Adrian Erlebacher, MD, PhD

Professor
Department of Laboratory Medicine
+1 415 502-3583
Research Overview: 

Immunology and epigenetics of pregnancy and parturition
Work in the Erlebacher laboratory lies at the intersection of immunology and developmental biology. In particular, we are interested in how the developmental properties of a tissue influence its ability to mount a successful immune response, and, conversely, how cells of the immune system influence tissue development and remodeling. The main platform for our research is the mouse uterus. This organ is not only a simple mucosal tissue amendable to extensive experimental manipulation, but its ability to accommodate the presence of immunologically foreign tissues during pregnancy (i.e. the fetus and placenta) provides a striking example of how the anatomical organization and developmental plasticity of a tissue determines its immunological properties. Moreover, reproductive success relies upon the immunological protection afforded the fetus and placenta by the uterus, with insight into how this process breaks down having implications for disorders of human pregnancy, including spontaneous abortion, intrauterine growth restriction, preeclampsia and preterm birth. We also study how the parenchymal cells of the uterus, through their specialized developmental and epigenetic properties, determine pregnancy outcome independently of their effects over immune cells. Lastly, we study how the uterine adaptation to pregnancy finds parallels in the adaptations of the tumor microenvironment that facilitate tumor escape from immune destruction. 

Current Projects

Mechanisms of “fetomaternal tolerance” and the immunology of the maternal-fetal interface. The mystery of how the fetus avoids rejection by the maternal immune system has fascinated both reproductive biologists and immunologists alike for over 70 years. The fact that underlying mechanisms have remained obscure for so long is all the more remarkable given that pregnancy formally demonstrates the possibility of establishing immune tolerance to entire organs. We have identified several of the major mechanisms of fetomaternal tolerance in mice. These include restrictions on dendritic cell trafficking from the pregnant uterus (Collins et al., J. Clin. Invest., 2009), limitations on the number of dendritic cells and macrophages that are able to come near the placenta (Collins et al., J. Clin. Invest., 2009; Tagliani et al., J. Exp. Med. 2011), the shedding of glycosylated trophoblast antigens into maternal blood that suppress, in an antigen-specific fashion, the activation maternal B and T cells specific for the placenta (Rizzuto et al., Nature, 2022; Erlebacher et al., J. Clin. Invest., 2007; Tay et al., PLoS ONE, 2013), and the inability of the decidua, the specialized uterine stromal tissue that encases the conceptus, to recruited activated T cells from the blood and foster type 1 immune responses (Nancy et al., Science, 2012; Osokine et al., Cell Reports, 2022; Nancy et al., J. Clin. Invest., 2018).  We are now studying these mechanisms in greater detail.

Epigenetic regulation of decidual stromal cells. We have found that the inability of the decidua to recruit T cells from the blood is associated with activation of an epigenetic program in decidual stromal cells that, through promoter accrual of the repressive histone mark H3K27me3, silences transcription of key T cell-attracting chemokine genes (Cxcl9, Cxcl10, etc.) (Nancy et al., Science, 2012). The program, however, affects ~800 genes in total, including ones that would otherwise induce classical wound healing responses, including tissue contraction (Osokine et al., Cell Reports, 2022; Nancy et al., J. Clin. Invest., 2018). Indeed, the suppression of wound healing at the maternal-fetal interface would appear as self-evident critical component of pregnancy success given that implantation and placental development profoundly disrupt uterine tissue integrity. We are thus studying broad impact of this program on pregnancy success, in particular its potential role in maintaining the uterus in a non-contractile, quiescent state until term gestation has been reached. 

Epigenetic and immunological control of labor onset. Parturition – the act of giving birth – remains one of the great mysteries in reproductive biology. Not only is the nature of the “clock” that times gestation length completely obscure, but little is known about the sequence of cellular and molecular events initiated at term gestation that ultimately culminate in uterine contraction. Our lack of understanding of such basic features of pregnancy has profound negative consequences for human heath, as preterm birth is not only a major cause of neonatal morbidity and mortality but also has sequelae that extend into adulthood. We study mechanisms of parturition onset from two perspectives, epigenetic and immunological. Specifically, we are determining 1) the pathways by which epigenetic programs in uterine stromal cells determine gestation length; 2) the mechanisms by which uterine immune cells become activated in late gestation and in turn themselves contribute to labor onset.

Mechanisms of uterine quiescence and parturition timing in humans. Although our most of our work relies upon mice, we also seek to determine the extent to which our findings in this species extend to humans. In particular, we are evaluating the extent to which epigenetic processes influence the function of human decidual stromal cells in both early and late pregnancy, and whether dysregulation of these processes contributes to human pregnancy complications, in particular preterm birth

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Immunology of pregnancy and uterine cancer
Mentorship Development: 

4/29/2019 - Sharpening your Mentoring Skills (SyMS) with Sharon Milgram 
11/23/2020 - Building Community in the UCSF MSTP 
5/27/2021 - Sharpening your Mentoring Skills (SyMS)
11/28//2021 - Sharpening your Mentoring Skills (SyMS)
1/12/2022 - Equity Based Interview Practices

Websites

Featured Publications: 

Establishment of fetomaternal tolerance through glycan-mediated B cell suppression.

Nature

Rizzuto G, Brooks JF, Tuomivaara ST, McIntyre TI, Ma S, Rideaux D, Zikherman J, Fisher SJ, Erlebacher A

Trophoblast antigens, fetal blood cell antigens, and the paradox of fetomaternal tolerance.

The Journal of experimental medicine

Rizzuto G, Erlebacher A

H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition.

The Journal of clinical investigation

Nancy P, Siewiera J, Rizzuto G, Tagliani E, Osokine I, Manandhar P, Dolgalev I, Clementi C, Tsirigos A, Erlebacher A

Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface.

Science (New York, N.Y.)

Nancy P, Tagliani E, Tay CS, Asp P, Levy DE, Erlebacher A

Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils.

The Journal of clinical investigation

Mahiddine K, Blaisdell A, Ma S, Créquer-Grandhomme A, Lowell CA, Erlebacher A

Baby's First Organ.

Scientific American

Erlebacher A, Fisher SJ