For millions of couples globally, fertility challenges stand as a significant barrier to starting a family.
Approximately 17% of couples experience difficulty conceiving, and male infertility accounts for about half of these cases.
Immunology-related male infertility occurs when the body’s immune system interferes with normal reproductive function. For example, some men produce antibodies that mistakenly target their own sperm, reducing motility and impairing function. Current estimates suggest these immune-related issues account for about 15% of male infertility cases.
However, this number might be low because immunological mechanisms are complex and not routinely tested in standard infertility evaluations. Many cases may go undetected as a result, leaving the true prevalence of immune-related male infertility uncertain.
Researchers such as Mass General Brigham's Maria Agustina Battistone, PhD, are working to advance our understanding of immune-related male infertility, which could lead to new treatments and potentially new strategies for male contraception.
We talked to Dr. Battistone to learn more about her research and its implications.
(The image above shows an epididymis, a tiny but crucial part of the male reproductive system. The clusters of anti-sperm antibodies are shown in green. They are surrounded by immune cells, shown in pink. This is an example of the mechanisms that contribute to immune-related male infertility.)
Q: What led you to focus your research on the immune system’s role in male infertility?
Maria Battistone, PhD
A: My interest in male reproductive health began when I discovered the extraordinary nature of sperm cells.
Sperm are highly specialized cells that are produced in the testes, then spend about 74 days maturing in a small coiled organ called the epididymis. They are made by the millions and travel in large numbers into the female reproductive system, undergoing important changes along the way.
For conception to occur, one sperm cell must travel through the vagina, past the cervix, through the uterus and down the fallopian tubes and fuse with the female egg to create a new life.
This incredible journey inspired me to pursue a scientific career focused on studying male reproduction, especially how it is impacted by conditions in the epididymis—a small organ but one that is vital for male fertility.
During my time as a postdoctoral research fellow at Massachusetts General Hospital, I studied how specific cells in the male reproductive system carefully regulate acid-base balance in the testes and epididymis during sperm production to help sperm mature and improve their viability.
While working on this with Sylvie Breton, PhD (previously at Massachusetts General Hospital, now at Université Laval in Quebec, Canada), we made a surprising discovery: These same cells also play a key role in the immune system's function in the epididymis. This unexpected discovery completely changed my focus.
Sylvie Breton, PhD
I became interested in how these epididymal cells and the immune system can cause inflammation in this organ, which might be an understudied cause of male infertility.
Now, my lab is dedicated to studying these immune-related processes to find new ways to prevent or treat male infertility.
We are also exploring how we might use this knowledge to develop new methods of male contraception.
Q: What are common misunderstandings about immune factors in male infertility?
A: Many people think the male reproductive system, especially the epididymis where sperm mature and are stored, has no immune activity at all.
But that is not accurate.
Because sperm cells only appear after puberty, the immune system does not recognize them as part of the body and could treat them as harmful invaders.
However, the solution is not a complete lack of immune activity in the epididymis. It is a carefully regulated immune environment.
Under ideal conditions, the epididymis contains specialized immune cells that create a tolerant setting that allows sperm to mature safely while preventing harmful inflammation.
Another common myth is that if there is no patient history of epididymitis (an infection of the epididymis that is often characterized by discomfort in the testes or scrotum), the immune system is not involved in infertility. That is also untrue.
Chronic or “silent” inflammation, which often has no symptoms, can still damage sperm or disrupt the delicate balance of the environment they need to thrive.
Q: How do regulatory T cells (Tregs) affect fertility in men?
A close-up look at human sperm captured under the microscope.
A: Regulatory T cells, or Tregs, act as the immune system’s peacekeepers, keeping the cells that identify and fight invaders in check and preventing them from overreacting or attacking the body’s own tissues.
Research has shown that mutations in specific genes essential for Treg function can lead to male infertility.
When these Treg cells malfunction, the immune system may attack sperm or reproductive tissues, which can lead to damaged or unviable sperm.
However, we still do not fully understand how this tolerance mechanism operates in the male reproductive system.
Uncovering these details could be crucial for developing treatments for immune-related infertility in the future.
Q: What are anti-sperm antibodies and how do they impact male infertility?
Anti-sperm antibodies are molecules made by the body’s immune system that see sperm as dangerous aggressors.
This immune response usually happens when something goes wrong in the male reproductive system—particularly in the epididymis.
If the immune system’s balance is disrupted, it creates these anti-sperm antibodies, which attack the sperm instead of protecting them.
These antibodies can block sperm movement, interfere with their ability to travel through the reproductive tract, and even prevent them from fertilizing an egg.
When this occurs, it can greatly reduce fertility or even cause total infertility in some men.
Q: What did your recent study discover about chronic inflammation in the epididymis and male infertility?
A: In our recent study published in Nature, we discovered something surprising: Chronic inflammation in the epididymis leads to the formation of unique immune structures that are generally not present in the epididymis.
These “pop-up” immune cores become centers of immune activity, producing anti-sperm antibodies, causing a state of chronic inflammation and damaging the reproductive tissues.
The presence of these pop-up cores and the inflammatory activity they promote interferes with how sperm mature and function.
Q: What new treatment ideas could come from your latest findings?
A: Our research provides new hope for treating immune-related male infertility.
About 50% of male infertility cases are unexplained, and this is mainly because we still understand very little about how the immune system works in the male reproductive tract.
By exploring how immune cells interact with sperm and reproductive tissues, we are beginning to close these knowledge gaps—and this could lead to better diagnoses and targeted treatments for many men. By testing infertile male patients for the presence of anti-sperm antibodies—which we did in our study—we can better identify cases of immunological infertility.
In some men, a simple anti-inflammatory treatment may be enough to restore fertility. For more complex cases, we might need to use immune-modulating therapies, similar to those used in cancer or autoimmune diseases, to target the specific immune cells causing damage in the epididymis.
These methods are still in early stages, but they bring us closer to new treatments for men affected by hidden immune factors.
Our findings could also help improve care for epididymitis, a painful inflammation that results in over 600,000 doctor visits each year in the U.S.
Better understanding the immune system’s role may lead to more effective, targeted therapies.
Q: How could your research help develop contraceptives for men?
A: Our findings also introduce a new and promising idea: Using the immune system as a tool for male contraception.
We discovered that specific immune responses in the epididymis can actually cause sperm to be destroyed.
If we can safely activate immune cells such as phagocytes, we could potentially eliminate sperm in a targeted way, leading to temporary infertility.
What makes this especially exciting is that the epididymis is an ideal target for male contraception.
Since it’s where sperm are stored — not produced — we might be able to block fertility without affecting sperm production in the testis or disrupting hormone levels like testosterone.
The goal would be to create a non-hormonal, reversible contraceptive that works by turning off the body’s natural sperm storage system in a localized manner.
This approach could give men more control over their reproductive health without permanent changes.
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