Both transplant surgery and blood transfusions have had problems from the recipients immune system interfering with the processes involved. The basic problem is the requirement that the immune system must be able to recognise ‘self’ to be able to defend us against infective organsims, which are ‘non-self’. Unfortunately donated blood or body organs are also ‘non-self’ and will be treated as an invading organism by are defence system.

Blood Groups: There are at least 50 different blood groups, but the two most discussed are the ABO and the Rhesus groups.

This should properly be called the A1, A2, B and O blood group since the A antigen can be resolved into two fractions by the use of agglutinating sera. Basically the groups are defined by the presence of a glycolipid on the red cells. The lipid fraction is attached to the cell membrane at one end while the other is attached to a carbohydrate chain.

This is connected to a group of sugar residues referred to as the H substance. The H substance has a sugar unit attached to its end and this can be either A-type sugar or B-type sugar (see above diagram for actual sugars involved). If no sugar is attached to the H substance the person is group O. There is no serum to detect group O but it can be detected by the use of a Gorse seed extract.

There are two codominant alleles I^A, and I^B. There is also a null allele I^O. Thus a group O individual has the genotype I^OI^O, a group A person may possess I^AI^O or I^AI^A, while a group B person can have I^BI^B or I^BI^O. We are ignoring the sub-sets of allele I^A in this discussion since in essence they are minor modifications of the I^A type. The fact that about 75% of individuals are found to secrete A or B antigen in their saliva and other fluids indicates that a gene for solubility is present, which we refer to as Se. This solubility gene has a recessive allele se. The secretion gene is at a different locus from the ABO locus and segregate independently. A further pair of alleles at a different locus, referred to as the Lewis locus are Le and the recessive le. These alleles form the Lewis antigens which are soluble and found in the plasma, but can also be found upon the red blood cell membranes if their concentration in the plasma is high. The reason they are mentioned here is that they are derived from the same materials as the ABO antigens and interact with the Se alleles. The diagram below illustrates the interaction and functioning of the three sets of alleles.

The distribution of the ABO blood group alleles varies greatly in different regions of the world the table below shows the percentage frequencies of the three main alleles:

The frequency of blood group alleles shows a clinal distribution through Europe. The clines form a pattern of IB frequencies ranging from 20-25% in eastern Europe to 0-5% in Spain. This is related, it is thought, to the wave of Mongol invasions which swept across Europe 1000 years ago and ended about 500 years ago.

The major problem with the ABO group is that the body automatically produces antibodies, referred to as agglutinins because they cause clotting of the blood cells. Each person produces agglutinins to the agglutinogens (antigens) which they do not possess. Thus a group A person produces b agglutinin, while a group B person produces a agglutinin. The group O person has no agglutinogens and therefore produces both a and b agglutinins. The agglutinins are in very dilute solution in the plasma and therefore in a small amount of donated blood the agglutinin does not matter, but the agglutinogen is significant and will react with the agglutinins of the recipient.

Note that O is the universal donor being able to give blood to any type since there are no agglutinins on the surface of the red cells, however they can only receive group O blood since their agglutinins would attack any A or B agglutinogens present on the transfused blood cells.

At first believed to be a simple dominant/recessive situation with the dominant allele causing a red blood cell antigen to be produced, the system soon became more complex as various refined sera were tested. The are two distinct viewpoints as to the genetic basis of the Rhesus group. Weiner suggests a single locus with a series of 8 alleles, while Fisher and Race suggest three loci named C, D and E. The main Rhesus effect is the result of the D locus in the latter system which is generally accepted as the most likely explanation of current observations. The presence of the allele D causes the formation of an antigen which is modified by the addition of antigen by the alleles C and E. The CDE system of loci form a supergene with the commonest haplotypes as CDe, cDE, cDe, cde. There are many irregularities found in the Rhesus group which are largely a mystery and defy a clearcut explanation; certain D antigens react weakly with anti-D serum and are designated Du and in African tribes these may be mistaken for D-negative since they range from no reaction through to normal agglutination. The discovery of individuals who lack any reaction to anti-sera except for D have been found and presumably have the haplotype -D-, and some have no reaction at all ie they have no active rhesus loci! Rhesus factor gained much attention because of its role in the disease Rhesus Haemolytic Anaemia (RHA) of the newborn which results in the lysis of foetal red blood cells. A Rh^- mother becomes sensitised to the Rhesus factor if she has been transfused with Rh⁺ blood, or has received a small dose from a Rh⁺ baby during placenta detachment at birth. She produces antibodies which may attack later Rh⁺foetuses causing extensive damage to the foetal blood cells, or will attack transfused Rhesus positive blood cells with the release of porphyrin rings from the haemoglobin in these cells, this can cause some nasty effects.

The distribution of Rhesus positive types in populations varies widely, in Caucasians 84% +ve and 16% -ve; up to 99% +ve in American Indians, Orientals and Africans. The Spanish Basques have only 66% +ve individuals. Interestingly, the American Negro population has a much higher -ve component (9%) than African Negro groups, due to interbreeding with Caucasians.

In a Caucasian population the chances of a mating between a Rh- mother and a homozygous (DD) Rh+ father is: 0.16 x 0.36 = 0.058 (5.8%)

When tissues from one individual are grafted onto another, the grafted tissue is recognised as foreign and it is attacked by white blood cells. The mechanism of this response between the host and graft tissues is known to be due to the ability of white cells to recognise the antigens on cell surfaces as being "self" or "non-self". If it is found to be non-self then the T8 cytotoxic cells in our system will attack it with lysozymes and destroy it. The genetic basis of this “self” system is a series of loci on chromosome 6, which are closely linked so that they act as a supergene system known as the Major Histocompatibility Complex. The easiest of the protein antigens to recognise are those on the white blood cells and they are known as the Human Leucocyte Antigen system, or HLA for short. There are four genes which are referred to in various ways by various authors but the modern terms are HLA-A, HLA-B, HLA-C and HLA-D, or A,B,C,D for short. The genes are in the sequence D-B-C-A with gene D nearest to the centromere on the short arm of chromosome 6. Each gene has many alleles, the actual number being uncertain, but up to 35. Thus there are many millions of possible allele combinations within any population. This is a good example of a genetic polymorphism, defined as a range of distinct discontinuous types or morphs living in the same area and in such frequencies that they cannot be maintained by recurrent mutation alone.

The HLA loci, acting as a supergene with recombination at an extremely low level, are inherited as haplotype blocks from each parent.

Thus although the compatibility between tissues from unrelated individuals is low, there is a one in four chance that a sibling will have the same set of haplotypes and therefore show tissue compatibility.

It is known that certain HLA alleles are associated with a tendency towards certain diseases; eg 90% of sufferers of ankolysing spondylitis, an inflammatory disease of the spinal column, have the allele B27 in their haplotype; the allele DRw2 is associated with a form of muscular dystrophy; B5 can increase the risk of ulcerative colitis, a large intestine defect.

The only way to ensure that a transplant is not rejected is to find a donor whose HLA system is as close as possible to the recipients. The bigger the difference then the greater the range and number of activated cytotoxic cells there will be and the faster the transplant is killed off. To reduce this rejection the cytotoxic cells can be killed off using radiation treatment prior to the transplant, or immunosuppressant drugs can be used to switch off the cytotoxic cells. Clearly the closer the match the less drastic the suppression of the immune system has to be. Suppressing the immune system too much can lead to opportunistic diseases in the recipient, much as in AIDS. The perfect match would be either an identical twin or the one sibling in four carrying the same supergenes, if he or she exists!

Human immunodeficiency virus is a retrovirus which enters the body through a damaged surface and it must be transmitted in a human fluid, such as blood or semen. The virus is delicate and damaged by drying out. The virus initially enters T4 helper cells and reverse transcribes its RNA into DNA which is attached to the host cells DNA. The virus may remain inactive for a long period of time. Eventually the virus will replicate and unlike many viruses it does not always cause its host cell to burst or lyse. Instead it alters its chemistry slightly so that it will fuse with any other T-helper cell it meets. Also the infected cell produces cytoplasmic extensions with a virus at the tip of each. When these extensions contact another T-helper cell the virus is passed on. This makes attacking the virus very difficult. Although the virus is released into the tissue fluids where it can be attacked, it also sneaks from cell to cell directly and thus cannot be attacked. Added to this problem the virus is unstable and mutates into new strains very frequently. Thus the initial antibody production may be entirely useless against the virus which later reappears from the infected T-helper cells. Once the T-helper cell population is reduced in number and effectiveness the immune system fails, because it is the T-helper cells which activate the b-lymphocytes to clone and produce antibodies. At this point AIDS occurs, various diseases which are extremely rare in the population generally can take hold and kill the human host. A particular form of Pneumonia is common, as is Karposi’s sarcoma, a cancer of the blood capillary walls, Tuberculosis is frequently seen in AIDS sufferers. The development of treatment for HIV positive individuals (ie those infected with the virus but not yet with AIDS) has concentrated upon a cocktail of antiviral drugs which tend to limit the replication of the virus. There is no positive prospect of a vaccine in the near future. One positive note is that a very tiny proportion of the human population carries a gene which stops this virus from attacking the helper cells in the first place.

The virus is best avoided by using condoms when having sex, avoiding blood transfusions, injections or any form of blood to blood contact in any country where the virus is to be found and where control procedures is not absolutely first class. Remember that many UK patients now have the disease as a result of treatments they have received here in the recent past.

Autoimmune diseases

If the ability to recognise our own tissues as ‘self’ is lost or fails to develop then we will attack our own tissues and cause them to be destroyed. There are a number of such autoimmune diseases, multiple sclerosis being one example. The T-killer cells may mutate or some types may fail to be deactivated by the thymus gland after birth. These rogue killer cells may now be in a position to recognise substances in the cell membranes of specific tissues and this means they should be foreign. The cells are attacked and this damages specific tissues within body organs. In multiple sclerosis progressive damage is done to the myelin sheath of nerve cell axons and this results in progressive failure of nervous control. Immunosupressant drugs can be used to suppress the abnormal immune response but a possible new treatment using monoclonal antibodies which can recognise the specific killer cells involved and kill them off is being developed.