Antibody against ZP3 may cause infertility

February 8, 2012Carole 3 Comments »

Unexplained infertility is a frustrating diagnosis. The usual diagnostic work up has no “AHA!!”  moment and clear treatment plan. In spite of no obvious problems, there’s still no pregnancy month after month. Scientist Dr Megan Lloyd and her team announced the discovery of an antibody against the glycoprotein zona pellucida 3 (ZP3) which induces sterility in mice. Interestingly, antibodies to the same protein have been found in women but this study shows that targeted ovarian antibodies may be sufficient to cause sterility.

What is the zona pellucida and why is it important to the egg? The zona pellucida or ZP is a porous glycoprotein coat that surrounds the egg. A glycoprotein is simply a protein molecule with carbohydrate groups (the glyco part) hanging off the protein. These sugar-protein hybrid molecules often have specific jobs and being receptors for cell-cell interaction is one possible  job for these molecules. When the egg forms within the ovarian follicle, the follicle  lays down a matrix of glycoprotein molecules  around the egg. In the human, there are four varieties of glycoprotein molecules (ZP1, ZP2,ZP3 and ZP4) that create the finished zona pellucida. All the ZP proteins are synthesized by the egg as it lies in the ovarian follicle, growing and maturing over months prior to ovulation. Different roles have been identified for some of  these proteins.

ZP1 is synthesized by the oocyte and surrounds the oocyte. ZP1 crosslinks ZP2 and ZP3.

ZP2 provides a critical gate-keeper function at fertilization. Sperm bind to ZP2 which is a receptor molecule that induces the acrosome reaction in bound sperm. The acrosome reaction is an important step in fertilization. During the acrosome reaction the sperm sheds the acrosomal membrane, a sac of enzymes located at the tip of the sperm head, releasing sperm enzymes which help the sperm digest a path through the zona to get to the egg inside. Once the acrosome reaction has occurred,  in addition to providing digestive enzymes, the sperm head now has newly exposed proteins that can bind to the ZP2 molecule. One of these exposed sperm proteins is called (drum roll) the zona pellucida binding protein which gives sperm the ability to bind to zona proteins. After fertilization occurs and the sperm membrane and egg membranes interact, the ZP2 protein is removed via an enzymatic reaction initiated by the egg (the zona reaction) which slams the door shut on any other sperm that are trying to fertilize the egg, preventing polyspermy. Polyspermy, like it sounds, is an abnormal event in which many many sperm enter the egg which does not result in normal fertilization but typically results in egg death.

ZP3 is necessary molecule for the initial steps of laying down the zona matrix. At fertilization, it plays a role in species-specific recognition and binding of sperm.

ZP4 has several jobs including participating in the creation of the initial zona matrix , helping during the induction of the acrosome reaction and inhibiting the binding of excess sperm after fertilization.

A nice summary of molecular events at fertilization can be found here.

Obviously these zona proteins are essential for normal fertilization, so anything that can bind to these zona receptors and block the sperm interaction could prevent normal fertilization. Antibodies against zona proteins produced by vaccination in several species appear to be able to cause sterility by binding to zona proteins, blocking sperm access to the egg. Vaccines against zona proteins in both domestic and wildlife species have been shown to be effective  for population control.

Most recently, a study by researchers at UWA’s school of Biomedical, Biomolecular and Chemical Sciences found another mechanism by which antibodies could cause infertility. Specifically, researchers were able to deplete follicles in the mouse ovary using a vaccine against ZP3. This study shows that antibodies can be used to cause ovarian damage, not just prevent fertilization by interfering with egg-sperm binding.  ZP3 antibodies have been found in the blood of some women suffering for infertility so this may explain some cases of infertility that were previously unexplained.

In fact, ovarian autoimmune disease has previously been identified as a possible underlying cause for both premature ovarian failure and subsequent infertility. Interestingly, more than 40 years ago, an article published by WJ Irvine and others suggested that the high incidence of premature ovarian failure in women with Addison’s disease (an autoimmune disease) may suggest a form of ovarian autoimmune disease. The antibodies that Irvine was seeing in  slices of ovarian tissue was generally against “endocrine producing cells” in the ovary and were likely targeting multiple unidentified proteins inside the ovary. The zona proteins were likely one of the antibody targets detected in this early study.

Tests to look for antibodies against zona proteins are commercially available, but  I suspect they are not as widely used as the more established sperm antibody tests. Sperm antibody tests  look for antibodies to sperm in either the female’s serum or male’s semen.  Urologists may order testing of semen for antibodies to sperm (not uncommon after testicular trauma or vasectomy) which can cause problems with agglutination in which live sperm clump together in non-functional masses, also contributing to male infertility.

If antibodies against either sperm or egg proteins are detected, intracytoplasmic sperm injection (ICSI) may be indicated, because sperm injection neatly bypasses all sperm-egg binding issues that could inhibit fertilization.

(Note that I have no financial interest in any of these diagnostic tests.)

© 2012, Carole. All rights reserved.

3 Responses to this entry

  • Jay Says:

    I’m glad I’ve discovered your blog. I’m an immunologist, and I’ve grown fascinated with reproductive biology/immunology since I’ve myself had issues in this area (2 pregnancy losses).

    This is a nice explanation of the situation you have given here. Basically, as you said, IVF + ICSI should be able to get around this problem, if there is a sufficient ovarian reserve still remaining. However, I wonder if these antibodies correlate with other immune parameters like NK cells/ activated T cells or autoantibodies of different specificities which could impede implantation or the progression of a healthy pregnancy.

    Switching gears completely, but have you ever looked into the role of Vitamin D in fertility and pregnancy? That was the only thing to have been ‘off’ with me, and extensive reading and anecdotal experience tells me it really may be important.

  • Carole Says:

    Hi jay,
    Thanks for your question. There are lots of interesting areas of research regarding natural killer cells and implantation There are lots of interesting intersections (and possible research) between immunology and reproductive biology, especially to explain recurrent pregnancy loss. When you think about it, the fact that pregnancy is possible at all is amazing because you have a half-foreign embryo that isn’t rejected by its own mother. About Vitamin D, I haven’t looked at it but here’s a clinical trial on the role of Vit D on IVF outcomes. You might contact them for more specific information. Good Luck! Carole

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