Immunity to Spunk

At the risk of seeming like a one-trick pony, and piggybacking on my recent appearance on the Savage Lovecast, I thought I would close the loop on immune reactions to semen. I've already written about allergens being transmitted in semen, and about women having allergies to seminal plasma itself. In the latter case, I say women having allergies not only because the only examples I found were in women, but also because by definition men cannot have allergic reactions to semen. In response to a comment on that post I wrote:

If a man did get an immune response, it would probably be called "autoimmunity" rather than allergy. And the symptoms would likely be quite different - the cells that produced the protein in the prostate (alliteration not intended) would likely be destroyed without much outward symptoms, but the man might be infertile.

I wasn't far off the mark. Allergies aren't the only type of immunity gone wrong (they're just among the most annoying).

Antisperm antibodies and conception

Antisperm antibodies (ASA) may be found in both males and females and are reported in up to 9-12.8% of infertile couples. However, these antibodies are present also in approximately 1-2.5% of fertile men and in 1.4% of fertile women[...]

So what's going on here?

As you might imagine, developing an immune reaction to sperm might be a bit of a downer in terms of reproductive fitness. If men make antibodies to their sperm, their swimmers are going to be destroyed or hobbled or made incapable of fertilizing any eggs. Similarly, if women make antibodies to sperm that make it into their reproductive tract, they'll flag all incoming semen as foreign and may destroy, hobble or block them before they reach the egg in the fallopian tube. But sperm are definitely antigenic - they can elicit an immune response (an illicit immune response?) - so how to prevent this? It turns out that males and females use very different strategies.

You might think that men could just use the same strategy we do for the rest of our tissues. After all, we have systems in place (that work most of the time) to prevent our immune system from attacking our kidneys and muscles, so why not the same for our testes? I haven't written much about this process, broadly called "self tolerance," but there are two complementary mechanisms. In "central tolerance," newly minted T-cells and B-cells are exposed to self tissues and all the potentially antigenic molecules they could eventually see. At this stage of development, however, if those cells are able to recognize anything, they are killed off instead of activated, thus eliminating a huge pool of potentially self reactive immune cells.

The system isn't perfect, however; many weakly self-reactive T-cells and B-cells manage to escape central tolerance. So "peripheral tolerance" picks up the slack. There are several different ways to do this, but all of them boil down to catching self-reactive cells once they're out in circulation, but before they can cause any real harm. So why not use the same strategy for sperm?

Well, unlike most self-derived proteins, the proteins present in semen are developmentally regulated. In other words, boys have 10-13 years to develop potentially ball-busting immune cells before the constituent parts are available to clear by central tolerance.

That's a level of slack that those peripheral mechanisms are ill-equipped to handle. Instead, we've evolved a blood-testis barrier - a tight knot of cells that prevents any immune cells or circulating antibodies from making their way into the sperm factories.

Women have a different problem. Sperm is always foreign, and vaginal intercourse is often accompanied by at least mild inflammation. In most circumstances, inflammation + foreign = robust immune response, so one might expect all sexually active women to have anti-sperm antibodies floating around. As the authors of this review put it:

how is it that despite repeated exposure to relatively large antigen loads during intercourse, most women do not produce [anti-sperm antibodies]?

How indeed? Shutting the female reproductive tract off from the immune system entirely the way men do it would be a serious mistake - any woman that's ever had a yeast infection knows that the vagina is a very inviting environment for pathogens - so what's the solution? It turns out we've developed a way to link immunosuppression with sex.

Semen doesn't just contain sperm. Among the accessory proteins present in semen are molecules called prostaglandins (originally discovered in prostate fluid, hence the name) and a cytokine called TGFβ. These molecules have known roles in tamping down immune responses and preventing hyper-inflammatory disorders, and it's presumed that, when present in ejaculate, may prevent the female partner's immune system from freaking out and seeing sperm as a threat.

I should point out that last hypothesis hasn't been definitively proven, and there may be other mechanisms that we're unaware of. The upshot of all of this knowledge is that we may be able to leverage anti-sperm antibodies as a contraceptive - one that wouldn't require altering hormones or daily pills (and it might get around those personhood amendments should they actually pass in any states). More on that in a future post.