Immunology of Pregnancy Lecture PDF

Immunology of pregnancy. Transplantation and tumour immunology, immune therapy 1  Basic Concepts Transplantation The transfer of tissue or an organ from its original environment to a foreign one. Graft The tra...

Immunology of pregnancy. Transplantation and tumour immunology, immune therapy 1  Basic Concepts Transplantation The transfer of tissue or an organ from its original environment to a foreign one. Graft The transplanted tissue or organ. Donor The organism that provides the graft. Recipient / Host The organism that receives the graft. Tissue Incompatibility / Incompatibility The graft is recognized as foreign by the host's immune system. Rejection The recipient's immune system separates the graft with tissue-damaging effects. 2 Pregnancy Immunology 3  The immunology of the maternal-fetal relationship Fetal antigens are partly of paternal origin, meaning the fetus is an allograft to the maternal immune system, so a rejection response would be expected. Mechanisms ensuring an immunosuppressive environment suppress the maternal immune response. The activation of the immune system is a prerequisite for the maintenance of pregnancy; therefore, a disturbance in the recognition of fetal antigens can lead to pregnancy loss. The fetus’s genetic material is half inherited from the mother and half from the father. Therefore, the presence of paternal alloantigens could potentially trigger the rejection of the fetus as an allograft. However, this is prevented by mechanisms that ensure an immunosuppressive environment, suppressing the maternal immune response. As an indication of this, antibodies reactive to paternal antigens can be detected in 20% of women after their first pregnancy and in 40–60% of multiparous women. However, these antibodies do not pose a threat to the fetus. It has been proven that an immunological interaction develops between the mother and the fetus, creating an immune environment that ensures the survival of the fetus. In other words, the activation of the immune system is a prerequisite for maintaining pregnancy, and disturbances in the recognition of fetal antigens can lead to pregnancy termination. 4 1.The fetus is only partially accessible to the maternal immune system → the placenta acts as an anatomical barrier. In the human placenta, fetal syncytiotrophoblasts form the contact surface between the maternal and fetal sides. The immunosuppressive effect protecting the fetus is ensured by the non-classical MHC-I molecules (HLA-G, HLA-E) expressed on these cells, as well as by inhibitory cells (NK, Treg) and factors (cytokines, PIBF – Progesterone Induced Blocking Factor) present in the maternal blood. 5  The Role of MHC in Immune Tolerance Trophoblast:Transcription level → HLA-A, -B, -C, -E, and -G molecules Translation level → HLA-E, HLA-G molecules → In small amounts, HLA-C molecules HLA-G and -E antigens: → Lower molecular weight → Limited polymorphism → fewer variations → less immunogenic → Do not contain paternal or maternal allodeterminants HLA-G plays an important role in the immunological interaction between the fetus and the mother. The HLA-G molecule is particularly important in the regulation of natural killer (NK) cells present in the uterus → provides inhibitory signals → prevents them from attacking trophoblast cells. sHLA-G = soluble HLA-G molecules: → present in circulation → also play a role in the systemic suppression of the maternal immune response. HLA-G is capable of suppressing the activity of maternal immune cells, such as NK cells and cytotoxic T cells. Under normal conditions, NK cells (natural killer cells) recognize and destroy cells that do not express normal HLA-I molecules. However, HLA-G sends inhibitory signals to the NK cells, allowing the survival of fetal trophoblast cells. The HLA expression pattern of trophoblast cells—the absence of classical HLA molecules and the presence of non-classical HLA molecules—ensures that the maternal immune system suppresses the potential immune response. These soluble HLA-G molecules are immunomodulatory because they suppress the activity of maternal T cells and NK cells throughout the body, not just in the placenta. Therefore, sHLA-G molecules contribute to tolerance at a systemic level. HLA-G binds to inhibitory receptors; both its membrane-bound and soluble forms inhibit NK cell cytotoxicity, T cell allogeneic proliferation, and antigen- specific T cell cytotoxicity. 6  Role of T cells in immune tolerance During pregnancy, the maternal cytokine profile changes → TH2 dominance → prevents the maternal immune system from launching an attack against fetal cells. Th2 dominance: → The ratio and activity of Th2-type helper T cells increase compared to Th1-type helper T cells. Th2 cytokines: → e.g., IL-10 and IL-4 → Directly promote the maintenance of a tolerant immune state → Inhibit the activation of maternal immune cells against fetal cells → Support the activity of Treg cells → Maintain tolerance towards the fetus Treg cells → Produce IL-10 and TGF-β IL-10 and TGF-β → Also present in circulation → Systemically inhibit immune responses directed against fetal antigens. Th2 dominance is particularly prominent during the second and third trimesters of pregnancy when the fetus is rapidly developing, and inflammatory reactions could pose a risk to the fetus. Cytokines produced by Th1 cells, such as IFN-γ and TNF-α, generally trigger a strong inflammatory response. Activation of the immune system in this way can be dangerous to the fetus during pregnancy. Cytokines produced by Th2 cells, such as IL-4, IL-5, and IL-10, have immunomodulatory and anti-inflammatory effects. During pregnancy, the Th2- type immune response becomes more prominent, especially in the second and third trimesters. This shift in the Th1/Th2 ratio helps maintain an inflammation- free environment in the uterus, contributing to the development and maintenance of fetal tolerance. TH2 dominance: Instead of pro-inflammatory TH1 cytokines (such as IFN-γ and TNF-α), TH2 cytokines (e.g., IL-4, IL-10) dominate, which primarily inhibit the immune response. This TH2 dominance prevents the maternal immune system from launching an attack against fetal cells. Role of anti-inflammatory cytokines: The production of IL-10 and TGF-β cytokines is particularly important in 7 maintaining tolerance, as these cytokines inhibit the activation of immune cells and inflammatory responses. Both trophoblast cells and maternal immune cells produce IL-10 and TGF-β, thereby continuously supporting the harmonious coexistence of fetal and maternal cells. The balance of T cell subpopulations—especially the shift from Th1 to Th2 cells, the suppression of Th17 cells, and the increased activity of Treg cells—is crucial for maintaining a successful pregnancy. 7  The Role of Decidual NK Cells in Immune Tolerance Decidual NK (dNK) cells recognize the HLA-G molecules on trophoblasts, which inhibits their cytotoxic activity and ensures that the fetus is not targeted by the maternal immune system. dNK cells interact with regulatory T cells, which are also critical for maintaining immune tolerance. Cytokines produced by dNK cells support the activity of Treg cells, thereby ensuring that immune responses against the fetus remain minimal. They play a role in regulating trophoblast invasion and contribute to the development of the placenta’s blood vessels through cytokine production. Additionally, they help create a favorable microenvironment for the fetus while also providing the necessary tools to defend against intrauterine infections. Decidual NK (dNK) cells differ from peripheral NK cells both in their phenotype and function. dNK cells help create an anti-inflammatory environment, support the formation of the placental vasculature, and maintain immunological balance between the mother and fetus. dNK cells express various receptors (such as KIR receptors) that recognize HLA molecules on the surface of fetal trophoblast cells, thereby contributing to the suppression of immune responses against the fetus. 8  Role of PIBF in Pregnancy Immune Tolerance During pregnancy, progesterone is produced in increased amounts, and progesterone receptors (PRs) are expressed in large numbers on lymphocytes.  The binding of progesterone to these PRs triggers the production of an important regulatory molecule, the Progesterone-Induced Blocking Factor (PIBF). PIBF plays a vital role in maintaining immune tolerance during pregnancy by: Shifting the immune response towards an anti-inflammatory, Th2-type direction. Stimulating IL-10 production and inhibiting pro-inflammatory cytokines. Reducing the cytotoxic activity of NK cells. Supporting trophoblast invasion and the function of Treg cells. The absence of PIBF is associated with increased NK cell activity, which can lead to pregnancy loss. The Progesterone-Induced Blocking Factor (PIBF) is a key molecule produced in response to the progesterone hormone by various cells, including T-cells. During pregnancy, PIBF plays a critical role in maintaining immune tolerance between the mother and the fetus. As progesterone levels steadily increase throughout pregnancy, PIBF production also rises, contributing to the fetus's immunological protection. The increased expression of progesterone receptors (PRs) may be linked to lymphocyte stimulation triggered by fetal alloantigens. When progesterone binds to PRs, it induces the production of PIBF, a regulatory molecule with immunomodulatory effects. These effects include: Promoting the production of Th2 cytokines, which are favorable for pregnancy. Reducing the cytotoxic activity of NK cells. PIBF production begins in the early stages of pregnancy, its concentration increases as gestation progresses, and it decreases just before delivery. This dynamic regulation ensures immune protection during pregnancy while allowing the maternal immune system to adapt appropriately as gestation nears 9 completion. 9 Transplantation Immunology 10 Name of the graft Meghatározás Example Rejection Autograft The transplantation of Autologous blood or no one's own tissue from bone marrow one part of the body to reinfusion; skin another. grafting within the same organism. Syngraft (syngeneic Transplantation Tissue or organ no graft, isograft) between genetically transplantation identical individuals. between identical twins or individuals of an inbred mouse strain. Allograft Transplantation Tissue or organ yes between two transplantation from individuals of the one human to another, same species. or between individuals of two different inbred mouse strains. 11 12  The most important transplantation antigens: 1. Major Histocompatibility Complex (MHC) Antigens → Human Leukocyte Antigens (HLA): These are the most crucial genes for tissue compatibility. They are highly polymorphic. Each individual has a unique HLA pattern → the HLA molecules from a foreign donor may significantly differ from those of the recipient. The chance of incompatibility is high. In case of incompatibility, acute rejection is expected (within days). Organ and tissue transplants are more successful when the donor and recipient's HLA haplotypes are closely matched, meaning that as the differences between MHC alleles decrease, the likelihood of success increases significantly. 13  The most important transplantation antigens: 2. Minor Tissue Compatibility Antigens - These antigens may originate from proteins synthesized within a specific cell, with different sequences being presented in different individuals. - Most of them are peptides bound to MHC class I, which are recognized by cytotoxic T cells. - Many are non-specific proteins (e.g., HY, UTY, DBY). - They are less polymorphic. - Immunologically, they are less visible. - Their differences do not by themselves trigger a strong rejection response but can increase the intensity of the rejection process initiated by differences in MHC antigens. - Differences in several minor-H antigens, even with a perfect MHC match, can prevent the graft from being accepted. - The chance of incompatibility is lower. - In case of incompatibility, chronic rejection reactions can occur (over weeks to years). Minor-H antigens do not induce an antibody response, and the number of T cells that react to them is significantly smaller compared to the number of T lymphocytes that recognize different MHC proteins. 14  The most important transplantation antigens: 3.Blood group antigens - Blood group antigens are alloantigens found on red blood cells. - IgM-type antibodies are produced against antigens that are missing from an individual's own red blood cells, while tolerance is developed against the blood group antigens that are naturally present. - Tolerance to blood group antigens is the basis for the well-known transfusion rule, according to which individuals with the AB blood group are universal recipients, as their bodies do not produce antibodies against either A or B antigens. On the other hand, individuals with the O blood group are universal donors, as their red blood cells do not express either A or B alloantigens. 15 16 Hemolytic disease of the newborn occurs when the developing fetus's red blood cells immunize the mother's immune system. This most commonly happens with Rh (D) antigens, when an Rh (D) negative mother carries an Rh (D) positive fetus. The IgG antibodies produced in response cross the placenta and damage the red blood cells of a subsequent Rh (D) positive fetus. This hemolytic reaction can be prevented with anti-RhD antibodies administered to the at-risk mother (Rh prophylaxis). The antibody is injected into the Rh-negative mother after the birth of the first Rh- positive fetus to eliminate any incompatible red blood cells that might enter the mother's bloodstream during delivery. As a result, during the next pregnancy, there will be no antibodies in the Rh- negative mother's body that would react with Rh (D) positive red blood cells, preventing damage to the fetus. 17  The Types of Rejection Reactions Hyperacute rejection: The hyperacute reaction is triggered when antibodies that bind to the alloantigen of the graft's endothelial cells activate the complement system, leading to inflammation and, within a very short time, to intravascular thrombosis and necrosis. It occurs immediately or within a few minutes to hours after transplantation. In hyperacute rejection, antibodies of the IgM isotype that specifically react with carbohydrate-type antigens play a prominent role, but IgG antibodies also contribute to the process. In some cases, antibody-mediated cytotoxic reactions (ADCC) can also be detected. This reaction is typically characterized by thrombosis of blood vessels and rapid graft failure. Treatment:Hyperacute rejection is virtually unstoppable and requires immediate organ removal. IgM izotípusú ellenanyagok pl. ABO vércsoport-inkompatibilitás esetén 18 19  Acute rejection: Acute rejection occurring within 2–20 days is primarily mediated by CD8+ T cells activated by alloantigens, but alloreactive antibodies also play a role in this response. During the reaction, the graft's parenchymal cells are damaged, and inflammation develops. Early acute rejection: This occurs within 2-5 days after graft transplantation. CD8+ T cells are responsible, and they are activated by alloantigens on the endothelial and parenchymal cells, leading to the destruction of these cells. Late acute rejection: This occurs on average 7-21 days after transplantation, but in some cases, it may occur much later, even after several months. Treatment: Acute rejection is generally controllable with immunosuppressive therapy, which suppresses the recipient's immune response and thus protects the transplant. Immunszuppresszív kezeléseK például kortikoszteroidokkal vagy T-sejt specifikus gyógyszerek 20 21  Chronic rejection In chronic rejection, alloantigen-specific CD4+ DTH T-cells play a key role. Chronic rejection occurs after six months, characterized by the narrowing of the graft- surrounding vessels due to the proliferation of smooth muscle cells in the intima, ultimately leading to ischemic tissue damage. This proliferation is induced by growth factors and chemokines produced in response to IFNγ and TNF secreted by alloreactive T-cells. Nowadays, chronic rejection is the leading cause of transplanted organ loss. Histological changes include glomerulosclerosis, fibrosis, and arteriosclerosis. Treatment:Chronic rejection is difficult to manage. Traditional immunosuppressive drugs are not always effective in halting the process. Specialized immunosuppressive strategies and continuous monitoring of the transplanted organ are required. However, in many cases, a new transplantation becomes necessary in the long term.. DTH (Delayed Type Hypersensitivity) In chronic rejection, which develops over several months, alloantigen-specific CD4+ DTH T-cells are involved. As a result of this process, the walls of the graft’s blood vessels thicken (arteriosclerosis), and the reduction in vessel diameter leads to necrosis of the transplanted tissue. 22 23 Tumor immunology 24  The tumor and the immune system Our body is constantly exposed to biological, chemical, and physical carcinogenic influences; however, tumors rarely develop. One reason for this may be that the immune system continuously monitors (surveillance) every cell in our body. All immune cells can participate in this defense. Tumor cells, as a result of genetic and epigenetic changes, may become immunologically distinguishable from healthy cells. These changes can activate cells of both the innate and adaptive immune systems, so ideally, the body can eliminate the abnormal cells in a manner similar to how it deals with pathogens, preventing the development of disease. 25 Destruction of Tumor Cells by the Immune System 26 27  In tissues, NK cells, NKT cells, and γ/δ T cells are present even in a resting state. They detect signs of dedifferentiation, stress, and viral infection on the surface of cells. NK cells are active when tumor cells do not express MHC-I molecules (for example, when these molecules are downregulated or disappear from the cell surface to evade detection by T cells). NK cells recognize these "MHC-deficient" cells and destroy them. Activated NK cells can directly kill tumor cells through the exocytosis of granzymes and perforin, as well as via death receptors (such as Fas, TRAILR). NK cells also produce IFNγ, which enhances MHC expression on tumor cells, increases the cytotoxic activity of local macrophages, inhibits angiogenesis, and activates elements of the adaptive immune system. NKT cells primarily aid this process through cytokine secretion. γ/δ T cells contribute to tumor elimination with their cytotoxic abilities. The resulting cytokine environment and cell death enhance the killing and phagocytic capabilities of resident macrophages and promote the maturation of dendritic cells. The expression of non-classical MHC molecules on tumor cells can promote the activation of NK cells, as these molecules serve as ligands for activating NK receptors. Activated NK cells can directly kill tumor cells through the exocytosis of granzymes and perforin, as well as via death receptors (such as Fas and TRAILR). 28 29  Mutations in tumor cells lead to the production of abnormal proteins, which serve as tumor antigens. Dendritic cells transport these antigens to the lymph nodes, where they present them to T cells, particularly CD8+ cytotoxic T cells. Upon recognizing the appropriate antigen, T cells become activated and differentiate into tumor-specific effector cells, capable of destroying tumor cells. Activated CD8+ T cells (CTLs) migrate through the bloodstream to the tumor site, where they recognize tumor cells based on the tumor antigens presented on MHC-I molecules. When a CD8+ T cell recognizes a tumor cell, it selectively destroys it. During the developing immune response, neutrophils and eosinophils may also appear in the tumor tissue, further promoting tumor elimination. Dendritic cells (DCs) that present tumor cell antigens migrate to the local lymph nodes, where they activate CD4+ and CD8+ T cells, as well as B cells. The resulting tumor-specific T lymphocytes and antibodies then travel through the bloodstream to reach the tumor cells. 30  Tumor Antigens Tumor Antigens:These are antigens that typically appear on tumor cells. Tumor-Specific Antigens:→ These antigens are expressed only in tumor cells within the body. → They may originate from viruses or altered proteins due to genetic mutations, which makes them foreign to the body. Tumor-specific antigens can be the protein products of oncogenes, as these contain mutations. Tumor-Associated Antigens: → These antigens appear in abnormal quantities, in abnormal tissues, and at inappropriate times, similar to self-antigens. Tumor-associated antigens are significantly more common. Their abnormal appearance at the wrong time indicates that, under normal conditions, these proteins are only expressed during fetal development but are re-expressed in adulthood. Since adult immune system cells do not encounter these proteins during their selection process, they recognize them as foreign. This type is called oncofetal antigens..A tumorasszociált antigének abnormális időben, szövetben vagy mennyiségben megjelenő fehérjék 31 32  Immunotherapeutic possibilities in the treatment of tumors We can distinguish between active and passive immunization. The former introduces tumor antigens into the body in a form with enhanced immunogenicity, while the latter involves administering antibodies or cells with effector functions. Since the tumor is already present in the body, the task is to modulate the established immune response and break through tolerance. Strategies can be distinguished based on whether they deliver the antigen, the tumor cell, or the antigen-presenting cell itself into the body. Thanks to advancements in monoclonal antibody technology and molecular biotechnology, recombinant human antibodies can now be used for therapeutic purposes. Antibodies produced against epitopes on the surface of cancer cells can be utilized to destroy tumors. 33 Monoclonal antibodies and their modified forms, which recognize antigens found on tumors, can exert their antitumor effects through various mechanisms. By targeting internalizing receptors, radioactive isotopes, toxins, and cytostatic drugs can be delivered to tumor cells. Effector functions mediated by the Fc region of antibodies (ADCC, CDC – Complement Dependent Cytotoxicity) cause the lysis of tumor cells. Cross-linking of death receptors induces apoptosis in the cells. The growth of tumors is inhibited by blocking growth factors (GF – Growth Factor) or their receptors. Bispecific antibodies, which bind both to tumor cells and killer cells, facilitate the destruction of target cells. Fusing cytokines to tumor-specific antibodies enhances the activity of antigen-presenting cells. 34  Tumor Therapy Options Based on Monoclonal Antibodies These antibodies are recombinant humanized or human antibodies produced through recombinant technology, used either in unconjugated form or as chemically conjugated variants equipped with various cell-destroying molecules. In terms of structure, they can be full-length antibodies, fragments, or fusion proteins containing additional protein domains. Based on their recognition capabilities, in addition to natural monospecific forms, bispecific variants are also utilized. Unconjugated antibodies can exert their cell-destructive effects partly through interaction with the target and partly via effector functions mediated by the Fc region. Bispecific antibodies are capable of simultaneously recognizing a tumor antigen and an effector cell receptor, thereby facilitating physical contact between the target cell and the destructive cell, stabilizing this interaction, and activating the effector cell. The killing capacity of these antibodies can be enhanced by conjugation with toxins or radioactive isotopes (radioimmunotherapy). The essence of this technique is that cell destruction becomes targeted, and thanks to the specificity of the antibodies, it ideally remains confined to the tumor, sparing the rest of the body. 35 Thank you for your attention! 36