Calcium Signaling: From Normal B Cell Development to Tolerance Breakdown and Autoimmunity.

Abstract

Maintenance of self-tolerance of auto-reactive lymphocytes is a fundamental mechanism to prevent the onset of autoimmune diseases. Deciphering the mechanisms involved in the deregulations leading to tolerance disruption and autoimmunity is still a major area of interest to identify new therapeutic targets and options. Ca2+ signaling plays a major role in B cell normal development and is therefore finely tuned by B cell receptor (BCR)-dependent and independent pathways. Developmental changes in the characteristics of BCR-dependent Ca2+ signals as well as the modulation of basal intracellular concentration ([Ca2+]i) contribute strongly to self-tolerance maintaining mechanisms responsible for the physical or functional elimination of autoreactive B cells such as clonal deletion, receptor editing, and anergy. Implication of Ca2+ signals in B tolerance mechanisms mainly occurs through the specific activation of transcriptional programs depending on the amplitude, shape, and duration of Ca2+ signals. A large number of studies reported Ca2+ signaling defects in autoimmune pathology such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary Sjӧgren's syndrome (pSS). However, the precise nature of the molecular events responsible for these deregulations is not fully understood. Moreover, the demonstration of a direct correlation between Ca2+ signaling defects and tolerance disruption is still lacking. The recent identification of proteins involved in B cell Ca2+ signals such as ORAI, stromal interaction molecule and transient receptor potential is opening new horizons for understanding Ca2+ signaling defects observed in autoimmune diseases and for proposing potentially new therapeutic solutions. This review aims to present an overview of the developmental evolution of BCR dependent Ca2+ signaling and to place this signaling pathway in the context of mechanisms involved in tolerance maintenance and breakdown.

• Authors: Patrice Hemon, Yves Renaudineau, Marjolaine Debant, Nelig Le Goux, Sreya Mukherjee, Wesley Brooks, Olivier Mignen
• Journal: Clinical reviews in allergy & immunology (Clin Rev Allergy Immunol) Vol. 53 Issue 2 Pg. 141-165 (Oct 2017) ISSN: 1559-0267 [Electronic] United States
• PMID: 28500564 (Publication Type: Journal Article, Review)

Chemical References

• Autoantigens
• Receptors, Antigen, B-Cell

Topics

• Animals
• Autoantigens (immunology)
• Autoimmune Diseases (immunology)
• Autoimmunity
• B-Lymphocytes (physiology)
• Calcium Signaling
• Cell Differentiation
• Clonal Selection, Antigen-Mediated
• Humans
• Immune Tolerance
• Lymphocyte Activation
• Receptors, Antigen, B-Cell (metabolism)