Damage to the protective blood–testis barrier may affect sperm production and motility.
Autoimmune disease, antisperm antibodies and the gut microbiome offer new clues to the causes of male infertility.
Why do sperm counts fall, or sperm become less mobile?
Genetic abnormalities, varicocele, hormonal imbalances, smoking and obesity have long been considered major contributors. More recently, research has drawn attention to the possibility that the immune system, which protects us from disease, can also interfere with sperm production and function.
Disruption of the immune barrier protecting the testes, or persistent inflammation elsewhere in the body, may disturb normal sperm development. Age-related inflammation and the gut microbial environment may also influence male reproductive capacity.
A review published in Clinical Reviews in Allergy & Immunology on October 23, 2026 examined the relationships between male infertility, autoimmunity and chronic inflammation.
The authors reviewed clinical and experimental research to describe pathways through which immune disturbances may affect sperm production and fertilizing ability. This was a review of existing evidence, not a new experiment involving patients.
What happens when the blood–testis barrier is damaged?
The testes receive special immune protection. Because sperm production begins in earnest after puberty, the immune system may mistakenly recognize some sperm proteins as foreign.
The blood–testis barrier helps prevent this. Formed by Sertoli cells within the testes, it separates the compartment where sperm develop from immune cells in the blood and maintains an environment needed for normal sperm production.
Problems can arise when this protection is damaged. Infections such as orchitis and epididymitis, testicular trauma and some operations may affect barrier function. Varicocele is also associated with testicular inflammation and oxidative stress.
Barrier disruption may expose sperm-related antigens that are normally concealed from the immune system, activating an immune response. Inflammatory substances can increase, potentially impairing cells involved in sperm production.
The authors explain that the testicular immune environment does more than defend against pathogens: it also helps regulate sperm production and development.
Antisperm antibodies: when immunity targets sperm
Antisperm antibodies provide a prominent example of the relationship between immunity and male infertility.
These antibodies form when the immune system recognizes particular sperm proteins as targets. Binding to the sperm surface can interfere with movement or the process of joining with an egg.
Sperm may clump together or become less mobile. Antibodies may also affect passage through the protective layers around the egg and sperm–egg fusion.
Some studies have reported associations between antisperm antibodies, sperm DNA damage and increased oxidative stress. This suggests that immune responses may affect sperm quality as well as movement.
However, detecting these antibodies does not inevitably mean infertility. Their effects can differ according to antibody type, binding location and the clinical significance of the test result.
This is one reason antisperm antibody testing is not recommended for every patient during the initial evaluation of male infertility.
The possible gut–testis connection
The review also examines the relationship between gut microbes and male reproductive function.
Gut microbes contribute not only to digestion but also to immune responses and inflammation regulation. An imbalance may increase inflammatory substances, potentially influencing the immune environment in the testes.
The authors describe this as the gut–testis axis: changes in gut microbes may connect with testicular function through immune-cell activation, inflammatory signals and oxidative stress.
Some animal experiments have identified mechanisms through which microbial imbalance may contribute to testicular inflammation and impaired sperm production. Human studies have also reported associations between particular gut microbes and measures of male reproductive function.
Nevertheless, changes in the gut microbiome have not been established as a direct cause of male infertility in humans. Evidence is also insufficient to conclude that probiotics or microbiome-directed treatments increase sperm counts or pregnancy rates.
Age-related chronic inflammation and sperm quality
The authors also consider the persistent, low-grade inflammation associated with aging.
As people age, immune regulation changes, and low-level inflammation may persist without an obvious infection. This is often called inflammaging.
These changes may affect Sertoli cells, which support sperm production, and Leydig cells, which produce testosterone.
Inflammation and oxidative stress may reinforce one another, damaging sperm membranes and DNA and potentially impairing motility and fertilizing ability.
Obesity, insulin resistance and type 2 diabetes are also associated with chronic inflammation. Evaluating male fertility therefore calls for attention to overall health as well as the reproductive organs.
Further research is needed to determine how much age-related immune change directly contributes to declining sperm counts in humans.
Could immune treatment improve male infertility?
Could correcting immune disturbances restore sperm counts or motility?
A cautious approach is needed. The review summarizes evidence that immune abnormalities and chronic inflammation may contribute to male infertility. It does not establish that immunosuppressants or anti-inflammatory treatment improve pregnancy success in men with infertility generally.
Intrauterine insemination, IVF or ICSI may be considered for some patients with antisperm antibodies. Antibody detection alone, however, does not establish that a particular assisted reproductive technique is necessarily superior.
For men with autoimmune disease, both the disease-related inflammation and the reproductive effects of treatment warrant consideration. Counseling about sperm cryopreservation before treatment may be appropriate when a medication could affect sperm production.
The authors envisage an approach that retains semen analysis, hormone testing and reproductive assessment as its foundation, while adding immune evaluation for selected patients.
The central point is not that the immune system is the sole cause of male infertility. Rather, the immune environment and chronic inflammation may help shape sperm number, motility and fertilizing ability, and these mechanisms require closer investigation.
Research into male infertility is expanding from sperm themselves to the immune environment of the testes and inflammation throughout the body.
Source: This article is based on “Autoimmunity and Inflammaging in Male Infertility,” published October 23, 2026 in Clinical Reviews in Allergy & Immunology by Irene Monticciolo, Nicoletta Di Simone, Vito Lomuscio, Carlo Selmi, Francesca Motta and colleagues at Humanitas University and Humanitas Research Hospital, Italy. The review primarily examined research published from 2010 to 2026 on autoimmunity, chronic inflammation, blood–testis barrier damage, antisperm antibodies and the gut microbiome. DOI: 10.1007/s12016-026-09208-9.
Image disclosure: The image was created using generative AI (ChatGPT, OpenAI).
For background on ovarian reserve, semen analysis and when additional investigations may be considered, see our guide to the first fertility clinic visit.
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