by Edward Tenner M.D.

    When doctors looked into the causes of pemphigus, one area of interest was if there was any genetic or familial basis for these diseases. In the medical literature the number of reports of pemphigus occurring in the same family was very few. However, a genetic basis of pemphigus has been found and is felt to relate to predisposing genes involved with the human leukocyte antigen (HLA) system, the human version of the major histocompatibility complex (MHC). You may have heard of this system because it is involved in tissue typing which is used when doing organ transplantation. It is also involved in the body’s adaptive immune system’s response to foreign bacteria and viruses. In some instances when things go awry it can be associated with certain autoimmune diseases.

    The HLA complex is on chromosome 6 and contains many genes. We all inherit some of them from each of our parents and there is a 50/50 chance we will pass a specific HLA gene to our children.

     In different ethnic groups and nationalities these HLA genes are present at different rates. It has been discovered that certain HLA genes are present in people with pemphigus at rates much higher than the general population. For instance, in Jewish and non-Jewish pemphigus vulgaris (PV) patients HLA DRB1*0402, HLA DRB1*0401 and HLA DQB1*0503 (these designations represent a specific gene) are highly prevalent. In patients with pemphigus foliaceus (PF), HLA DR4 genes including DRB1*04 and DRB1*14 are often present.

    Detailed studies have revealed that these specific HLA genes in humans do seem to have a role in the etiology of pemphigus. In Ashkenazi Jews who develop PV,  over 90% are found to have the gene HLA DRB1*0402.  However, according to certain Israeli studies noted by Dr Anhalt only about one in 10,000 with this gene go on to develop pemphigus vulgaris. While many have looked into what may cause or trigger PV to develop in those who have a susceptible HLA gene, except for certain medications that are known to trigger pemphigus like penicillamine and ACE inhibitors, little specifically is known about why some people go on to develop pemphigus.

    The reason why these  HLA genes increase the possibility that someone will develop the autoimmune disease pemphigus is very interesting. The scenario goes like this:

• In autoimmune diseases, antibodies are made against antigens or proteins that are part of the person, so called self-antigens. In pemphigus vulgaris the autoantibodies are against desmoglein 3 which is a protein that makes up structures that hold skin cells and mucous membrane cells together. In pemphigus foliaceus the autoantibodies are against desmoglein 1 which also helps hold skin cells together though in a different layer of the skin than desmoglein 3. Desmoglein 1 and 3 are proteins made of amino acids which are linked together in a chain which in real life fold together into complex shapes. When the desmoglein molecules are attacked by autoantibodies they are not able to function and skin cells pull apart and form blisters.
   
• HLA genes control special proteins on the surface of cells that act as receptors which present antigen to white blood cells as part of the immune response of our bodies. Within these receptors are groves or pockets (think of a lock) into which will fit bits or parts of a protein (think of a key). These small pieces of protein are also called epitopes. When the “lock” is filled with an appropriate “key”  this cell-antigen or cell-epitope complex can then link up with a T cell and aided by some other signaling chemicals start the immune response that leads to antibodies formation against the epitope or the “key” that fits this unique “lock”.
   
• Researchers have been able to look at the HLA grooves relevant to pemphigus and have been able to figure out that parts of the desmoglein protein molecule fit into them. Different HLA markers have different “locks” on them and thus react to different pieces of the protein. In other words, the shape of the grove on certain HLA receptors fit pieces of the desmoglein molecule which sometimes leads to the formation of antibodies against desmoglein causing pemphigus in some people.

    In the case of the Peptimmune clinical trial only people with the HLA DRB1*0402 gene are being involved in the study.  This is because the treatment is based on this gene and its corresponding receptor which would not necessarily work for others with pemphigus and a different gene. The treatment involves using a piece of the desmoglein 3 protein i.e. the immunodominant epitope that fits into these groves in an effort to alter the immune response. This very specific treatment it is hoped will turn off autoantibody production which in turn would help control pemphigus without affecting the rest of the immune system like all of the present treatments for the disease do.

    So in summary we all inherit HLA genes from our parents and some of them have been found to be associated with pemphigus, an autoimmune disease. However not everyone one with these genes goes on to have disease. Something has to trigger the body into making autoantibodies. Therefore even if we pass these genes to our children, it is very unlikely they will also develop the same disease. Also by studying these predisposing HLA genes doctors may be able to devise medications which will stop the production of autoantibodies that cause pemphigus.