2025 Volume 58 Issue 1 Pages 1-8
Immune tolerance is essential for safeguarding the body’s own tissues from immune system attacks. During pregnancy, the maternal immune system tolerates the semi-allogeneic fetus through mechanisms such as placental programmed cell death 1 (PD-1)-ligand 1 (PD-L1) expression, regulatory T cells (Tregs), cytokine modulation, and hormonal changes. Placental PD-L1 is particularly important in suppressing maternal immune responses and preventing fetal rejection. Following delivery, the loss of the PD-L1-rich placenta can destabilize immune tolerance, potentially leading to postpartum autoimmune diseases such as fulminant type 1 diabetes, characterized by rapid insulin depletion and severe hyperglycemia. Similarly, immune checkpoint inhibitors (ICIs), widely used in cancer immunotherapy, block immune checkpoints like PD-1 and PD-L1 to enhance antitumor immunity by disrupting immunotolerance to tumors. However, this mechanism can sometimes result in immune-related adverse events (irAEs), including fulminant type 1 diabetes. Given the critical role of HLA haplotypes and environmental factors in the development of autoimmune conditions, identifying shared factors among postpartum individuals and patients undergoing ICI therapy who experience immune system abnormalities could provide valuable insights. Such understanding may improve strategies for managing autoimmune diseases associated with both postpartum immune changes and ICI treatments.
Patients with autoimmune diseases often experience symptom relief during pregnancy, only to face exacerbations or the onset of new autoimmune conditions postpartum [2]. For example, pregnancy-associated type 1 diabetes, a fulminant form of the disease that can occur immediately after delivery, is characterized by a sudden depletion of insulin, leading to severe hyperglycemia and ketoacidosis, which can be life-threatening for the mother [18, 20]. Similarly, with the growing use of immune checkpoint inhibitors in cancer immunotherapy, reports of immune-related adverse events (irAEs) have increased. Among these, rare but extremely severe cases of fulminant type 1 diabetes have been documented [43]. Interestingly, this irAE-related condition is similar to what we have observed in cases of postpartum fulminant type 1 diabetes mellitus [18]. We suggest that a shared underlying mechanism, specifically the rapid decline of programmed cell death 1 (PD-1)-ligand 1 (PD-L1) [5, 29], could potentially explain both conditions.
This review begins by summarizing the general mechanisms of immune tolerance and then focuses on a shared phenomenon—the rapid decline of PD-L1. This process is evident both in cancer immunotherapy with anti-PD-L1 antibodies [36] and in the postpartum clearance of PD-L1-rich placental tissue [18], both of which disrupt immune tolerance mechanisms.
The immune system is regulated by two types of molecules: co-stimulatory molecules, which enhance immune responses, and co-suppressive molecules, which inhibit immune activity [27, 28, 32, 33]. The latter, known as “immune checkpoints,” are essential for preventing autoimmunity by suppressing inappropriate immune responses against the body’s own cells and tissues, as well as mitigating excessive inflammatory reactions [27, 28, 32, 33]. Key examples of immune checkpoint molecules include inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 [10, 30]. These inhibitory receptors are expressed on regulatory T cells (Tregs), which use their signaling pathways to regulate other immune cells, particularly effector T cells, to maintain immune balance and homeostasis [10]. The PD-1 receptor, expressed on T cells, plays a crucial role in suppressing T cell activation, including the regulation of immune responses against self-antigens. When immune responses are suppressed, the ligand to PD-1 (PD-L1 and PD-L2) binds to the PD-1 receptor to mediate this inhibition [35].
Cancer cells evade immune attacks by downregulating immune responses [13]. Notably, tumor cells have been shown to express PD-L1, which binds to PD-1 receptors on T cells, thereby attenuating the immune response and facilitating immune evasion by the tumor cells [27]. Immune checkpoint inhibitors (ICIs) have been developed to block this inhibitory mechanism, thereby activating the immune system, and are now widely used in cancer immunotherapy for various cancer types [33]. Anti-PD-1 antibodies are designed to bind to the PD-1 receptor, preventing the interaction of PD-L1 expressed by tumor cells with PD-1, thereby promoting an antitumor immune response [33] (Fig. 1).
Schematic representation of the PD-1 and PD-L1 system in immune tolerance and cancer immunotherapy targeting immune-evading tumor cells with anti-PD-L1 antibodies. When PD-L1 is present on the surface of tumor cells, regulatory T cells (Treg cells) enter a state of immune tolerance, meaning they do not attack or destroy the tumor. However, when an anti-PD-L1 antibody blocks the interaction between PD-1 and PD-L1, the Treg cells identify the tumor cells as harmful and launch an immune response to eliminate them.
ICIs are effective in cancer treatment but can cause immune-related adverse events (irAEs) that affect various organs throughout the body [6]. Therefore, selecting cancers that are likely to respond to immune checkpoint inhibitors (ICIs) is critically important. Pathologists assess the expression of PD-L1 protein in pathological tissue sections obtained through surgery or biopsy to determine whether treatment with anti-PD-L1 antibodies is expected to be effective [7, 19]. Cases showing high PD-L1 expression in tumor tissues (Fig. 2A and B) showed marked respond well to ICIs [34], and in some instances, nearly all tumor lesions disappear following treatment (Fig. 2C).
PD-L1 Immunostaining and immunotherapy for clear cell renal cell carcinoma. This example demonstrates biopsy-derived renal cell carcinoma tissue (A, H.E.) and immunohistochemical analysis (B) of PD-L1 expression in. In this case, PD-L1 was detected on the tumor cell surface and within some cytoplasmic areas. The patient was classified as PD-L1 positive and deemed eligible for ICI therapy using PD-L1-targeting antibodies. Significant tumor shrinkage was observed (region enclosed by a dashed line) as a result of immunotherapy, with only a small number of viable tumor cells remaining in the area indicated by the arrows (C). Bars = 50 μm (A and B), Bar = 5 mm (C).
The most common irAEs are skin-related, with rashes and pruritus occurring in approximately 20–30% of patients [15]. In the gastrointestinal system, diarrhea and colitis are observed in about 10–20% of cases, and severe conditions can lead to complications such as perforation or dehydration. Liver involvement occurs in approximately 5–10% of patients, presenting as liver dysfunction. Endocrine irAEs include thyroid dysfunction (5–10%), hypophysitis (1–5%), and, in rare cases, rapidly progressive (fulminant) type 1 diabetes [14, 15, 25, 26]. In the lungs, interstitial pneumonitis develops in 1–5% of patients and can become life-threatening in severe cases [24]. Neurological events, such as Guillain-Barré syndrome and encephalitis, are rare but serious [31], while cardiovascular irAEs, including myocarditis and pericarditis, have also been reported [37]. The frequency of these adverse events varies depending on the type of ICI and the treatment context, making early detection and appropriate management essential [15].
The development of irAEs has been associated with following mechanisms [15]: (1) T-cell responses targeting shared antigens in normal tissues (e.g., vitiligo in malignant melanoma); (2) increased levels of inflammatory cytokines (e.g., enteritis); (3) expansion of pre-existing autoreactive lymphocytes (e.g., thyroiditis); and (4) complement-mediated inflammation triggered by anti-CTLA-4 antibody binding to CTLA-4 expressed in normal tissues (e.g., pituitary inflammation). Ebi et al. identified five characteristics of irAEs [9]: (1) diversity, as they can affect multiple organs and present with a variety of symptoms; (2) uniqueness, as they may display clinical presentations distinct from spontaneous autoimmune diseases (e.g., pituitary inflammation, myasthenia gravis); (3) multiplicity, as irAEs can manifest in multiple locations over time; (4) persistence, with irAEs potentially continuing alongside the treatment response; and (5) correlation, as tumor immunity and autoimmunity share molecular pathways, establishing a link between therapeutic efficacy and the occurrence of irAEs.
Pregnancy represents a physiological state in which the maternal immune system tolerates a semi-allogeneic fetus [8]. It has been well-established that numerous maternal lymphocytes accumulate around the implanted embryo [22]. This implies that the fetus, having breached the basement membrane of the endometrial epithelium and infiltrated the maternal stroma, is recognized by the maternal immune system. Typically, such a foreign entity would elicit an immune rejection; however, the fetus is not rejected due to a state of immunological tolerance established at conception [41]. This tolerance mechanism has been pivotal in enabling the evolutionary success of eutherian mammals—organisms that develop a placenta, undergo intrauterine development, and, post-birth, rely on maternal lactation [40].
The primary mechanisms of immune tolerance during pregnancy are hypothesized as follows [1, 3, 21, 39]:
1) Expression of immunosuppressive molecules in the placentaPlacental cells, particularly trophoblasts, express immunosuppressive molecules such as PD-L1 and HLA-G. These molecules function to prevent maternal immune cells, especially T cells, from attacking the fetus. HLA-G, a non-classical MHC molecule specifically expressed in the placenta, plays a role in concealing the fetus from the maternal immune system.
2) Role of regulatory T cells (Tregs)During pregnancy, maternal immune systems show an increase in Treg cells, which serve to suppress immune responses, thereby preventing attacks on the fetus. This increase in Tregs allows the maternal immune system to recognize the fetus more readily as “self.” Treg cells also modulate the immune environment around the placenta and uterus to prevent aggressive immune responses against the fetus.
3) Cytokine balance adjustmentDuring pregnancy, the maternal immune system regulates the balance of cytokines, which are proteins that modulate immune responses. Specifically, pro-inflammatory Th1 cytokines are suppressed, while anti-inflammatory Th2 cytokines, which promote immune tolerance, are increased. This cytokine balance reduces the likelihood of the fetus being recognized as foreign and suppresses aggressive immune responses.
4) Role of the endometrium (decidua)During pregnancy, the endometrium transforms into a structure known as the decidua, which promotes immune tolerance. The decidua contains a high number of natural killer cells (dNK) that, unlike conventional NK cells, exhibit characteristics that suppress aggressive responses towards the fetus. dNK cells strengthen the maternal-fetal interface and contribute to immune tolerance while supporting the nutrient supply required for fetal growth.
5) Role of exosomesRecent studies indicate that placenta-derived exosomes, small vesicles that facilitate intercellular communication, play a significant role in maternal immune tolerance. Exosomes convey information regarding the state of the placenta and fetus to the maternal system, helping to adjust immune responses appropriately. This mechanism enables the maternal body to adapt to pregnancy-related changes, thereby maintaining immune tolerance towards the fetus.
6) Influence of hormonesDuring pregnancy, levels of hormones such as estrogen and progesterone increase, contributing to immune system regulation. These hormones help to suppress the strength of immune responses, thereby protecting the fetus from being targeted by the maternal immune system.
These mechanisms collectively enable the maternal body to recognize the fetus as “self” and suppress immune attacks, establishing immune tolerance. A breakdown of immunological tolerance during pregnancy can lead to abnormal pregnancies, such as premature birth, miscarriage, or pregnancy disorders [39]. In addition, some immune abnormality may cause the baby to be considered a foreign body, leading to infertility [12].
Among these mechanisms, PD-L1 expression in the placenta plays a particularly crucial role [42]. PD-L1 is highly expressed on placental cells, especially trophoblasts, and functions to protect the placenta from destruction by maternal immune cells [23] (Fig. 3A–D). By being expressed in the placenta, PD-L1 helps prevent the maternal immune system from attacking the fetus, thus contributing to the maintenance of fetal immune tolerance [8]. PD-L1 is highly expressed even in early pregnancy and is essential for sustaining a normal pregnancy [38]. However, with the expulsion of the placenta during delivery, placental PD-L1 is also lost, disrupting the balance of immune tolerance mechanisms mediated by PD-L1 (Fig. 4). Similarly, immune checkpoint inhibitors using anti-PD-L1 antibodies result in the blockade and elimination of PD-L1 function (Fig. 1), creating an unstable immune tolerance balance resembling the post-delivery state in mothers (Fig. 5). Indeed, in a pathological autopsy case of a patient who unfortunately passed away due to fulminant type-1 diabetes immediately after delivery, extensive lymphocytic infiltration was observed around the islets of Langerhans in the pancreas, with the majority being CD8-positive T lymphocytes [18] (Fig. 6A). Similarly, in liver biopsy samples from a patient who developed liver injury during ICI therapy, lymphocytic infiltration causing bile duct destruction was observed in the portal areas, and most of these lymphocytes were also CD8-positive T lymphocytes (Fig. 6B). Although the organs under observation differed between the two cases, the pathological features of cellular damage were remarkably similar.
PD-L1 Expression in placental tissue. In placental tissue, including fetal components (A, H.E., low magnification), immunostaining reveals no PD-L1 expression in the fetal structures but strong PD-L1 expression in the chorionic tissue (B). Under high magnification (C, H.E.), placental trophoblastic and decidual structures are identified. Immunostaining shows strong PD-L1 expression in the syncytial layer of the trophoblastic tissue, with weaker expression observed in the decidual tissue (D). Bars = 50 μm.
System of immune tolerance mediated by PD-L1 expression in placental tissue and its decline after parturition. In placental tissue, PD-L1 expression induces immune tolerance by regulatory T cells (Treg cells), preventing them from attacking the hemizygotic fetus. After the placenta is delivered, the immune tolerance regulated by the PD-1/PD-L1 pathway rapidly diminishes, leading to a loss of balance in the immune tolerance system.
Activation of CD8-positive cytotoxic T Lymphocytes due to loss of PD-L1. The disruption of the PD-1/PD-L1 interaction suppresses immunosuppressive CD4-positive T cells while simultaneously activating cytotoxic CD8-positive T cells, enabling them to target and destroy tissue.
Pancreatic insulitis observed in an autopsy case of fulminant type 1 diabetes onset shortly after delivery (A) and cholangitis observed in a biopsied case of ICI-Induced irAE (B). In a pathological autopsy case of a pregnant woman who developed fulminant type 1 diabetes immediately after delivery and succumbed to ketoacidosis, extensive lymphocytic infiltration was observed in the pancreatic islets of Langerhans (A), predominantly composed of CD8-positive T cells (lower right inset). Similarly, a liver biopsy from a patient with ICI-induced liver injury revealed significant lymphocytic infiltration in the portal region, leading to the destruction of small bile ducts (B). The majority of these lymphocytes were also CD8-positive T cells (B, lower right inset). Bars = 50 μm.
Despite the rapid loss of PD-L1, many postpartum women progress through the postpartum period without developing severe autoimmune abnormalities, likely because other immune tolerance mechanisms remain functional and gradually fade over time. Similarly, many patients treated with immune checkpoint inhibitors do not develop immune-related adverse events (irAEs), or if they do, the manifestations are typically mild. This raises the question of why certain pregnant or postpartum women, as well as specific patients undergoing cancer immunotherapy, develop severe complications such as fulminant type 1 diabetes. While the underlying mechanisms are not fully understood, a strong association has been reported between fulminant type 1 diabetes and specific Human Leukocyte Antigen (HLA) gene SNPs, particularly rs9268853 in class II DR [16, 17]. Studies have shown that particular HLA types are linked to an increased risk of immune-related adverse events (irAEs) [11]. However, irAE development is also influenced by non-HLA genetic factors and environmental factors, meaning that HLA type alone does not fully determine risk. Recently, germline genetic variants in NLRC5 have also been implicated as significant in ICI-induced type 1 diabetes [4], suggesting that further data accumulation may reveal shared genetic variations between the two conditions.
We discuss the rapid decrease in PD-L1 as a common factor in postpartum fulminant type 1 diabetes and fulminant type 1 diabetes as an immune-related adverse event (irAE), based on an autopsy case of postpartum fulminant type 1 diabetes.
The authors declare no conflicts of interest.
We thank Ms. Mari Hashimoto and Ms. Yuki Takaoka for their excellent technical assistance.
