How Autoimmunity and Reproductive Health are Related

THE SYNERGY BETWEEN AUTOIMMUNITY AND REPRODUCTION 

To recognize and acknowledge how conceptually connected autoimmunity and pregnancy are in biological terms is essential for both of these major areas of scientific exploration. What establishes this essential conceptual link is only one thing, the development of “tolerance.”

Let us explain: Our daily survival is fully dependent on the normal functioning of our immune systems which, in principle, has two basic functions: As we all are, of course, fully aware of, 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 and – here is its second major function – it does all of this while, at the same time also fully recognizing that it, in all of its protective functions, is not supposed to attack our own body’s components, a process called self-tolerance.

In other words – if functioning correctly – our immune system can differentiate between “self” and “foreign” and, even within “self,” it can differentiate between healthy and unhealthy “self,” fully recognizing that “self” in principle is never to be attacked (unless, as in cancer unhealthy), while “foreign” always must be attacked as soon as it gains access to our organism. Therefore, maintaining normal functions within the immune system must be a highly complex and multilayered, and while, enormous progress has been made in understanding how our immune systems work (and at times malfunction), much is still to be discovered.

And like all complex systems, from our bodies to rockets we are sending to the stars, our immune system at times malfunctions 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 and 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! And the reason is that an embryo which has to implant in a woman’s uterus is genetically a foreign invader, attempting to achieve what our immune system sees as one of its principal responsibilities, to prevent such invasions from happening.

Under normal circumstances, 50% of this invader is “foreign” because it genetically represents the woman’s male partner (if an egg donor is involved, the invading embryo is even 100% “foreign”). Under normal circumstances the female immune system, therefore, should instantly aggressively attack this invading organism and rejects it - not different from how it would with great likelihood reject an organ transplant from the same male. But, amazingly, no such rejection occurs if the mother’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 any accidentally accompanying bacteria, viruses, etc. - to enter the holy grounds of the woman’s body without being rejected. 

In other words, the woman’s immune system induces immunologic “tolerance” for the paternal part of the embryo that under all basic biological rules should aggressively be rejected. And – even though only partially understood – the tolerance pathways induced in this process by the maternal immune system have quite significant similarities with pathways our immune systems use for 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 suggests, similar pathways of tolerance inductions in certain ways may also have over evolutionary processes been acquired by cancers, thereby allowing malignant tumors to evade the usual immune responses and 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 but also with the other 50% which represents the mother’s own genetics. In other words, the maternal immune system has to face an invader with its own genetic make-up; yet, if it were to mount an immune response against this autologous half of the embryo, that at the same time would be an “auto-immune” response which, of course would be destructive to the mother’s well-being.

In short, the fact that the maternal immune system – if functioning normally – does not attack the invading (i.e., implanting) embryo in many ways has to be viewed as a “miracle of nature” and must represent an enormously complicated cascade of reprogramming events within the maternal immune system. And in women with a hyperactive immune system (i.e., evidence of autoimmunity, inflammation, and/or just severe allergies) this reprogramming process often malfunctions to smaller or larger degrees, resulting in the embryo not being fully protected from being attacked and pregnancies, therefore, prone to miscarriages.

HIGH PREVALENCE IN POPULATION AND STRONG FEMALE PREPONDERANCE 

This somewhat lengthy introduction to this section – we feel – was necessary to explain why autoimmunity is in such a symbiotic relationship with reproduction. On a clinical level this relationship is well demonstrated by the fact that several autoimmune diseases characteristically improve clinically (patients “feel better than they have felt in ages”) after the first trimester, once normal tolerance of the pregnancy has been established and the tolerance pathways established for pregnancy also cross-react with self-tolerance. 

At the same time, every pregnancy in patients with any autoimmune disease faces increased risks early in pregnancy when tolerance must be established (as noted, leading to miscarriages) and again in in the third trimester and leading into the postpartum period because pregnancy tolerance in women with hyperactive immune systems often – one indeed can say almost always – wears off early, leading to premature labor and deliveries in association with practically all autoimmune diseases, increased risk for preeclampsia, and significant risk for peripartum and postpartum autoimmune disease flares, and often first clinical presentation of autoimmune diseases.

And autoimmunity is common, affecting in the U.S. approximately 5% of the population or by 2022, over 15 million people (1). Roughly two-third of cases occurred in women (63%, - a 1.7 to 1 ratio), increasing with advancing age, and peaking above age 65. Autoimmunity, moreover, is highly polygenic in that having one autoimmune disease predisposes significantly to other autoimmune diseases. Indeed, roughly 24% of autoimmune patients were reported to have two, 8% had three, and 2% had four or more diseases.

The most frequently diagnosed autoimmune disease is rheumatoid arthritis, followed by psoriasis, type 1 diabetes, Grave’s disease, and autoimmune thyroiditis (Hashimoto’s). Moreover 19/20 autoimmune diseases were more frequent in women than men (2).

References

1.      Choudhury J. Medscape Medical News. January 13, 2025. https://www.medscape.com/viewarticle/around-5-us-population-diagnosed-autoimmune-disease-2025a10000of

2.      Abend et al., J Clin Invest 2025;135(4):e178722

Various autoimmunity-related subjects

MENOPAUSAL HORMONE THERAPY INCREASES AUTOIMMUNE DISEASE RISK

A recent paper in Rheumatology offered rather convincing evidence that menopausal hormone therapy increased risk for developing systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) (1).

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 a local hormone treatments had the highest risk of developing both conditions. Another consideration in using hormone replacement therapy in postmenopausal women!

Reference

1.      Patasova et al., Rheumatology 2025; keaf004.doi: 10.1093/rheumatology/keaf004. Online ahead of print.

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. 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 triple X syndrome conferred a nonproportional, synergistic dose effect on the development of SLE and SjD when compared with the general population (1). 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 female have such a preponderance in autoimmune diseases in comparison to males.

Reference

1.      Palmer A-K, Tan IJ. ACR Open Rgeumatology  2025;7(1):e11778

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, 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 under its new name, “axSpA” and, whether it is visible on X-ray is only of academic but not clinical interest (1).

Sjögren’s syndrome also has been assigned a new name to reflect better the current understanding of the disease and its clinical seriousness, here the change is easy to implement by just changing “syndrome” to “disease” but the reasoning for the renaming appears a little strained 

References

1.      Healio. November 22, 2024. https://www.healio.com/nes/rheumatology/20241121/name-change-for-sjrens-axial-spondyloarthritis-a-big-deal-for-researchspatients 

WHERE THE GLUTEN REACTION BEGINS 

Coming, as part of an anti-inflammatory diet, off gluten and dairy has become a quite 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 barely can induce quite significant symptoms in individuals. This becomes very apparent in patients with celiac disease (which, of course is an autoimmune disease of primarily 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 ca. 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 believed, that gluten induces the inflammatory response inside the gut wall, exclusively involving immune cell. Using gut organoids, they discovered that the epithelium of the gut – made up of usually unrelated cells 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 (1.) 

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.      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-DRB*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 in the U.S. the concept of paternal lymphocyte immunization of women with repeated pregnancy loss. There were several reasons behind this decision, among those 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 we hear from patients from outside the U.S., including Canada and Mexico, that there still are IVF clinics that offer this treatment.

One such clinic in Iran now published a study that suggested that paternal lymphocyte immunization may confer benefits in improving pregnancy outcomes, though – paradoxically –“ its efficacy may be influenced by the presence of Anti-TPO antibodies” (1). 

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 date 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 notes that what really matters is not the lymphocyte treatment, but the TPO Ab 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!

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.