ReviewProgesterone and autoimmune disease
Introduction
At roughly the same time 500 million years ago, two major adaptations arose in primitive vertebrates: the adaptive immune system and highly specific steroid hormone receptors [1], [2]. The subsequent development of placental reproduction posed immunological “problems” for the adaptive immune system, as Sir Peter Medawar, pioneer in transplantation immunology, put it in 1953 [3]. He posited that the fetus might avoid attack from its mother's immune system by means of physical barriers, immunological inertness and suppression of maternal immune responses. As Medawar himself suspected [3], physical separation of maternal and fetal circulations is critical, but so too are certain adaptations of the mother's immune system. Accordingly, the human immune system bears evidence of sexual selection. This is most obvious in the female predominance of certain autoimmune diseases (ADs) (Fig. 1), and to a lesser extent, sexual dimorphism in responses to infections. Several theories attempt to explain the female predominance of ADs: immunomodulatory effects of sex hormones; sex-dependent genetic factors; microchimerism; and gender-related factors [4]. The importance of sex hormones, particularly the sex steroids, in human AD is supported by considerable observational and experimental evidence. In this regard, much attention has been given to estrogen (Es) and androgens, important determinants of sexual dimorphism, but far less has been given to progesterone (Pg), the hormone of pregnancy. Long known for its immunoregulatory properties, Pg's impacts on human AD are not well understood. This review article will summarize what is known about Pg and AD.
First, I will outline observations supporting a role for female sex steroids in AD, correlating them with recent genetic discoveries. Next, I will briefly discuss the molecular actions of Pg, followed by a more detailed description of how Pg impacts functions of select components of the immune system. With this framework in place, I will discuss what is known about Pg, individual ADs and their animal models.
Section snippets
Progesterone and mammalian biology
Pg is a cholesterol-derived hormone critical to pregnancy [5]. Indeed, the name ultimately derives from the prefix pro and the Latin gestāre to carry. Through a variety of mechanisms, Pg is required for normal function at multiple stages of mammalian reproduction: oocyte maturation, differentiation of the endometrium, implantation of the embryo, growth of the placenta, quiescence of uterine muscle during fetal development and differentiation of mammary gland tissues. Pg also contributes to some
Sexual dimorphism in human AD
The female predominance of AD remains unexplained, but several non-competing hypotheses have been proposed. The first idea is that female sex hormones modulate the immune system to increase risk of AD in genetically susceptible individuals; the converse is that male sex steroids are protective. While this may be the most intuitive explanation, it is not the only one. X-linked immune genes, particularly if they escape inactivation or are duplicated [8], could play a major role in female
Progesterone — mechanisms of action
Steroid hormones exert their influence on physiological processes via direct effects on cellular functions. Sex steroids are synthesized primarily in the gonads, adrenal glands and, during pregnancy, the placenta. They are delivered via the bloodstream, largely protein-bound, to target tissues. Steroid hormones signal via highly specific receptors found in the plasma membrane, cytosol and nucleus of cells. [5]
Pg utilizes both cell surface and intracellular receptors. Best characterized are
Effects of progesterone on immune functions
Four general lines of evidence together indicate that Pg modulates immune functions in vivo: 1) post-pubertal female predominance of ADs; 2) systemic immunomodulation during times of high circulating Pg (pregnancy, luteal phase of the ovulatory cycle); 3) immunomodulation after Pg treatment; and 4) in vitro experiments showing direct effects on immune cells. In this section, I will discuss these last three lines of evidence, reserving the first for Section 6, “Progesterone and Autoimmune
Progesterone and autoimmune disease
As summarized in the previous section, Pg can impact many immune pathways involved in AD. This section will examine what is known about Pg and the female-predominant ADs, drawing on the previous sections to highlight possible mechanisms and future lines of investigation. For general review of the topic of female sex steroids and AD, see McCombe et al. [4] and Matocchia et al. [23]
Summary and future directions
The evolutionary requirements of placental reproduction have driven sexual dimorphism in mammalian immune systems. This dimorphism is most obvious in the extreme female predominance of certain human ADs. Sexual immune dimorphism almost certainly involves modulatory actions of sex steroids like T, Es and Pg. Pg exerts these effects via direct actions on immune cells and induction of immunomodulatory molecules in non-hematopoietic tissues. The effects of Pg and synthetic progestins depend greatly
Acknowledgments
I would like to thank Edward A. Clark, Ph.D., Peter Thomas, Ph.D., and Parul Sharma, D.O., for their helpful comments during the writing of this review.
References (184)
Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors
Mol Cell Endocrinol
(2011)The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar
J Reprod Immunol
(2003)- et al.
Progestogens and brain: an update
Maturitas
(2009) - et al.
Multiple sclerosis: geoepidemiology, genetics and the environment
Autoimmun Rev
(2010) - et al.
Pubertal correlates in black and white girls
J Pediatr
(2006) - et al.
Pediatric-onset primary biliary cirrhosis
Gastroenterology
(2003) - et al.
Sex hormones and autoimmunity
Immunol Lett
(2010) - et al.
Role for interferon regulatory factors in autoimmunity
Joint Bone Spine
(2010) - et al.
Genes, environment and immunity in the development of rheumatoid arthritis
Curr Opin Immunol
(2006) - et al.
Comparison between steroid binding to membrane progesterone receptor alpha(mPRalpha) and to nuclear progesterone receptor: Correlation with physicochemical properties assessed by comparative molecular field analysis and identification of mPRalpha-specific agonists
Steroids
(2010)
Characteristics of membrane progestin receptor alpha (mPR-alpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions
Front Neuroendocrinol
Membrane progesterone receptor expression in mammalian tissues: a review of regulation and physiological implications
Steroids
Reprint of classification and pharmacology of progestins
Maturitas
Highly effective contraception and acquisition of HIV and other sexually transmitted infections
Best Pract Res Clin Obstet Gynaecol
Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception
Steroids
Sex steroids as inflammatory regulators
J Steroid Biochem Mol Biol
The role of glycodelin as an immune-modulating agent at the feto–maternal interface
J Reprod Immunol
Mechanisms involved in the expansion of Tregs during pregnancy: role of IL-2/STAT5 signalling
J Reprod Immunol
How immune mechanisms are affected by pregnancy
Vaccine
Progesterone induces a switch in oligosaccharyltransferase isoform expression: consequences on IgG N-glycosylation
Immunol Lett
The role of sex steroids and gonadectomy in the control of thymic involution
Cell Immunol
Progesterone in pregnancy; receptor-ligand interaction and signaling pathways
J Reprod Immunol
Treatment with progesterone analogues decreases macrophage Fc-gamma receptors expression
Clin Immunol Immunopathol
Innate and adaptive immune response to apoptotic cells
J Autoimmun
The evolution of immune mechanisms
J Exp Zool B Mol Dev Evol
Sexual dimorphism in autoimmune disease
Curr Mol Med
Obstetrics: Normal and Problem Pregnancies
Enhanced sexual behaviors and androgen receptor immunoreactivity in the male progesterone receptor knockout mouse
Endocrinology
Genetics of systemic lupus erythematosus and Sjogren's syndrome
Curr Opin Rheumatol
Michrochimerism: an investigative frontier in autoimmunity and transplantation
JAMA
Influence of microbial environment on autoimmunity
Nat Immunol
The national database of the German Collaborative Arthritis Centres: I. Structure, aims, and patients
Ann Rheum Dis
The Unexplained Female Predominance of Systemic Lupus Erythematosus: Clues from Genetic and Cytokine Studies
Clin Rev Allergy Immunol
The role of sex hormones in systemic lupus erythematosus
Curr Opin Rheumatol
Prevalence and burden of pediatric-onset systemic lupus erythematosus
Nat Rev Rheumatol
Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes
Lupus
Puberty is associated with a marked increase of the female sex predominance in chronic autoimmune thyroiditis
Horm Res
A child with primary Sjogren syndrome and a review of the literature
Clin Pediatr (Phila)
Sex-specific genetic architecture of human disease
Nat Rev Genet
Sex steroids in autoimmune diseases
Curr Top Med Chem
Primary immunodeficiency and autoimmunity: lessons from human diseases
Scand J Immunol
Genetic susceptibility to SLE: new insights form fine mapping and genome-wide association studies
Nat Rev Genet
Recent insights into the genetic basis of systemic lupus erythematosus
Genes Immun
Impact of C1q deficiency on the severity and outcome of childhood systemic lupus erythematosus
Int J Rheum Dis
The role of complement in the development of systemic lupus erythematosus
Annu Rev Immunol
Are pediatric autoimmune diseases primarily genetic diseases
Curr Opin Rheumatol
Sex-Specific Genetic Architecture of Systemic Lupus Erythematosus
Dubois' Lupus Erythematosus
A catolog of published genome-wide association studies
STAT4: Genetics, Mechanisms, and Implications for Autoimmunity
Curr Allergy Asthma Rep
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