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.

Regulation of Immunoglobulin Class-Switch Recombination

“…In contrast, progesterone-bound progesterone receptor reportedly inhibits transcription of the Aicda locus by binding around the RI region upstream of the promoter (Pauklin & Petersen-Mahrt, 2009). The regulation of AID by hormonal factors could have implications in hormone-based oncogenesis and autoimmunity; however, their importance in the normal CSR mechanism remains to be elucidated (Incorvaia, Sicouri, Petersen-Mahrt, & Schmitz, 2013; Maul & Gearhart, 2009; Pauklin & Petersen-Mahrt, 2009; Pauklin et al, 2009). …”

Altered IgG autoantibody levels and CD4+T cell subsets in lupus-proneNba2mice lacking the nuclear progesterone receptor

“…Together, these results suggest an effect on pathways leading to IgG CSR in autoreactive B cells. We did not observe major effects on B cell abundance or activation, but it is possible that there were important effects on the GC B cell subset, particularly its expression of activation-induced deaminase, which is required in B cells for CSR and may be under the transcriptional control of PR (15, 41). Consistent with this idea, PR loss resulted in lower levels of total IgM in aged female mice (Fig.…”

“…In uterine tissue, PR can repress the expression of the ER-α gene ( esr1 ); and in female NZB/W mice, esr1 gene deficiency causes selective reduction in serum autoAbs of the IgG 2a subclass (equivalent to IgG 2c subclass in B6 strains) (15). Nevertheless, PR loss resulted in reduced esr1 mRNA levels in splenic leukocytes from female mice (Fig.…”

“…Important estrogen effects are mediated by estrogen receptor alpha (ER-α) (13, 14), a nuclear receptor critically involved in female reproductive physiology. Estrogen enhances lupus autoimmunity through several immunologic nodes including activation of type 1 and type 2 interferon (IFN), increased T helper type 1 (T H 1) cell differentiation, enhanced survival of autoreactive B cell clones and their production of class-switched IgG autoAbs, particularly those of the pathogenic IgG 2a/2c subclass (reviewed in references (4, 15, 16)). The mechanisms by which testosterone and other male factors suppresses lupus autoimmunity remain poorly understood.…”

Aid and Apobec Deaminases: Balancing Dna Damage in Epigenetics and Immunity

“…With the DNA deaminase being intimately linked to the balance of various systems, their innate function as DNA damaging proteins, and the loss of their regulation leading to deleterious effects on DNA, it is not surprising that this family of proteins is playing a profound role in cancer biology [44,[182][183][184]. Therefore, understanding the precise molecular and biochemical properties of AID/APOBEC deaminase proteins and their interplay with the DNA damage response pathways will be important for health and disease.…”