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.

Prep1 (pKnox1) is a homeodomain transcription factor essential for in utero and post-natal development and an oncosuppressor gene in human and adult mice. We have analyzed its role in the development of the mouse mammary gland. We used Prep1i/i hypomorphic and Prep1F/F-Ker5CRE crosses to analyze the role of Prep1 in vivo in adult mouse mammary gland development. We also cultured mammary gland stem/progenitor cells in mammospheres to perform biochemical studies. Prep1 was expressed in mammary gland progenitors and fully differentiated mammary gland cells. Using different Prep1-deficient mouse models we show that in vivo Prep1 contributes to mammary gland branching since the branching efficiency of the mammary gland in Prep1-deleted or Prep1 hypomorphic mice was largely reduced. In-vitro, Prep1 sustained functions of the mammary stem/progenitor compartment. Prep1-deficient mammary stem/progenitor cells showed reduced ability to form mammospheres; they were not able to branch in a 3D assay, and exhibited reduced expression of Snail1, Snail2 and vimentin. The branching phenotype associated with increased Tp53-dependent apoptosis and inability to properly activate signals involved in branching morphogenesis. Finally, Prep1 formed complexes with Snail2, a transcription factor essential in branching morphogenesis, and its absence destabilizes and promotes Snail2 proteasome-mediated degradation. We conclude that Prep1 is required for normal adult mammary gland development, in particular at its branching morphogenesis step. By binding Snail2, Prep1 protects it from the proteasomal degradation.