; **, p < or = to 0.01).

Figure 3.. Principal component analysis of the frequency of polyreactive and autoreactive B cells in seven distinct autoimmune diseases, healthy donors carrying 1858T PTPN22 risk allele(s) and non-carrier healthy donors.

Proportions of polyreactive antibodies expressed by new emigrant/transitional B cells and proportions of both polyreactive and autoreactive antibodies expressed by mature naïve B cells were plotted for each subject group. Healthy donor (HD)-derived B cells populations (light blue) cluster together, reflecting the low frequencies of polyreactive and autoreactive clones correlating with functional early B cell tolerance checkpoints. Type 1 diabetes (T1D), rheumatoid arthritis (RA), pediatric systemic lupus erythematosus (SLE), Sjögren’s syndrome (SjS), myasthenia gravis (MG), and neuromyelitis optica spectrum disease (NMOSD) segregate away from healthy donors, illustrating the accumulation of polyreactive and autoreactive B cells due to impaired central and peripheral B cell tolerance checkpoints. Healthy donors with either a heterozygous (C/T) or homozygous (T/T) PTPN22 polymorphism (dark blue), who also display defective early B cell tolerance checkpoints, cluster with the autoimmune disease cohort. B cells from MS patients (green) display a heterogeneous pattern. While two patients with MS cluster with the autoimmune cohort and displayed impaired central and peripheral B cell tolerance checkpoints, most MS patients cluster as an independent group characterized by specific defects of the peripheral B cell tolerance checkpoint.

Figure 4.. Variable region family usage is skewed in the naïve BCR repertoire of patients with myasthenia gravis who suffer from impaired early B cell tolerance checkpoints.

Antibody heavy chain variable region family usage for the naïve (IgM) B cell compartment. The analysis was performed with 114,296 unique sequences collected from four HDs, three AChR autoantibody positive MG patients (AChR), and three MuSK autoantibody positive MG patients (MuSK). Usage is shown as a frequency of the total unique IGHV sequences (y-axis) for each subject (symbols). Horizontal bars indicate the mean abundance over all subjects of a given status and vertical shading indicates +/− 1 SD about the mean. Data previously reported .