Loss of an IgG plasma cell checkpoint in lupus

Publication date: Available online 13 November 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Jolien Suurmond, Yemil Atisha-Fregoso, Emiliano Marasco, Ashley N. Barlev, Naveed Ahmed, Silvia A. Calderon, Mei Yin Wong, Meggan C. Mackay, Cynthia Aranow, Betty Diamond

Abstract

Background

IgG anti-nuclear antibodies (ANA) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in autoimmune disease are not fully understood.

Objectives

To study whether autoreactive plasma cells in lupus models and SLE patients arise as a consequence of defective antigen-specific selection or a global enhancement of IgG PC differentiation.

Methods and Results

We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and PC. We observed a major checkpoint for generation of ANA+ IgG+ PC in both non-autoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ PC despite normal tolerance checkpoints in immature and naïve B cells in lupus-prone MRL/lpr and NZB/W mice as well as patients with systemic lupus erythematosus (SLE). This increase was due to increased numbers of total IgG+ PC rather than lack of selection against ANA+ PC.

Conclusion

Using a method that permits quick and accurate quantification of autoreactive B cells and PC in vivo within a native B cell repertoire in mice and humans, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANA. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B cell differentiation rather than a defect in antigen-specific B cell tolerance.

Clinical implication

Therapies for SLE might need to be targeted at IgG plasma cell differentiation rather than antigen-specific tolerance.

Graphical abstract

https://ift.tt/2Qzm43r