How a mother’s immunity can help or harm her children before and after birth By Dr. Peter H Kay
In this fascinating article, we discuss how a mother’s immunity can help or harm her children before and after birth. To optimise the diagnosis and treatment of any form of ill-health, it is vital that the precise pathogenesis is recognised. These notes have been prepared by Dr Peter H Kay – The CMA’s Scientific Education Advisor, to enable health practitioners to understand an often misunderstood pathobiological pathway that underpins the development of many diseases in offspring before and after birth. It also enables practitioners to give helpful information to those who may be considering parenthood.
Dr Kay has designed this article to be useful to both complementary and conventional medical personnel, and makes fascinating reading as he takes a deep dive into the function of maternal immunity.
Increased susceptibility to development of many forms of ill-health can be caused by the presence of maternal antibodies in a mother’s circulation which react with foetal tissues during pregnancy.
A brief introduction to immunity
The immune machinery comprises many different components. They are basically divided into the adaptive and the innate immune systems.
The adaptive system responds to a wide range of infectious agents, toxins and foreign substances that everyone is exposed to on a daily basis. The innate system supports the adaptive immune system’s activity when it responds to a particular foreign substance, toxin or infectious agent.
The adaptive immune machinery is derived from different types of white cells which originate from the bone marrow. One type of adaptive white cell called a B cell can produce soluble proteins or antibodies (immunoglobulins) that can kill or neutralise infectious invaders such as bacteria, viruses and fungi with the co-operation of the complement system, outlined later. B cells can also respond to proteins and other substances that are genetically different from those of the host. This is an important consideration.
B cell immunity
As stated, B cells originate from precursor cells within the bone marrow. B cells are so called because, unlike T cells, they mature and diversify in antigen recognition by passage through the equivalent of the avian Bursa of Fabricius.
On contact with their specific antigenic target, B cells, with the aid of CD4+ or helper T cells, differentiate into plasma cells and produce soluble antibodies against the foreign or toxic substance that they have been genetically programmed to respond to.
Generation of the ability to recognise a wide range of foreign, genetically different substances or infectious agents by B cells is accomplished by the ability of a small number of genes to form a wide range of antigen receptors on B cells.
The adaptability of immune recognition is a remarkable genetic phenomenon in which just a small number of genes including immunoglobulin heavy and light chain (IgH and IgL) encoding genes can re-arrange themselves to produce perhaps up to a billion or more different gene products or antigen receptors at any one time. Each of the IgH and IgL chain genes have constant and hyper-variable regions which re-organise themselves to end up with billions of different antigen receptor molecules on the surface of different B cells. If newly formed B cells do not come into contact with their target molecule (antigen) within a few weeks, they die so that other new B cells can be made to replace them.
When a B cell encounters its target molecule or antigen it differentiates into a plasma cell with the assistance of helper T cells. That is why helper T cells are so important in promoting immune responsiveness. It is the plasma cell that actually synthesises the antibody that interacts with the target antigen. They also form memory B cells which respond more rapidly to the same antigenic target when encountered again.
Different types of antibody
B cells have the capacity to differentiate and synthesise a number of different types of antibody, namely IgG, IgM, IgA, IgD and IgE.
IgM
When a substance that can be recognised as immunologically foreign is encountered by a B cell for the first time, IgM antibodies are the first type of antibody to be produced. It takes around 2 or 3 weeks before IgM antibodies are produced.
IgM antibodies are the largest immunoglobulin molecules and consist of five basic immunoglobulin sub-units. Because of their size, their presence is mainly restricted to the blood.
IgM antibodies are very good at fixing the complement system (see below) and can kill invading bacteria very well. They cannot cross the placenta and cannot offer immunological protection to the neonate.
IgG
IgG immunoglobulin is the most abundant antibody type. It is formed after a second or prolonged exposure to its target molecule. IgG antibodies bind very effectively to their target molecules or antigens. IgG antibodies also have a much longer half-life compared to IgM antibodies.
Because they are smaller in size compared to IgM antibodies, they consist of only a single basic antibody unit, they are found not only in the bloodstream but in fluids outside the bloodstream. They can even be passed through the placenta into the developing foetus to protect the baby against infection during pregnancy and for a few months after birth.
Immunoglobulin molecules have two important regions, the Fc region and the Fab region. The Fab region includes the part which binds to the molecule’s antigenic target. The Fc region plays an important role in initiating activation of the complement system. The Fc region of IgG antibodies also plays an important role in enabling them to be actively transported across the placenta into the circulation of the foetus. As indicated below, this is an important immunological protective mechanism for the developing foetus. Unfortunately, as will become clear later, a mother may have IgG antibodies which cross the placenta and react with proteins in the developing foetus.
There are four different sub-classes of IgG, IgG1, IgG2, IgG3 and IgG4. IgG sub-classes have slightly different functions. For example, IgG1 and IgG3 sub-classes are rich in antibodies against proteins such as the toxins produced by the diphtheria and tetanus bacteria, as well as antibodies against viral proteins. By contrast, IgG2 antibodies are predominantly directed against the surface polysaccharide of some disease-producing bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. Thus, IgG antibodies have the capacity to react with a wide range of antigenic substances, including foetal proteins, see below.
The IgG sub-classes IgG1 and IgG3 are able to be transported most effectively across the placenta and into the baby’s circulation (1)
IgA
Another type of antibody is called IgA. During synthesis, IgA antibodies have a secretory piece attached to them. This allows them to be secreted through many epithelial layers into places like the gut and into saliva to afford immunity to regions of the body inaccessible to IgM and IgG antibodies.
IgE
IgE antibodies are quite different. These are the antibodies that cause some allergic reactions. They can become bound to the surface of mast cells. Mast cells are found on the surface of many tissues such as the airways, nose, eyes and mouth. When a mast cell is exposed to a foreign substance such as pollen (in the case of IgE reactivity it is called an allergen) to which an IgE antibody, specific for that allergen, has been bound, the mast cell bursts open. This releases highly reactive pro-inflammatory molecules such as histamine and serotonin. These are the substances that set off a rapid local inflammatory process or allergic reaction.
The complement system
It is important to be aware of the complement system because it plays a significant role in the killing and removal of cells that have been attacked by antibodies.
Antibodies usually fix or activate the complement system via the classical pathway. When the complement system has been activated by the Fc portion of a bound antibody, an enzyme cascade follows, starting with activation of the tri-molecular complex C1, eventually leading to death (referred to as lysis) of a cell or invading bacteria by the drilling of a lethal molecular hole which causes the cell’s contents to leak out. The complement factor that finally drills a molecular hole in the in the invading organism or cell is C9, part of the membrane attack complex.
The order of classical complement activation involves binding of a set of C1 proteins C1q, C1r and C1s which bind to the immunoglobulin Fc region of bound antibody. The C1 complex then activates C4 which then sequentially activates C2 and then C3 and so on to C9. Factors such as C3a and C5a, released during the enzyme cascade and following activation of C3 and C5 respectfully, are highly potent inflammatory mediators and attractants for phagocytic cells that engulf killed cells. The C3 sub-component, C3b attaches to target cells rendering them much more readily phagocytosed or “eaten up” by cells such as neutrophils and macrophages.
It is important to note that the complement system is well established in the early stages of foetal development.
The complement system causes serious tissue damage in antibody mediated auto-immune diseases.
Alloantibodies and autoantibodies
Antibodies including maternal IgG antibodies may be divided into two types, alloantibodies and autoantibodies. Alloantibodies react with all antigens other than those that are present on or part of the mother’s or host’s cells and tissues. On the other hand, autoantibodies react with antigens present on the host’s cells or tissues. Both allotypic and autoimmune antibodies of the IgG type cross the placenta and have the potential to protect or cause disease in the foetus before and after birth.
Foetal diseases caused by maternal immunity – IgG alloantibodies
One of the best known foetal diseases caused by a mother’s immunity is haemolytic disease of the new-born (HDN). It is usually caused by transfer of maternal IgG Rhesus antibodies across the placenta and into the Rhesus positive Rh+ (D+) foetus in the womb.
Maternal Rhesus antibodies are formed following passage of a baby’s Rhesus Rh + (D+) red cells into the bloodstream of an Rh- (D-) mother during pregnancy and as part of the birthing process. The mother’s immune system then recognises the Rhesus D+ antigen on the baby’s red cells as immunologically foreign. The mother’s immune system then makes an IgG antibody against the D antigen on the baby’s red cells. As it takes a while before IgG Rh (anti-D) antibodies are formed in the mother’s blood, it is invariably the second or subsequent Rhesus D+ babies that are likely to be affected. Children who are Rh – (D-) are unaffected. Binding of the mother’s anti-D antibody to the baby’s Rh+ (D+) red cells in utero causes destruction of the baby’s red cells leading to severe anaemia and jaundice, which may prove fatal.
The Rhesus blood group system includes other genetically controlled antigens called C, E, c, e and combinations thereof. Genetic differences in these other Rhesus antigens between mother and child can also be a cause of Rhesus HDN.
Genetic differences between mother and child involving other genetically controlled red cell antigen systems such as the Kell, Duffy, Kidd or other red cell blood group systems can also be a cause of IgG antibody mediated HDN.
Other types of baby’s blood cells such as white cells and platelets also pass into the mother’s circulation during pregnancy and at birth. The mother may produce antibodies to components of these cells if they differ genetically from the mother’s cells. Usually, the antigen system involved in destruction of white cells involves the production of antibodies against the human leukocyte antigen (HLA) system. Placental transfer of a mother’s IgG anti HLA alloantibodies against the baby’s white cells (lymphocytes, monocytes or granulocytes) into the baby’s circulation is one cause of premature birth. Mothers may also produce HLA alloantibodies following multiple transfusions or receipt of a transplanted organ.
Platelets or thrombocytes are small cells that play an important role in arresting bleeding. They harbour a series of genetically defined antigen systems such as as human platelet antigen (HPA) system HPA 1, 2, 3, 4 and 5.
Genetic differences in platelet antigens between mother and foetus can result in the formation of maternal IgG anti-platelet alloantibodies which can cross the placenta and destroy genetically incompatible foetal platelets causing neonatal alloimmune thrombocytopenia (NAIT). NAIT lads to excessive bleeding and brain haemorrhage in the foetus. Most cases are caused by anti-HPA-1a or anti-HPA-5b maternal alloantibodies. In contrast to HDN, NAIT may be induced by maternal HPA antibodies even in the first child following transfusion of genetically non-identical platelets.
NAIT may be treated by transfusion of platelets which are shown not to react with the mother’s anti-platelet antibody.
A simple way of predicting the possibility of some alloantibody induced illnesses in the unborn foetus involves testing the potential mother’s serum against the father’s red cells, white cells and platelets.
Foetal diseases caused by maternal immunity – IgG autoantibodies
Unfortunately, autoantibodies that react with a mother’s own tissues and cause various autoimmune diseases such as myasthenia gravis, caused by autoantibodies directed against the acetylcholine receptor in the neuromuscular junction; thyroid disease, caused by autoantibodies directed against the thyroid stimulating hormone receptor; type 1 diabetes caused by autoantibodies directed against the insulin secreting islet cells in the pancreas and many other autoimmune disorders may be of the IgG type. If so, they can pass into the unborn baby’s circulation and cause transient development of the same disorders in the new-born.
Mothers who suffer from the autoimmune disease systemic lupus erythematosus (SLE) often have a wide range of IgG autoantibodies including some called anti-Ro and La. These autoantibodies, particularly anti-Ro can cause irreversible heart disease in the child. This irreversible cardiac damage involving calcium regulation, is related to the expression of Ro and La proteins in foetal cardiac tissue during the 18th to 24th weeks of gestation. Under these circumstances, the proper development of cardiac tissue is impaired. This may lead to development of heart disease at birth and development of heart problems in later life that may need the insertion of a pace-maker.
Importantly, it has been found that anti-Ro autoantibodies may sometimes be found in asymptomatic subjects. Thus, it may be helpful to be tested for the presence of anti-Ro antibodies prior to pregnancy.
In the past, it was postulated that, because maternal IgG antibodies are able to cross the placenta, some childhood neurological disorders may be caused by impairment of some early developmental processes in the womb because of the presence of maternal IgG autoantibodies directed against critical foetal neural developmental proteins. In recent years, this postulate has been proven (2). It is now recognised that development of autism, autism spectrum disorders, dyslexia, learning difficulties and other neurological disorders in early childhood is associated with the presence of maternal IgG autoantibodies directed against many proteins involved in neurological development in the foetus. Some of the critical foetal neurological developmental proteins targeted by maternal autoantibodies include lactate dehydrogenase A and B, stress-induced phosphoprotein 1, guanine deaminase, collapsin response mediator proteins 1 and 2, and Y-box binding protein (3). These maternal autoantibodies do not affect the mother because they are unable to cross the mother’s blood-brain-barrier. However, they can cause neurological problems in the foetus because the protective blood-brain-barrier is not fully functional in the foetus until about 8 weeks of gestation.
That some cases of autism are caused by a maternal autoimmune process is further supported by the results of a study by Patel and colleagues who have found that autoimmune conditions are more prevalent in mothers of children with autism (4).
A possible further clue comes from the understanding of the development of paediatric autoimmune neuropsychiatric disorders (PANS) such as those associated with streptococcal infections and viruses such as herpes and EB viruses. In these situations, it is possible that alloantibodies formed in the mother that react with specific antigens on such infective agents are also cross-reactive with some embryonic neural development proteins.
Interestingly, investigations have shown that there is an association between autism and increased susceptibility to organ specific illnesses in later life raising the possibility that other developmental foetal organ specific antibodies are passed on to the foetus during pregnancy (5).
Treatment or prevention of foetal disorders caused by transfer of maternal IgG antibodies
There are number of ways in which maternal IgG mediated foetal disorders can be treated or prevented.
Firstly, the maternal allo- or autoantibody burden can be reduced by removal of some of the mother’s blood plasma (which contains the harmful antibodies) by a process called plasmapheresis. The removed plasma is replaced by plasma from healthy subjects. This process reduces the amount of anti-foetal antibodies that can be transferred to the developing foetus.
Because offending antibodies rely on binding to placental Fc receptors to enter the foetal circulation, the availability of these receptors can be blocked by infusion of pooled concentrated immunoglobulin (gammaglobulin) into the mother during pregnancy. Inhibition or blocking of Fc receptor activity in the placenta has proven to be very effective in preventing passage of damaging maternal IgG antibody into the foetus.
Diseases caused by maternal antibodies directed against foetal red and white cells can be treated by exchange transfusions at birth. Infusion of pooled gammaglobulin at birth has also been shown to be helpful in these circumstances.
To block formation of maternal anti D
If a mother is Rhesus D negative and the baby is Rhesus D positive, an injection of anti-D immunoglobulin into the mother within 3 days after giving birth can prevent the formation of a maternal anti-D antibody. The injected anti-D destroys any D+ red cells that have leaked into the mother’s circulation at birth before they can provoke the formation of a maternal anti-D that could harm subsequent children.
Advantageous harnessing of foeto-maternal immunity
As outlined above, a mother may produce harmful IgG auto- or allo-antibodies which cross the placenta and harm the child before and after birth depending on the IgG sub-class of the mother’s IgG antibodies.
Fortunately, helpful IgG antibodies can also be formed in the mother if she is vaccinated. Generally, live vaccines are contraindicated during pregnancy as they may cause foetal viremia or bacteremia. Inactivated vaccines are generally safe. Vaccines that can be safely administered to pregnant mothers are tetanus toxoid, diphtheria, pertussis and influenza vaccines. These vaccines should be administered to the mother preferably between weeks 16 and 32 of pregnancy. Flu vaccine can be given to all mothers at any time during pregnancy. Maternal IgG antibodies developed following these vaccinations provide important immunological protection for children before and after birth (6).
Predicting foeto-maternal immunological difficulties
As indicated above, the prospect of producing maternal IgG antibodies against the baby’s blood borne cells can be determined by testing the mother’s serum against the father’s red cells, white cells and platelets prior to pregnancy Any positive results would lead to more specific investigations.
Full autoimmune profiling of the mother would help in determining whether protective measures as described above should be considered. In my view, in a future healthcare setting, it would be of great benefit if a testing system was established that was dedicated to analysis of a mother’s allo- and autoantibody profile so that immunological damage to her children could be reduced as much as possible, particularly with respect to mothers who suffer from one of the very many autoimmune diseases.
With respect autoimmune diseases, presently, there are at least 100 different autoimmune disorders known. Most of the autoantibody targets are well recognised (7). Many of the different autoantibodies will have an IgG component which can cross the placenta and possibly react with molecules involved in some form of foetal development. These pathobiological immune reactions may lead to ill-health in the offspring’s later life. Thus, understanding of the specificity and IgG subtypes of allo- and autoantibodies in prospective mothers may have a major impact on the health of offspring.
Much more work is warranted in this area of health.
References
1. Clements T, et al. Update on transplacental transfer of IgG subclasses: impact of maternal and fetal factors. Immunological Tolerance and Regulation Volume 11 – 2020 https://doi.org/10.3389/fimmu.2020.01920
2. Palmeira P, et al. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:985646. doi: 10.1155/2012/985646
3. Edmiston E, et al. Autoimmunity, autoantibodies, and autism spectrum disorder. Biol Psychiatry. 2017 Mar 1;81(5):383-390. doi: 10.1016/j.biopsych.2016.08.031.
4. Patel, S, et al. Maternal immune conditions are increased in males with autism spectrum disorders and are associated with behavioural and emotional but not cognitive co-morbidity. Translational Psychiatry 10, 286 (2020). https://doi.org/10.1038/s41398-020-00976-2
5. Ward, J.H, et al. Increased rates of chronic physical health conditions across all organ systems in autistic adolescents and adults. Molecular Autism 14, 35 (2023). https://doi.org/10.1186/s13229-023-00565-2
6. Arora M and Lakshmi R. Vaccines – safety in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2021 Oct;76:23-40. doi: 10.1016/j.bpobgyn.2021.02.002.