All foreign antigens are recognized by the cells via specific receptors, called the major histocompatibility complex. These MHC molecules encompass a wide diversity in structure and actions. What follows is a review of the MHC molecules and their interactions with an antigen.


Image: “T lymphocytes within myocardium.” by Cannons Law Firm, Glasgow, UK - Cannons Law Firm acting on behalf of the Westgate Research Team, also distributed as handout at press conference in Berlin, Germany on 2015-07-15. License: CC BY 4.0


Overview

Whenever a foreign organism invades the body, our immune system is alerted to its presence. This is due to the presence of small glycoprotein antigens on the surface of these foreign organisms that the body identifies as foreign.

Every cell has antigens on their surface; the body can differentiate between the different self- and non-self-antigens because of the selection process during birth and in early years of life. Initially, due to great diversity of DNA splicing and recombination, every possible combination of nuclear material for the antigens is created.

This results in formation of lymphocytes complimentary to every possible antigen, even those of the fetus itself. Our lymphocytes are then matured and T cells are carried to thymus while B cells are sent to bone marrow for further processing.

In these locations, respective lymphocytes are exposed to every antigen in the fetus’ body. Whichever lymphocyte reacts, it is killed on the spot. So, normally, a human being does not have those lymphocytes that correspond to the self-antigens.

Now, only those lymphocytes are present that will essentially attack foreign antigens. However, these are stored in numerous peripheral and central lymph node organs. An antigen needs to be transported to them for activation.

To perceive and battle the extensive variety of pathogens that an individual will experience, lymphocytes of the adaptive immune system have developed to identify an incredible assortment of various antigens from micro-organisms, infections, and others.

Recognition of Antigens

Antigen-identifying parts of B cells are the immunoglobulins (Ig). These proteins are created by B cells in an array of antigen specificities, every B cell delivering immunoglobulin of a single specificity. Some of these are bound to the B-cell surface and serve as the cell’s receptor for antigen and are known as the B-cell receptor (BCR).

The immunoglobulin of similar antigen specificity is emitted as an immune response by mature B cells, the plasma cells. The discharge of antibodies, which bind pathogens in extracellular spaces of the body is the fundamental effector capacity of B cells.

T cells, on the other hand, have antigen recognizing proteins on their cell membrane. These are called TCR (T cell receptor) and bear an enormous similarity to antibodies of B cells. They even have both the V and C regions and are produced by a process of variability not very different from that of B cells, as mentioned above.

However, there is one difference that T cells do not recognize antigens like B cells do. On the contrary, T cells need their antigens to be presented as short peptides, bound to special Major Histocompatibility Complex (MHC) molecules. Only then will the antigens be effective and will be able to activate the T cells.

antigen processing and presentation

Image: “Antigen processing and presentation.” by OpenStax College – Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. License: CC BY 3.0

These antigens are presented to the T cells via specific molecules which are present on the antigen presenting cells. The protein antigens are presented by the MHC molecules but the lipid antigens are presented by the CD1 molecules. These are explained in more detail below.

MHC molecules are coded by a specific segment of the DNA. Another thing is that T cells only respond to processed antigens which are short amino acid sequences called peptides i.e. only those antigens that have been broken down into peptides will be effective in eliciting a response. This is called antigen processing.

It all begins with the invasion of foreign organisms. These are ingested by the antigen presenting cells. Antigen presenting cells are of 3 types, but the majority of them include dendritic cells.

Once organisms are phagocytosed, they form an endosome which is fused with lysosomes that contain enzymes to kill and digest the organisms. Antigens are, however, conserved.

These antigens are taken to endoplasmic reticulum where they are processed to form small peptides. These peptides are then combined with MHC molecules and expressed on surfaces and are thus capable of activating T cells by attaching to relevant T cell molecule with complimentary TCR.

Types of MHC Molecules

The capacity of MHC molecules is to bind and express antigen peptides derived from pathogens, on surface so that they are acknowledged by the appropriate T cells. The outcomes are quite often injurious to pathogen, with common sequelae of infected cells being killed.

Macrophages are stimulated to eliminate micro-organisms living in their intracellular vesicles and B cells are stimulated to deliver antibodies that take out or kill extracellular pathogens. In this way, there are huge grounds for proliferation of any pathogen that has changed in a manner that it escapes presentation by an MHC molecule.

There are two major classes of MHC molecules, each with their own specificities and functions. They both consist of two a and b chains from different sources. MHC class I molecules consist of a heavy chain spanning the membrane, which is coded by MHC genes, while b chain is a light chain and is produced by b2-microglobulin gene. MHC class II molecules contain 2 chains which both span the membrane and are both coded for by MHC genes.

Both MHC molecules consist of a groove which binds the peptides, forming a complex, enabling them to be presented to T cells. The groove has a special name known as peptide-binding groove.

These molecules are also major determinants of success of transplants. This is because transplant cells can act just like regular cells and stimulate an adaptive immune response. These complexes are also often called the HLA complex or human leukocyte complex in the context of tissue matching.

MHC class I molecules are present on all nucleated cells of body. They present those antigens that are present in cytoplasm of cells. These can include foreign proteins, self-proteins, viral proteins and so on.

Once MHC class I molecules complex with antigenic peptides to be displayed on cell surface, they mainly activate cytotoxic T lymphocytes. Killer T cells can then identify the potentially toxic cell and kill it. MHC molecules are basically part of the HLA antigen group. Those HLA antigens that correspond to MHC class I molecules include HLA-A, B, C.

MHC class II molecules are only present on antigen presenting cells. These include dendritic cells, macrophages, and B lymphocytes. These molecules are responsible for presenting antigens that are present extracellularly. This is done by phagocytosing the potentially harmful organism, degrading it, processing the antigen and then presenting it to T cells.

Once these molecules complex with antigens and are displayed on surface of antigen presenting cells, they activate T helper cells. As mentioned, HLA antigens are the MHC molecules. Those HLA antigens that correspond to MHC class II molecules include HLA-DP, DQ, DR, DM, DOA and DOB.

The coding for different MHC proteins is by MHC gene, which is located on chromosome 6. Initial part of the locus codes for MHC protein class II and latter part codes for MHC protein class I.

Polymorphism of MHC Molecules

Two separate properties of MHC make it impossible for pathogens to avoid it. To start with, MHC is polygenic: it contains a few distinctive MHC class I and MHC class II qualities so that each person has an arrangement of MHC molecules that have varying specificities for different peptides.

t cell activation

Image: “The T lymphocyte activation pathway is triggered when a T cell encounters its cognate antigen, coupled to a MHC molecule, on the surface of an infected cell or a phagocyte.” Derivative work by Hazmat2. License: Public Domain

Second, MHC is profoundly polymorphic; i.e. there are multiple variants of every gene, giving rise to a magnificent diversity within the population. MHC qualities are, indeed, the most polymorphic qualities known.

TCR

Once the antigens are presented on the surface of the cells, bound to the MHC molecules, they need to activate the T cells as well. To ensure the attachment and action of these antigens, the T cells possess TCR. These receptors are specific for specific antigens and bind the antigen attached to the MHC molecules, stabilizing it. This allows the second messenger systems to come into play, which activates the T cells.

Two Pathways of Antigen Processing

The process of antigen processing occurs in two distinct ways. Obviously, as there are two distinct types of antigens being processed, their processes must be different also. Here we describe the two pathways separately.

The endogenous pathway

This pathway is used for the MHC class I molecules which are associated with all the endogenous antigens. The process starts with ubiquitination of the endogenous antigens which marks them for degradation by the proteasomes.

The proteasomes function to break these antigenic proteins into small peptides about 8-9 amino acids long, which are in turn transported with the TAP into the endoplasmic reticulum.

At the same time, chaperone proteins within the rough endoplasmic reticulum help facilitate the proper folding of the MHC class I molecules and β2 microglobulin. These partially folded MHC class I molecules are then associated with TAP via another protein called tapasin. The molecules complex together and are then secreted from the cell by the Golgi apparatus, to be displayed on the cell surface.

The exogenous pathway

This pathway is for the MHC class II molecules and is used by the antigen presenting cells. Initially, the proteins are phagocytosed and broken down by proteases in endosomes to peptides that are about 15 amino acids long.

In the rough endoplasmic reticulum, the naïve MHC class II molecules are prevented from binding any endogenous protein by forming a complex with Ii which is the invariant chain.

This is then combined with the endosome containing the antigen peptides. The invariant chain is broken down, and as it leaves the MHC class II molecules, only a small part called CLIP remains attached to the peptide binding groove.

Then, another protein called the HLA-DM removes CLIP and allows the chain to start attaching to the peptides. These complexed MHC class II molecules are then moved to the cell surface for antigen presentation.

Cross-presentation

There is no clear differentiation between the endogenous and the exogenous pathway. In this process, peptides derived exogenously are presented via the MHC class I molecules. The cell begins the process by exogenous pathway but ends up diverting the antigens to the endogenous pathway, allowing the cell to skip some of the parts of the exogenous pathway.

As the exogenous pathway can involve infection before presenting the antigens, the cross-presentation allows the dendritic cells to process and present antigens without being infected.

This allows the antigens to stimulate different T cells, the endogenous antigens stimulating the helper T cells via class II molecules and the exogenous ones cross stimulating the cytotoxic T cells via the class I molecules. However, not every antigen presenting cell can utilize the ability to cross-present.

Presentation of Lipid Antigens by CD 1

Aside from the proteinaceous antigens, some cells also possess lipid antigens. These cannot be presented via the MHC molecules. For these antigens, the body has CD 1 molecules.

These molecules are a non-polymorphic family of glycoproteins that are capable of presenting lipid antigens to T cells. The molecules have a unique binding structure that allows them to bind to and present a wide variety of lipid antigens.

The process starts by phagocytosis of the antigen into the cell and action of lipases, which degrade them into the smallest piece. The CD 1 molecule is present in the endoplasmic reticulum. The small pieces of lipid antigens are mixed and complexed with the CD 1 molecules which are then exocytosed to the cell surface. There they present their antigens to the T cells and the natural killer cells.

In short, the body has the capability of expressing both lipid and protein antigens. Our immune system is equipped to fight every foreign invader with complex and intricate processes that are nothing short of a miracle.

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