THE IMMUNE SYSTEM IN REPRODUCTION
Autoimmunity and reproduction
GENERAL CONCEPTS - To recognize and acknowledge how conceptually connected autoimmunity and pregnancy are in biological terms is essential for both of these areas of scientific exploration. What establishes this absolutely essential conceptual link is only one thing: the underlying need to develop immunologic tolerance.
Let us explain: Our daily survival is fully dependent on the normal functioning of our immune systems, which, in principle, have two basic functions. It is our immune system that protects us from invaders such as bacteria, viruses, parasites, etc. Our immune system, however, also protects us from developing cancers—its second major function—and it does all of this under normal health conditions while fully respecting our own body’s tissue components, a process called self-tolerance.
In other words, a normally functioning immune system can differentiate between self and non-self, or foreign. Even within self, it can differentiate between healthy and unhealthy self, fully recognizing that self, in principle, is never to be attacked, with cancer obviously being an exception. Foreign, in contrast, must always be immediately attacked after gaining access to our body. A normally functioning immune system, therefore, must be a highly complex and multilayered apparatus. And, while enormous progress has been made in understanding how our immune system works (and at times malfunctions), much is still to be discovered.
All complex systems, whether our bodies or rockets we are sending to the stars, at times malfunction. And so does our immune system in one or more of its components. If such a malfunction involves self-tolerance, we develop autoimmunity; if it involves failure to recognize and/or failure to properly attack an invader, we develop an infectious disease; and if it means that the immune system fails to eliminate early cancer, we develop cancer. So, what does all of this then have to do with reproduction?
The answer is: everything!
Every implanting embryo—being 50% genetically of paternal origin, and in cases of egg donation or gestational carrier pregnancies, even 100% foreign—is, after all, a foreign invader, attempting to breach our immune system’s principal responsibilities, which are to precisely avoid such invasions from happening. Under normal circumstances, the female immune system, therefore, should instantly and aggressively attack this invading organism and reject it, not differently from how it would with great likelihood reject an organ transplant from the same male. But, fascinatingly, no such rejection occurs if the woman’s immune system works properly because, once made aware of the embryo’s desire to implant (i.e., to invade), the female’s immune system reprograms itself in a highly embryo-specific way that allows it—and only it, without accidentally accompanying bacteria, viruses, or other invaders—to enter the holy grounds of the woman’s body without being rejected.
In other words, the woman’s immune system induces immunological “tolerance” for the paternal part of the embryo that, under all basic biological rules, should be aggressively rejected. And—even though still only partially understood—the tolerance pathways induced in this process by the maternal immune system have quite significant similarities with pathways our immune system uses for the above-described “self-tolerance,” which prevents our immune system from attacking our own bodies. These pathways also share similarities with pathways parasites induce in hosts that allow them to evade the host’s immune system and, as increasing evidence also suggests, similar abilities to induce immunologic tolerance have also been acquired through evolutionary processes by metastatic cancers, allowing them to metastasize.
Returning to the invading embryo during implantation, the maternal immune system does not only have to deal with the 50% allogeneic half of the embryo that comes from the father. The other 50% from the mother is also not completely innocent and immunologically quiet because the maternal immune system now faces an invader with both allogeneic and self-genetic makeup. If the maternal immune system were to mount an immune response against this implanting embryo—it could be an anti-paternal as well as an anti-self-immune response. Inducing an allogeneic immune response along with an autoimmune response can, therefore, be very damaging to the mother and/or offspring.
The very close interplay of pregnancy with autoimmunity and of autoimmunity with pregnancy, therefore, must be viewed as an amazing but essential entanglement without which humankind could not exist. That the maternal immune system—if functioning normally—does not attack the invading (i.e., implanting) embryo in many ways, therefore, has to be viewed as a miracle of nature. Because of its perfect specificity to only the embryos, it, moreover, as already noted, must represent an enormously complicated cascade of reprogramming events within the maternal immune system which, as is now understood, in women with a hyperactive immune system (i.e., evidence of autoimmunity, inflammation, and/or just severe allergies) to variable degrees often malfunctions, resulting in the embryo not being fully protected and, therefore, leading to immunological pregnancy loss.
Who then can be surprised that, once this complex tolerance by the beginning of the second trimester has taken shape, women with autoimmune diseases like systemic lupus erythematosus (SLE) start feeling better, often noting that they have not felt so well in years—only to regress once the tolerance toward the fetus usually in the late third trimester starts waning, only to be completely shut off with the onset of labor and certainly with delivery.
CLINICAL RELEVANCE AND STRONG FEMALE PREPONDERANCE
As already noted, on a clinical level, the linkage between autoimmunity and pregnancy is demonstrated by the fact that several autoimmune diseases characteristically improve clinically once full pregnancy tolerance has been established (patients “feel better than they have felt in ages”) after the first trimester. The reason is that the tolerance pathways induced in the maternal immune system by pregnancy cross-react with self-tolerance, and vice versa.
At the same time, every pregnancy in patients with any autoimmune disease faces increased risks early in pregnancy when full tolerance must still be established (as noted, leading to miscarriages); and, again, from the third trimester of pregnancy into the postpartum period, because pregnancy tolerance in women with hyperactive immune systems often wears off earlier than in women unaffected by autoimmunity. Early diminishing tolerance then can lead to premature labor and delivery. Premature deliveries are, indeed, an increased risk factor with any maternal autoimmune disease (1). Early diminishing pregnancy tolerance is likely also causal in increased preeclampsia risk in women with autoimmune diseases and, of course, can also be reflected in the well-known postpartum risk for flares of autoimmune diseases.
Autoimmune diseases, of course, are very common, affecting in the U.S. approximately 5% of the population. By 2022, that meant over 15 million people (2). These numbers, moreover, do not include asymptomatic individuals with autoimmune abnormalities on laboratory tests. And subclinical autoimmunity can, indeed, significantly affect reproductive success.
Roughly two-thirds (63%) of clinically diagnosed autoimmune diseases occur in women, representing a 1.7 to 1 ratio to men. They increase with advancing age, peaking above age 65. Autoimmunity, moreover, is highly polygenic in that having one autoimmune disease significantly predisposes to other autoimmune diseases. Indeed, roughly 24% of individuals affected by autoimmune diseases have been reported to have two, 8% three, and 2% four or more autoimmune conditions.
The most frequently diagnosed autoimmune disease is rheumatoid arthritis, followed by psoriasis, type 1 diabetes, Graves’ disease, and autoimmune thyroiditis (Hashimoto’s). Moreover, 19 of 20 autoimmune diseases occur more frequently in women than men (3)
MENOPAUSAL HORMONE THERAPY INCREASES AUTOIMMUNE DISEASE RISK - A recent paper in Rheumatology offered rather convincing evidence that menopausal hormone therapy increased the risk for developing systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) (4).
Studying 943 women with SLE and 733 with SSc, the authors found close associations between menopausal hormone use and both conditions. Moreover, women who received systemic as well as local hormone treatments had the highest risk of developing both conditions. Here is another potentially important consideration in using hormone replacement therapy in postmenopausal women!
AND SO, APPARENTLY, DOES AN EXTRA X CHROMOSOME - Two investigators from Jefferson University in Philadelphia investigated the dose effect of an extra X chromosome on the development of SLE and Sjögren’s syndrome, both autoimmune diseases with significant female preponderance. A reason for the study was that, in Klinefelter syndrome (KS), the prevalence of SLE has been known for some time to be increased.
What they found was that the extra X chromosome in KS and in the triple X syndrome conferred a nonproportional, synergistic dose effect on the development of SLE and SjD when compared with the general population (5).
Considering the many immune system-related genes on the X chromosome, this finding should be no surprise. That this fact was now, however, confirmed, informs to a degree on why females have such a preponderance in autoimmune diseases in comparison to males.
NAME CHANGES FOR DISEASES; DO THEY REALLY MAKE A DIFFERENCE? - A recent article by Healio informed about several name changes for major autoimmune rheumatologic diseases, including ankylosing spondylitis and Sjögren’s syndrome. We, of course, have all used the term ankylosing spondylitis for decades; we also agreed to a subdivision for this term into radiographic and non-radiographic subtypes; but we will now have to get used to calling the disease by its new name, “axSpA,” and whether it is visible on X-ray is only of academic but not of clinical interest (6).
Sjögren’s syndrome has also been assigned a new name to better reflect the current understanding of the disease and its clinical seriousness—but here the change is easy to implement by just changing “syndrome” to “disease,” though the reasoning for the renaming appears a little strained as well.
WHERE THE GLUTEN REACTION BEGINS
As part of an anti-inflammatory diet, eliminating gluten and dairy has become quite a common dietary support intervention in autoimmune conditions. To a degree, it has also become “fashionable” in infertility practice because, especially gluten, a protein in wheat, rye, and barley, can induce quite significant symptoms in individuals. This becomes very apparent in patients with celiac disease (which, of course, is an autoimmune disease primarily of the gut) but can also elicit all kinds of symptoms in patients with just “sensitivity” to gluten. The prevalence of celiac disease in the population is only approximately 1%.
Now, a large consortium of investigators from all over the world reported interesting new information on how gluten initiates the celiac disease pathology in the gut. And it is not, as was previously believed, that gluten induces the inflammatory response inside the gut wall, exclusively involving immune cells. Using gut organoids, they discovered that the epithelium of the gut—made up of cells usually unrelated to the immune system—also plays an important part in producing the inflammatory response to gluten. Specifically, they discovered that gluten antigens are efficiently presented by MHCII-expressing IECs, resulting in the activation of gluten-specific CD4+ T cells, which is then enhanced by gluten pre-digestion with microbial elastase.
Therapeutics directed at intestinal epithelial cells may, therefore, offer a novel approach for modulating both adaptive and innate immunity in patients with celiac disease.
References
1. Gleicher N. Clin Rev Allergy Immunol 2010[39(3):194-206
2. Choudhury J. Medscape Medical News. January 13, 2025. https://www.medscape.com/viewarticle/around-5-us-population-diagnosed-autoimmune-disease-2025a10000of
3. Abend et al., J Clin Invest 2025;135(4):e178722
4. Patasova et al., Rheumatology 2025; keaf004.doi: 10.1093/rheumatology/keaf004. Online ahead of print.
5. Palmer A-K, Tan IJ. ACR Open Rgeumatology 2025;7(1):e11778
6. Healio. November 22, 2024. https://www.healio.com/nes/rheumatology/20241121/name-change-for-sjrens-axial-spondyloarthritis-a-big-deal-for-researchspatients
7. Rahmani et al., Gastroenterology 20024;167(6):1113-1128
Severe ulcerative colitis appears associated with HLA-DRB1* 01:03
A Research Letter by Danish investigators in JAMA discovered a close association between severe ulcerative colitis and carrier status for HLA-DRB1*01:03, a relatively low-frequency allele. The authors suggest that, given the low cost of typing a single HLA allele, it could be useful for risk assessment of patients at diagnosis (1).
Reference
1. Vestergaard et al., JAMA 2024;332(22):1941-1943
Yes, intradermal lymphocyte immunization still exists!
Several decades ago, the FDA prohibited the concept of paternal lymphocyte immunization for women with repeated pregnancy loss in the U.S. There were several reasons behind this decision, among them concern about some published data which suggested that the procedure may even further enhance the frequently already hyperactive immune system of the miscarrying female.
But many U.S. patients still receive this treatment by going to Canada, Mexico, or other countries where IVF clinics still offer the treatment. We here at the CHR warned patients about the risk of lymphocyte immunizations even before the FDA issued its warning, and we, therefore, caution our patients against pursuing the treatment outside of the U.S. There nowadays exist much safer and—frankly—also better treatments for the prevention of miscarriages.
One clinic that still offers the treatment in Iran now published a study that suggested that paternal lymphocyte immunization may—after all—confer benefits in improving pregnancy outcomes (1) Paradoxically, however, the authors also claimed that “its efficacy may be influenced by the presence of anti-TPO thyroid autoantibodies.”
Though the authors concluded that their findings highlight the complex interplay between immune dysregulation and pregnancy outcomes in repeated pregnancy loss, this is not how we would interpret their data, and here is why: Anti-TPO negative patients with lymphocyte therapy had a lower miscarriage rate (10.53%) compared to anti-TPO positive RPL patients with lymphocyte immunization (40%). That observation, in our opinion, pretty categorically denotes that what really matters is not the lymphocyte treatment, but the TPO antibody status of the patient, and if, as above noted, a woman already has a hyperactive immune system (i.e., positive TPO Abs), lymphocyte immunization can make things worse!
Of course, as a likely consequence, pregnancy and live birth rates were also higher (89.47%) in anti-TPO negative patients with lymphocyte treatments compared to anti-TPO positive RPL patients with LIT (60% and 56% respectively), though it is unclear whether this difference is really significant. Simply a truly poor paper!
Reference
1. Ebrahimi et al., Hum Immunol 2025;86(2):111229.