Changes in Complement Proteins Affect Infertility in Women with Endometriosis

Abnormal levels of complement proteins as a possible cause of infertility in women with endometriosis.

Key Points

Highlights:

• This paper analyzes changes in complement regulatory proteins (CRPs) expression in women with and without endometriosis and tries to elucidate the molecular mechanisms by which decay accelerating factor (DAF) interacts with αvβ3 integrin.

Importance:

• The molecular mechanisms underlying endometriosis-related infertility is not well understood. Once this process is elucidated, researchers can develop treatments to increase fertility for women with endometriosis that are trying to start a family.

What’s done here?

• Women with (47)  and without (42) endometriosis participated in this study.
• Endometrial biopsies were collected from the participants by urinary LH surge detection (to collect samples at the proliferative or mid-secretory phase).
• Immunohistochemistry was used to determine the expression of following complement regulatory proteins:
  • Membrane cofactor protein (CD46), Decay-accelerating factor (DAF), Membrane attack complex inhibitory factor (CD59) and β3 integrin subunit.
• DAF protein quantities in endometriomas evaluated by Western blot.
• Epithelial cells were also isolated through Laser capture microdissection (LCM) to determine mRNA levels of above proteins.
• Paracrine regulation and co-localization evaluation for the expression and the interactions of DAF and β3 integrin were performed.

Key results:

• During the mid-secretory phase, DAF and β3 integrin expression levels were lower in the participants with endometriosis (decreased mRNA levels, low protein, and the minimal interactions).
• Women with endometriosis were also found to have disrupted epithelial DAF and β3 integrin expression. This expression is regulated by paracrine that is stromal compartment progesterone mediated.
• In short, the women with endometriosis have endometriomas that contain abnormal levels of complement proteins. This deviation from normalcy can lead to implantation failure and can adversely impact embryo survival.  

Limitations of the study:

• There were not a lot of participants in this study and the participants recruited only came from 2 different countries. This limitation in the number of participants and diversity of participants might prevent the results from being applicable on a global scale.

Lay Summary

Palomino et al. recently published a paper titled “The endometria of women with endometriosis exhibit dysfunctional expression of complement regulatory proteins during the mid-secretory phase” in the Journal of Reproductive Immunology where they look at the expression of CRPs during the menstrual cycle of women with and without endometriosis. They also hope to elucidate the molecular mechanisms that result in DAF and αvβ3 integrin interactions.

When an embryo forms and develops, it’s survival is dependent on the regulation of complement activation, part of the innate immune response, within the environment in which it develops. In order for a cell to avoid a complement attack, complement regulatory proteins (CRPs) must interact with cell adhesion molecules, such as αvβ3 integrin. Decay-accelerating factors (DAF) carry out their role by inhibiting assembly and promoting disassembly. 

47 of the participants had endometriosis whereas 42 participants did not have endometriosis. Endometrial biopsies were collected during the proliferative or mid-secretory phase. The researchers used a variety of techniques such as immunohistochemistry, western blot, Laser capture microdissection (LCM), qRT-PCR, paracrine regulation, in vitro assays, immunoprecipitation, and co-localization alongside dual immunofluorescence. These methods revealed the expression of different cofactors, factors, and subunits; quantity of DAF protein; mRNA levels; DAF and β3 integrin expression; and in vivo DAF and β3 integrin interactions.

The results showed that DAF and β3 integrin are expressed less during the mid-secretory phase in a woman with endometriosis. Furthermore, there was a notable decrease in protein concentration, very little DAF and β3 integrin interactions, and a decrease in mRNA levels within the cells. Additionally, it was found that women with endometriosis had disrupted epithelial DAF and β3 integrin expression that is paracrine regulated. This paracrine regulation is further mediated by the stromal compartment progesterone. In conclusion, women with endometriosis have abnormal levels of some complement proteins, which subsequently leads to implantation failure and can affect embryo survival.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/29153978