Disorders Associated With The Immune System |
|||
|
19. Define major histocompatibility complex. 20. Explain how tissue typing is done. 21. List the types of self-antigens. 22. Define privileged sites. 23. List and describe the types of transplants. 24. Describe the problems encountered with transplants and how we deal with them. 25. Define immunosuppression. |
Histocompatibility Antigens
We've already talked about HLA molecules, antigen presentation, and lymphocyte activation in the context of immune system response to foreign antigens and self-tolerance. Now let me tell you something else about those HLAs.
Class I HLAs are coded for by three different genes, Class I A, Class I B, and Class I C. The genes are polymorphic - there are over 100 different alleles identified for each of the Class I genes.
Class II HLAs are coded for by three different genes as well, the DR, DP, and DQ genes. They aren't quite as polymorphic but there are different alleles for each Class II gene, so it's possible that a person has two different alleles (one maternal and one paternal) for each HLA gene. That's 12 different HLA molecules presenting antigen to T-cells.
We just talked about autoimmunity and the loss of self-tolerance. How does that happen?
The thing to remember is that the interaction between an antigen receptor and the antigen it is supposed to recognize is shape driven.
The antigen binding site of an antibody has a complementary shape to the antigen it recognizes.
There are cases where antibodies cross-react with other proteins. When antibodies cross-react with self proteins we get an autoimmune condition.
The T-cell receptor recognizes the shape of the HLA-antigen complex, so stimulation of a T-cell is dependent on a shape that is formed by both the HLA molecule and the peptide that is bound in the HLA molecule's peptide binding site.
There are cases where the shape of an HLA molecule presenting a specific foreign antigen to the subset of T-cells that recognize that antigen is very similar to the shape of the same HLA molecule (or an HLA molecule coded for by a different allele) presenting certain self-peptides to that same subset of T-cells, .
Example: A child is infected with a virus (measles virus, rubella virus, mumps virus, and coxsackie virus have all been followed by the appearance of type I diabetes).
The viral peptide is presented to helper T-cells, cytotoxic T-cells, and B-cells, activating them to clear the viral infection.
Suppose the child's HLA type is such that the shape of the HLA-viral peptide is similar to the shape of an HLA-pancreatic beta cell derived normal peptide.
When the activated T-cells and antibodies produced from the viral infection encounter the HLA-peptide complex on the surface of an uninfected pancreatic beta cell they no longer "see" it as "self".
Instead, they "see" it as a virally infected cell, and attack, destroying the beta cells and eliminating insulin production.
If the HLA molecule itself is foreign (from a transplant donor) it will be recognized as foreign and attacked by CTLs.
Tissue Typing for Transplantation
Tissue typing to prevent transplant rejection includes both HLA and ABO matching.
Traditionally this was done serologically by taking lymphocytes from a patient and incubating them with selected specific antiserua. Complement and dye (trypan blue) were then added. If antibodies reacted specifically with the lymphocyte the cell would be damaged and take up the dye.
Serological Tissue Typing
Because of the high number of transplant rejections with tissues that were apparantly matched it was realized that serology isn't specific enough to guarantee a match. Tissue typing today, especially for bone marrow transplantation, is done by sequencing HLA genes of the donor and the recipient.
Graft rejection – tissue is recognized as foreign and may be attacked by cytotoxic T cells, macrophages, and antibodies .
Transplantation into a privileged site or with privileged tissue doesn’t cause rejection.
Privileged tissues are tissues that can be transplanted without stimulating the immune system and causing rejection. An example is pig heart valves that can be transplanted into the human heart without rejection.
Privileged sites are locations such as the cornea that allow for transportation without tissue matching. In this case it is because blood vessels do not normally grow into the cornea, thus the immune system cells to do reach the transplanted tissues. The brain is also a privileged site because of the blood-brain barrier that prevents immune system cells from entering.
Pluripotent stem cells may differentiate into a variety of tissues that made be used for transplantation (like bone marrow).
Types of transplants include:
Bone marrow transplants can cause graft-versus-host disease - a bone marrow transplant is basically an immune system transplant into a patient whose immune system failed. These patients are pre-conditioned to kill all of their leukocytes to kill any cancerous cells and to prevent graft rejection. If the transplanted bone marrow contains cells that don't recognize the recipient's HLAs as self they will attack the recipient's tissues.
Immunosuppressive drugs are often required to prevent rejection but then put the patient at risk for any number of opportunistic infections.
Drugs used for immunosuppression include: