Hormones and AID: Balancing immunity and autoimmunity

Abstract

The human immune system is a complex dynamic network of soluble factors and specialized cells that can and need to act in an instance or keep a lifelong protection, with the consequence that health has to be maintained through genetic and environmental stimuli. Autoimmunity is a multifactorial disease, where this combination of genetic predisposition and environmental factors lead to disease etiology. As some autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or other B cell autoimmunities have a very strong female gender bias, hormones, especially estrogen, have been implicated as environmental factors in driving the disease. One of the key regulators of B cell development is activation-induced deaminase (AID), as its molecular mechanism of cytosine deamination induces immunoglobulin affinity maturation and antibody class switching. In this review we will highlight some of the recent findings of how estrogen directly and indirectly activates AID expression, which in turn can lead to immune hyper-stimulation. Those regulatory pathways can be direct when the estrogen receptor (ER) binds the AID promoter, or indirect via activation of transcription factors that enhance AID expression (e.g., HoxC4). Estrogen's influence on AID will also be discussed in terms of microRNA processing for miRNA-155 and miRNA-181b. Important other external stimuli, such as EBV virus, in conjunction with estrogen can add another layer of regulation during autoimmune disease progression. Understanding these pathways will become more important as AID has now been implicated to play an important role in immune tolerance and actual elimination of autoantibodies.

Keywords::

• Estrogen
• autoantibodies
• immunoglobulin
• deamination
• lupus
• epigenetics

Acknowledgements

We wish to thank the editor of this issue during the publication process for providing stimulating support. We would like to apologize to all those who have contributed to this field, but may have been left out due to space limitations.

Declaration of interest: KMS is supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme. SKPM is supported from Istituto FIRC di Oncologia Molecolare, Italy (IFOM). All authors have no conflicting financial interests. All authors are responsible for the content and the writing of this article.