Often the new in medicine is based on the theory of genetics and immunology. Have we not forgotten it, at least in general terms? If in doubt, make yourself comfortable and let's reminisce.

One of the pillars of the immune system is its ability to recognize "own" and "foreign".

In this case, the task is not only to recognize and capture the stranger, but also to call for help from other memebers of immune team.

If a foreign antigen (AG) is already familiar to the immune system, it can be bound by the corresponding antibodies produced by B-cells. This requires nothing more than a specific key-locked match between antigen and antibody (AT).

The task is more difficult for immune cells that specialize in recognizing antigens, including those that the body encounters for the first time. T-lymphocytes have to recognize their molecules in the full sense of the word blindly by feel and interact with each other, delegating duties to different subtypes of immune relatives.

A central role in the interactions of the major T cell subpopulations is played by "major histocompatibility complex restriction".

If we move away from the complicated but memorable translation from English, we can also say this: these T-cells distinguish antigens only when they are simultaneously presented together with molecules synthesized on the basis of their own genes of the major histocompatibility complex (MHC). In humans, they are called HLA (Human Leukocyte Antigen) genes

What does "histo" mean?

"Histo" means "tissue" in Greek. Proteins made by these genes were first seen in tissue rejection during transplantation due to incompatibility. Later, details were discovered about how MHC genes make molecules that help lymphocytes mount an immune response.

The MHC genes are located on the short arm of chromosome 6 and are closely related.

They are devided into three classes:

• MHC class I genes
• MHC class II genes
• MHC class III genes

This classification is of practical importance. Molecules synthesized from genes in the same class are very similar in structure, function, and distribution in tissues. In humans, they are called human leukocyte antigens (HLA antigens). This is not quite correct because these glycoproteins are found not only on the surface of leukocytes.

HLA antigens are associated with organ transplant rejection and predisposition to autoimmune diseases.

MHC class III genes are located between the close families of MHC II genes and MHC I genes. They carry information about molecules of the complement system and TNF. This is not relevant to the AG presentation, so let's move on to the other groups.

The figure above shows the conditional inheritance pattern of the MHC genes. Keep in mind that the MHC I genes encode only one peptide chain, the alpha chain, while the MHC II genes encode two chains.  
α chains genes: DPA, DQA и DRA и β chain genes: DPB, DQB, DRB

• MHC-I : HLA-A, HLA-B и HLA-C isotops.
• MHC-II : HLA-DP, HLA-DQ и HLA-DR isotops.

The alleles of the MHC genes are codominant, i.e. they are expressed (manifested phenotypically) regardless of whether they are dominant or recessive. HLA genes are grouped into clusters called haplotypes. A person inherits one from each parent. Siblings have a 25% chance of having identical HLA antigens. Such an assessment can be useful not only in transplantology, but also in assessing the risk of developing certain autoimmune diseases in siblings.

Carrying HLA-DQ2 and HLA-DQ8 is associated with the risk of developing celiac disease. HLA-DR3 and HLA-DR4 - type 1 diabetes mellitus. The risk increases even more if you get both variants. An example of the association between HLA-B27 carriers and the risk of developing ankylosing spondyloarthritis is probably well known to everyone, as this association was noticed in 1973.

The MHC isotypes have a high degree of polymorphism (diversity of gene variants).

Why do we need this diversity?

The rich repertoire of MHC molecules makes it possible to distinguish between multiple intrinsic antigens, and hopefully some variant will prove useful when exposed to a previously unknown foreign AG. This will help to activate the formation and training of other immune cells capable of responding to the novel antigen.

Triggering antigen recognition by a T lymphocyte requires not only the presentation of the former by an MHC molecule, but also an optimal match between the three-dimensional structure of the antigen and the surface of the MHC molecule, which forms a bed for it with "pockets" in which the antigen should fit and anchor. This may also affect the strength of the response.

For example, it has been observed in a European population that the presence of asparagic acid at position 57 of the b-chain of the HLA-DQ protein, located on the inner surface of the AG "bed", may reduce the risk of developing type 1 diabetes (DQ2, DQ8), while its replacement by another amino acid increases the risk (DQ6). It is possible that asparagic acid carries a negative charge, while its substituents carry a neutral charge. In the latter case, the contact between the autoantigen and the T lymphocyte may be stronger and/or longer, allowing the T lymphocyte to recognize the autoantigen as foreign. No association with the presence of asparagic acid was observed in the Japanese population. However, the factor of spatial organization of the antigens and T lymphocyte receptor deserves further study.

Before the "umbrella" of the AG complex with the MHC molecule appears on the membrane surface, the initially large AG undergoes recycling.

Let's look at the details of the two main pathways of AG presentation.

The intrinsic pathway - utilizes endoantigens located in the cytoplasm. These can be viruses, tumor proteins, own defective molecules, and even obligate intracellular parasites.

Let's add some comments to the image.

• The first step in the internal pathway is to throw the AG into the furnace of the proteasome, where large AG molecules are broken down into small fragments by proteases.
• The antigen is then delivered to the rough endoplasmic reticulum (RER). In this factory, some of the protein residues may be sparingly set aside for reutilization. While others, after binding to the alpha chain of the MNS class I molecule, are used for AG presentation.

The α chain is stabilized by a β protein whose coding gene is not MHC (it is even located on a completely different chromosome).

The MHC I alpha chain doesn't differentiate between "foreign" and "own." It binds "self" and "foreign" antigens equally well. Specificity isn't the main feature of this binding, but the antigen must have the right size.

• The MHC I molecule and the associated antigen enter the Golgi apparatus, where a vacuole is formed, which in turn moves to the outer cell membrane, and our umbrella is ready to interact with CD8+ T cells.
• If this CD8+ T lymphocyte (killer) recognizes the antigen as foreign, it triggers the process of destroying the cell that has this antigen on its surface.

Different scenario plays out in the external pathway, the presentation of exogenous antigens framed by MSN II molecules. It involves professional antigen-presenting cells (APCs): macrophages, dendritic cells and B cells.

Let's briefly describe the sequence of events when a foreign antigen and, for example, a dendritic cell meet each other.

After an immature dendritic cell has captured a dangerous element by endocytosis, it initiates complex processes inside itself:

• Antigen undergoes phagolysosomal digestion (1) and hasn't reached RER
• MHC class II molecules are synthesized in the rough reticulum.
• Fusion of phagolysosome and vacuole with MHC II molecule occurs.
• Antigen inserted into the domain formed by the α and β chains of the MHC II molecule. 
  Now everything's ready for presentation of the foreign antigen to CD4+ T lymphocytes (helper cells).

Presentation of the CD4+ antigen does not lead to death of the APC.

On the contrary, the T lymphocyte, armed with new knowledge, begins to secrete cytokines that promote its maturation and activation.

When the B lymphocyte acts as an APC, CD4+ stimulates it to produce immunoglobulins.

Finally, activation of CD4+, the conductor of the immune response, leads to a chain of events that enables more efficient clearance of the pathogen from the environment.

Let's review:

1. The major histocompatibility complex genes encode MHC class I and class II molecules, which play a crucial role in antigen recognition by T lymphocytes.

2.MHC genes are characterized by significant polymorphism and are inherited in a co-dominant pattern.

3. Exogenous and endogenous antigens are processed in two pathways before being incorporated into the appropriate domains of MHC molecules.

4. The fate of cells presenting antigens combined with MHC molecules is distinct.

The outcome of the internal pathway may be cell death triggered by CD8+ T lymphocytes recognizing antigen as foreign.

The outcome of the external pathway is the initiation of complex events triggered by CD4+ T lymphocytes and activation of the APC themselves.

5. T cells are only able to recognize antigens if they are presented by HLA molecules, otherwise they simply do not "see" them.

6. How immunologic events unfold in response to AG depends on the strength, duration, and other characteristics of antigen binding to HLA molecules.

This article covers only a few important details of (immuno)genetics, where the major histocompatibility complex genes play one of the most important roles. Processes involving the products of these genes allow the fine-tuning of the complex immune response mechanism that protects the body from a huge number of potentially dangerous antigens.

Certain HLA alleles can increase the risk of autoimmune diseases.

Read more about this and many other topics not covered in this article.