Unraveling the mystery of “closed antibody and immunotherapy”

  The human MHC is the human leukocyte antigen (HLA). Each person’s HLA recognizes substances that she needs and does not need, and prevents the occurrence of foreign invasion, such as bacteria, viruses or cancer cells. When a mother becomes pregnant, her body must be primed to receive HLA protein molecules from the father (e.g., embryo, placenta), as well as its own HLA protein molecules (e.g., embryo, placenta). The embryo and placenta contain proteins from the paternal side, and paternal genes can influence the growth and invasive effects of the embryo and placenta in the maternal body, and must somehow escape the maternal immune defenses. Therefore, during a normal pregnancy, the mother is exposed to paternal antigens and produces an antibody, known as a “closed antibody”, which binds to the placental cell surface antigens, thus blocking the maternal cytotoxic T-cells or natural killer cells from launching an immune attack on the embryo, which plays a role in protecting the fetus and maintaining the pregnancy.  Therefore, theoretically, “closed antibodies” should be detectable in women with normal pregnancies, but are usually lacking in women with recurrent spontaneous abortions of the same immune type. The lack of “closed antibodies” results in a series of reactions that alter the ratio and function of lymphocytes in the immune system, such as an increase in cytotoxic T cells, a decrease in immunosuppressive T cells, an increase in the number and toxicity of natural killer cells, the embryo and placenta become targets of immune cell attack, and placental angiogenesis is impaired. Impaired placental angiogenesis occurs.  Clinically, however, not all normal pregnant women can detect “closed antibodies”. Why?  Because there are many types of “closed antibodies”, including at least: anti-HLA-D/DR antibodies, anti-husband lymphocytotoxic antibodies (APCA), anti-TLX antibodies (trophoblast and lymphocyte cross-reactive antibodies, Ab1), anti-unique antibodies (Ab2), mixed lymphocyte response closed antibodies (MLR-Bf) Many laboratories only measure one of these indicators to make a diagnosis, which is often not very comprehensive, so many people do not find out that the “closed antibody” is positive.  In the 1980s, Dr. Alan E. Beer in the United States began immunotherapy for recurrent spontaneous abortions in patients with “closed antibody” deficiency. What is immunotherapy?  There are two types of immunotherapy: active and passive.  Active immunization: Intradermal immunization of patients with husband’s lymphocytes/unrelated third party lymphocytes with the aim of producing the above mentioned antibodies, e.g., closed antibodies.  Treatment characteristics: slow action effect, long maintenance time, lack of specific indicators to monitor the treatment effect.  Disadvantages of treatment: not suitable for the timely treatment of patients with abnormal immunity after pregnancy, because the effect is slow and the blood b-HCG is long played out by the time it takes effect.  Active immunotherapy efficacy monitoring is based on the presence of closed antibodies in the patient’s blood. At present, some treatment centers in Japan and China do not monitor the changes of the above indicators after giving active immunization to patients and prepare for pregnancy directly; some repeatedly track the production of closed antibodies after treatment and wait for the presence of antibodies before preparing for pregnancy. However, many clinical studies have found that some patients do not produce closed antibodies after treatment, but the T-cell toxicity, immunosuppressive T-cell function, and natural killer cell toxicity in the body have all changed, and the immune disorder has improved.  Passive Immunity: Intravenous drip of C-immunoglobulin is used for the purpose of treatment: to reduce cytotoxic T-cell toxicity and quantity, to increase immunosuppressive T-cell function and quantity, to reduce natural killer cell quantity and toxicity, to regulate the balance of cytokines, and to control immune inflammation.  Therapeutic features: fast action effect, short maintenance time, metabolized in the body in 2-3 weeks. It can be used not only for homoimmune recurrent abortions but also for autoimmune recurrent abortions, such as: anticardiolipin syndrome, systemic lupus erythematosus, dry syndrome, Kawasaki disease, etc.  Disadvantages of treatment: expensive and has side effects such as allergy, fever, nausea, muscle pain and headache.  Methods of monitoring the effects of passive immunotherapy: measuring changes in the levels of toxicity and inflammatory factors such as T cells, natural killer cells, cytokines, etc.  These two immunotherapies have been used worldwide for many years, and although the efficacy is positive, there are significant differences in the reported efficacy, with the success rate of re-pregnancy fluctuating from 71% to 100%, with an average of 80%. Among the reports of 100% efficacy, the number of cases is actually only 2-4, which is not the result of a large clinical sample study, some of the reported cases failed the screening, and some reports did not exclude the interference of embryonic chromosomal abnormalities on the results, etc. Therefore, if we want to confirm the exact efficacy of these two immunotherapies, we must conduct a strict multicenter randomized controlled clinical trial with a large sample.  Because there are many pressing clinical issues with active and passive immunotherapy, and there is a lack of uniform treatment norms. The U.S. FDA suspended active immunotherapy, but clinical studies can be applied and passive immunotherapy can be carried out; many medical centers in Japan, the Philippines, and China carry out active immunotherapy, but the treatment protocols are not uniform from center to center. Due to laboratory conditions, passive immunotherapy (gammaglobulin) therapy is currently available at our hospital.