Major Histocompatibility Complex (MHC) Functions
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Published: Thu, 17 May 2018
The immune system is complex, containing thousands of components. On the whole this highly adaptive system works well, protecting the individual primarily against the threat of disease caused by infectious organisms (Wood, 2006). However, the immune system can deteriorate and fail should any component of this refined system be mutated or compromised.
In this report, an overview of the immune system will be covered, along with an explanation of how the Major Histocompatibility Complex (MHC) functions specifically. An example of how the immune system can be compromised should the MHC molecule be short or absent will also be discussed with reference to a condition known as Bare Lymphocyte Syndrome. How the MHC molecule contributes to a healthy immune system will be discussed, along with the effect an MHC deficiency has and how this compromises the immune system at a molecular level. Reference will be made to a case study related to the Bare Lymphocyte Syndrome and a conclusion will be made as to how this condition links to the MHC molecule specifically.
An Overview of the Immune System
The immune system can be split into two systems of immunity, innate and adaptive immunity. Innate immunity is the first line of defence against pathogens in the body, preventing most infections occurring by eliminating the pathogen within hours of being encountered. This is achieved by firstly possessing external barriers to infections such as skin, mucosa, gut flora and lysozymes in tears. Secondly, the immune system mounts an immediate attack against any infectious sources entering the host via pre-existing defence mechanisms within the body. Phagocytosis is the major element contributing to innate immunity. This is the ingestion and destruction of microbes by phagocytes in a process by which the phagocyte attaches to the microbe in question, engulfs the microbe, kills the microbe and then degrades the microbe using proteolytic enzymes (Wood, 2006). This process is aided by complement proteins and opsonisation. Another part of the innate immune response is for inflammation to occur. This enables cells and soluble factors from the bloodstream to be enlisted at a particular tissue site in order to assist in the fight against infection. These can be local or systemic and cause vasodilation to occur at the site of infection; cause the endothelium to have increased expression of adhesion molecules in the cells lining the blood vessels; cause increased vascular permeability and cause chemotactic factors to be produced, therefore attracting cells into the tissue from the bloodstream (Wood, 2006). Overall, innate immunity is the first step in combating infection in the body; however a more specific system is often required.
Acquired immunity occurs when a pathogen enters the body which the innate immune system cannot destroy, whether it is the pathogen has evolved a way of being avoided by the cells in the innate immune system or whether it be the pathogen expresses molecules similar to host cells as in the case of viruses. In such cases as these, acquired immunity is needed, where lymphocytes are used to identify, engulf and kill the pathogen in question. This is a more evolutionary advanced system compared to innate immunity. Two types of lymphocyte cells are employed in the acquired immune response; these are B lymphocyte cells, which are responsible for creating antibodies; and T lymphocyte cells, which are more complex in their receptor and require cell-to-cell contact. There are two types of T lymphocyte cells; those expressing CD4 molecules on their surface are referred to as Helper T cells or CD4 T cells, and those expressing CD8 molecules of their surface are referred to as cytotoxic T cells or CD8 T cells. The latter of these two T cells is important in the killing of virally infected cells (Kindt et. al., 2007). T cells recognise antigens by T cell Receptors (TcR) expressed on their surface; each T cell expresses only one TcR specifically. T cells do not recognise free antigens but recognise antigens associated with molecules on the surface of cells called Major Histocompatibility Complex (MHC) molecules (Wood, 2006). MHC molecules specifically for the human species are known as Human Leukocyte Antigens (HLA); these are located on chromosome 6 (Kindt et, al., 2007). The MHC constitutes important genetic components of the mammalian immune system. There are two types of MHC molecules, Class I and Class II MHC. Class I MHC molecules are glycoproteins expressed on the cell surface of most nucleated cells, whereas Class II MHC molecules are also glycoproteins but are restricted in their expression, primarily being found on cells of the immune system such as B cells, macrophages, dendritic cells and monocytes (Wood, 2006). Class I and II MHC molecules bind to antigens derived from pathogens and present them to T lymphocytes (Sommer, 2005). CD8 T cells recognise antigens presented by Class I MHC molecules whereas CD4 T cells recognise antigens presented by Class II MHC molecules. MHC molecules play an important role in immune defence against intracellular pathogens, peptides derived from viral proteins and cancer infected cells. (Sommer, 2005).
Antigen Presentation of MHC Class I
An event involving generation of peptides from proteins in the cell and displaying these peptides on the plasma membrane is called antigen processing and presentation (Benjamini et al., 1996). MHC Class I molecules consists of HLA-A, HLA-B and HLA-C. HLA are cell surface heterodimers consisting of a polymorphic α chain associated with a non-polymorphic β2 microglobulin protein (Chaplin, 2010). In the antigen presentation pathway of MHC Class I, the viral protein is degraded into peptides through proteasome-mediated proteolysis which is then transported into the endoplasmic reticulum (ER) (fig 1). This transport process is facilitated by a transporter associated with antigen processing (TAP). Once in the ER, the translocated peptide binds to MHC Class I α chains and β2 microglobulin through momentary interaction of MHC Class I heterodimers and TAP (Chaplin, 2010). This momentary interaction is carried out with the help of Tapasin (fig 2). This binding of peptide and MHC Class I results in structural changes; eventually leading to the dissociation of peptide-MHC Class I complex (Chaplin, 2010). This peptide-MHC Class I complex then migrates to the cell surface where it is recognised by CD8 T cells triggering the associated immune response. (Raghavan,1999).
When the immune system is working correctly, pathogens entering the body will be destroyed rapidly. However, if a component of the immune system is compromised, devastating effects can be seen. An example of this was seen in the case study of Tatiana and Alexander Islayev; two siblings originally from Russia who were suffering from symptoms linked to Bare Lymphocyte Syndrome. Tatiana had severe bronchiectasis and a persistent cough which produced yellow-green sputum. She had been chronically ill since the age of 4 when she had begun to have repeated infections of the sinuses, middle ear and lungs, all due to a variety of respiratory viruses. Both Haemophilus influenza and Streptococcus pneumonia bacteria could be cultured from her sputum. She had been prescribed frequent antibiotic treatments to control her fevers and cough with no success. Her brother, Alexander was also showing the same symptoms. When their blood was examined, both children had elevated IgG levels with over 90% of their T cells being CD4 and only 10% being CD8. Both children expressed very small amounts of MHC Class I molecules in their cells but expressed MHC Class II molecules normally. When the children’s DNA was analysed, it was found that they both had a mutation in the TAP-2 gene.
Type I Bare Lymphocyte Syndrome
Bare Lymphocyte Syndrome (BLS) Type I also known as MHC Class I deficiency, is characterized by a severe down-regulation of MHC class I and/or class II molecules (Gadola et. al., 2000). Type 1 BLS is due to a defect confined to MHC class I molecules, while type 2 BLS shows down-regulation of MHC class II molecules. Like any other cell surface protein MHC class I molecules are synthesised in the rough endoplasmic reticulum (RER), modified in the Golgi apparatus and are transported in transport vesicles to the cell surface (Wood, 2006). MHC class I molecules bind to different sets of peptides. Translocation of peptides derived from degradation of cytosolic proteins from the cytoplasm into the RER is negotiated by transporter molecules known as transporter associated with antigen processing (TAP) molecules. TAP is a heterodimer consisting of two subunits, TAP-1 and TAP-2, which are encoded in the class II region of the MHC locus on chromosome 6. Deletion or mutation of either or both TAP-1 and TAP-2 proteins severely impairs the translocation of peptides into the RER, the result of which is reduced surface expression of MHC class I molecules (Gadola et. al., 2000). BLS is manifested as a combined immunodeficiency presenting early in life. BLS manifests during the first 6 years of life where affected individuals are susceptible to recurrent opportunistic bacterial infections especially of the upper respiratory tract. In BLS, the underlying cause of Class I deficiency is due to a nonsense mutation in the TAP (Clement et. al., 1988).
As discussed earlier, TAP is involved in the critical step of transporting peptides to the inner lumen of ER. In BLS, the deficiencies of active TAP results in the impairment of the transport of peptide to ER. This inefficient transport means that few or no MHC Class I molecules can be complexed with peptides. The un-complexed MHC Class I molecules are highly unstable and are therefore degraded quickly. This ultimately results in low levels of peptide-MHC Class I complex being expressed on the plasma membrane. In this way, deficiency in active TAP leads to low antigen presentation via MHC Class I molecules resulting in inefficient activation of CD8 T lymphocytes and consequently a compromised immune response.
The basis of bare lymphocyte syndrome can be concluded from protein coded genes that are transformed and are not able to control the expression of the MHC I genes. Till today a beneficial treatment of TAP deficiency is not yet available; gene therapy isn’t possible as almost all of the HLA class I molecule express on nucleated cells. If there is damage to the bronchial and pulmonary tissue lung transplantation can be performed. Contact with tobacco and smoke should be avoided and also vaccinations should be performed against respiratory pathogens. Other than Bare lymphocyte syndrome, MHC class I allotype is also linked to various sero-negative spondarthropathies, such as Ankylosing spondylitis, Psoriatic Arthritis, Reiter’s Syndrome and Behcet’s syndrome.
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