Thursday, September 23, 2010

3.7 The HLA System - Predictor of Disease

Physician's Notebooks 3 - - See Homepage
Update 04 August 2020
Chapter 7. Human Lymphocyte Antigen Testing
The following descending column gives, in order of appearance, the main headings and is useful for readers using search & find or scrolling down.
The Lymphocyte
The ABO Blood Group
Human Lymphocyte Antigen
Self Recognition and Cancer Surveillance
HLA Testing and Infectious Disease
HLA Typing and Inflammation
HLA Testing and Disease Association
How is HLA Being Used and What is its Future?

The Lymphocyte (lymphos) is a White Blood Cell whose good-health actions ward off infection, limit development of cancer, and protect body cell from self destruction as happens in autoimmune disease like rheumatoid arthritis. Lymphos migrate through the body. Types are “natural killer cell” (because programmed to kill cell seen as foreign), “T-cell” (from Thymus gland) that targets germs, and “B cell”, which produces antibody to neutralize foreign chemicals, and phagocytes to eat up foreign material.

Antigen is a protein that your immune system treats as foreign and produces defensive antibody against. Lymphocyte response to foreign antigen (too much or too little response) or response against its own body tissue, or self-antigen (effective or defective antigen structure) is influenced by each person’s inheritance.
   An antigen may be part of foreign invading germ or a toxic substance; or come from another individual (blood transfusion, fetal cell into maternal blood) your T-cells recognize as not part of self. Or it may be some of your own protein that has gotten to be like a foreign protein to your immune system (self antigen in autoimmune disease).

The ABO Blood Group Antigens. Understanding the ABO gene on chromosome-9 and its translation to the ABO red blood cell (RBC) surface antigens helps to understand the HLA. All Red Blood Cells have on their outer membranes an ABO system antigen A or an antigen B, or a combination of A and B, or no antigen at all, giving the 4 ABO blood types – A, B, AB, or O.
   Each one of the pair of human chromosome-9 has one of the ABO genes. Possible ABO gene combinations of the chromosome-9 pair are AA, AO, BB, BO, AB and OO. Since one gene produces enough A or B antigen to show the effect on the RBC surface, a person with AA or AO on the chromosome-9 pair is blood type A, and a person with BB or BO is type B, and one with the A and B gene pair (the chromo 9 from Mother has A and the chromo 9 from Father, B) is type AB (expresses both A and B antigen on each RBC); and the others with defective ABO gene at each chromosome-9 locus of a pair are blood type O. (No ABO antigen on RBC surface)
   When a protein is expressed on any cell before birth, it is not recognized by your immune system as an antigen. But after birth, each ABO blood type person develops antibodies to the ABO antigen he or she was not born with. (Because these ABO antigens are in our natural environment) Thus a blood type A person develops antibody against B antigen, a blood type B person develops antibody against A antigen, and blood type O person develops antibodies against both antigens A and B. But a blood type AB person does not develop antibodies to the ABO system because he or she, as fetus, has coded A and B protein molecules as part of self.
   Early-on, associations between different ABO blood types and certain diseases were noted. But ABO antigens are too few and do not seem to serve any purpose, so whatever connection they may have with disease or good health appears due to chromosome location coincidence.

Human Lymphocyte Antigen first came to research attention in the 1950s in blood banks in pregnant women’s transfusion reactions that on testing proved not to be due to the usual RBC antigen-antibody. Instead, the WBC lymphocytes from a pregnant woman’s fetus were crossing the placenta into the mother’s blood and the antigens on the lymphocytes were making the mother produce destructive antibodies.
   The HLA system starts with genes that are encoded along a segment of chromosome-6. One each of your HLA system proteins are inherited from each one of the Chromo-6 gene pair. These protein molecules attach to surface of each lymphocyte and can be detected as antigens by cells of the immune system of individuals other than one’s self or one's identical twin. The HLA system is tested on lymphocytes. Like in the ABO system, you do not form antibody to your own HLA because your lymphos exhibited the antigens before birth. But there are important differences.

There is much individual variation in HLA. Recall that in ABO there are only 3 same-locus genes (A, B or C) and 4 RBC blood types (A, B, AB or O). In the HLA system there are thousands of genes and each individual has a unique set of surface proteins on all his lymphos. (Most persons share some but no one, except identical twins have exactly the same set) These proteins are closely related in structure but have key differences in amino acids. As implied by identical twins sameness of HLA, the closer the DNA relationship of individuals the more alike each one’s HLA surface proteins are to the other’s.

   Another difference is that, in contrast to the ABO system, which is only on the red blood cells, every cell in your body carries the same set of HLA proteins so that, in a cross-match, a close match of HLA proteins between donor and recipient is required before organ transplant.
   A third difference is that the HLA system serves an important immunity function that when working well assures healthy longevity but when not, puts one at risk for illness and premature death.

Self Recognition and Cancer Surveillance. The HLA system contains a wide-array of proteins that - though having basic similarity - differ in molecular structure. One type of HLA protein, Class I, is found on the surface of every cell from birth, and its presence gives a signal that on contact tells the cells of immune system, “I am one of you, a normal healthy cell.” This message is especially important to Natural Killer (NK) cells. It is a message Not to be killed. But when a cell is becoming cancerous; early on, it mutates a Class I HLA protein that alerts the NK cell to kill it. Immune surveillance explains the connection between possession of an HLA gene and increased risk of (or protection from) cancer.

HLA Testing and Infectious DiseaseThe immune system response to invading germ is central to preventing and curing infection. When immunity becomes disabled, infections increase and become deadly. One's HLA type correlates with risk of getting (and dying from) infection. For example, rapid progression of HIV/AIDS kills persons with Class I HLA B*3502/3503/3504 gene variants faster than those without. These HLA variants differ from variants that do not affect the course of AIDS by replacing a single amino acid in protein they encode for. To note: HLA typing can warn of high risk for particular infection; and, more importantly, amino acid analysis of the proteins involved may explain how HIV attacks the immune system. And from that might come a cure or prevention for AIDS.

HLA Typing and Inflammation; Its Affect on Disease:  The immune system works by recognizing a foreign protein, latching onto cells expressing it and then destroying the foreign protein and its cell by attacking them with T cells or neutralizing their toxic chemicals. This results in the inflammation we see and feel as swelling, pain and redness. So one’s genetic HLA type can influence inflammation and its diseases. Example is an experiment with type 1 diabetes mellitus. The DM-1 is caused by early infection and auto-immune reaction in the pancreas leading to inflammation destruction of the cells that make insulin; and the no insulin bring on diabetes. Several studies are in progress in families where a not-as-yet diabetic identical twin of a patient with diabetes is being closely monitored for immunologic signs of pancreatic insulin-producing cell-destruction inflammation, which may occur years before showing diabetes. The idea is that patients who develop DM-1 will have HLA genes that mutated to increase antigen-antibody inflammation against the pancreas's insulin producing cells. Having the altered HLA gene sets up a situation whereby the person possessing the mutated gene is at higher risk to develop stronger antigen-antibody reaction and inflammation destruction of pancreas cells causing  higher risk of diabetes. Presumably such patients got a virus infection, and it ticked off the destruction of the pancreas cells, perhaps repeatedly. And when enough cells are killed, then diabetes develops. In the diabetic with an HLA identical twin who has not developed diabetes, the knowledge of HLA type might allow treatment with anti-viral and/or immune suppressive or anti-inflammation agents to head off the diabetes.
HLA Testing and Disease Association. Disease association with HLA is what first made for HLA testing. What has given HLA testing its practical interest is the tremendous polymorphism (the physical variations) of HLA genes, the availability of HLA gene testing, and the known relationship of HLA to the immune system. To give further example of disease associations, those individuals found to have HLA-DQA1*0501 and –DQB1*0201 gene variants have a 500 times risk of developing celiac disease (chronic diarrhea from allergy to gluten in wheat). Here one can see the usefulness of HLA testing, since if you find such high-risk gene-variants in individuals who have not yet developed celiac disease, they can be warned to avoid gluten products from diet and thus avoid a terrible affliction.

Not only has HLA testing shown relationships of HLA gene types to high risk for disease, it has also shown that certain HLA types appear to protect against developing a disease. Best known example is HLA-DG6 and type-1 diabetes. Individuals with this gene variant are 50 times less likely to develop diabetes than ones who carry the normal HLA at that locus.

 HLA genes associated with high risk of disease do not cause the disease. What such genes set up is a predisposition to develop the disease in face of a key environmental event. For example, individuals with HLA-DQA1*0501 will only develop celiac disease if they eat a diet high in gluten; ones with HLA-DR3 will only develop diabetes if they have repeated viral infections targeting the pancreas. Most with such high-risk genes do not develop the disease they are at risk for, so HLA gene testing is not very useful in making a diagnosis. But it is also useful in pinpointing high risk person to known risk factor.

How is HLA Being Used and What is its Future?  HLA testing is on the cutting edge of testing technology. It is available but must be requested and is usually done in a special lab at University. How is it used?

1. With a difficult diagnosis in a negative way. Say, you complain of  sleepiness and are labeled, "narcolepsy"? Not being an HLA-DQ6 rules out the narcolepsy diagnosis.

2. Used by couples planning baby making? Take the case of high association between a particular HLA and risk of schizophrenia? Potential parents might decide against parenthood if they discovered they carried an HLA marker for strong risk of schizophrenia.

3. Preventive health HLA testing as in the type-1 diabetes case. If HLA has high risk for particular disease, preventive measure can be taken.

4. HLA gets to disease causation. Learning from HLA research that replacement of a single amino acid in an HLA type causes a greater susceptibility or resistance to a particular disease is getting closer to understanding it.

5. Finally, HLA typing for compatibility testing for organ transplant.

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