MHC (Major Histocompatibility Complex): Introduction, Discovery, Characteristics, and Types, Difference Between MHC I and MHC II, HLA (Human Leukocyte Antigen), HLA test, Functions and Significance of MHC, MHC Restriction, Practice Problems and FAQs

We all are living in a community. Here we always hear a lot about varieties of diseases. You know that some diseases are mild such as flu or common cold whereas some are deadly like kidney failure. You might have heard about a life threatening situation related to kidney failure, where a person is asked to undergo organ transplantation to survive. 

Do you know anything about organ transplantation? Yes, you are correct. It is a medical procedure in which an organ from the body of one person (donor) is removed and placed in the body of a recipient person. For the successful organ transplantation process, the donor and the recipient should possess some matching characteristics. Examples include blood typing. The genes of the donor and recipient must be matched so that the recipient can easily accept the transplanted organ. 

You might have heard about some cases where the recipient’s body was not compatible with the donor’s organ. Have you ever thought, why does this happen or what is responsible for this type of incompatibility? Yes, you are correct, our immune system is responsible for this rejection or incompatible process. Our body’s immune cells are able to differentiate between self and non-self cells. 

Fig: Self and nonself antigen recognition

The human leukocyte antigen (HLA) system is mainly responsible for this incompatibility of organ transplants in our body. These are the proteins or markers that are present in most of the cells of our body. These markers are used to identify self and non-self molecules. Let’s understand in depth about these proteins in this article.

Table of contents

• Introduction to MHC (Major Histocompatibility Complex)
• Discovery of MHC molecules
• Characteristics of MHC
• Types of MHC molecules
• Difference between MHC I and MHC II
• HLA (Human Leukocyte Antigen)
• HLA test
• Functions of MHC
• Significance of MHC
• MHC restriction 
• Practice Problems
• FAQs

Introduction to MHC (Major Histocompatibility Complex)

MHC or a major histocompatibility complex is described as a group of genes located on the short arm of chromosome 6 in humans that code for certain proteins. It is called human leukocyte antigen in humans and H-2 complex in mice. It is mainly responsible for immune response, formation of transplantation antigens and proteins of the complement system. 

MHC molecules 

The molecules produced by the genes of MHC or major histocompatibility complexes are called MHC molecules. They are normally located on the cell membranes of the nucleated cells of the body or in the blood serum. They are classified into different types. MHC proteins are normally found in all higher vertebrates. 

Discovery of MHC molecules

The MHC molecules were first identified due to their potent effect on the transplanted tissues. MHC was first recognised as a barrier to transplantation in mice in 1937. George Snell is the scientist who discovered the first components of the MHC in the 1940s in mice. In mice they are located on chromosome 17. In humans, they were first discovered because of the antigenic differences between the white blood cells of different individuals. MHC is a specilaised region located on the short arm of chromosome 6 which contains more than 200 genes.

Fig: Major histocompatibility complex molecules

Characteristics of MHC 

There are two main characteristics of MHC due to which pathogens are not able to evade the immune system:

• Polygenic
• Polymorphic

MHC is polygenic 

The molecule of MHC is polygenic because it contains different MHC-I and MHC-II genes. As a result, every person has a set of MHC molecules with a variety of peptide-binding specificities. 

MHC is polymorphic

The molecule of MHC is highly polymorphic. They show the greatest degree of polymorphism in the human genome. In a population, there are multiple variants of each gene present. These different variants are known as alleles, which are inherited from the parents. 

Types of MHC molecules

There are three major types of MHC protein molecules as follows:

• Class I MHC molecules
• Class II MHC molecules
• Class III MHC molecules

Class I MHC molecules

All nucleated cells and platelets express a glycoprotein molecule on their surface (on plasma membrane) that is encoded by the class I MHC gene. They are called human leukocyte antigens (HLA) in humans as they were first identified using human leukocytes. The class I MHC molecule is a complex of two polypeptide chains such as ɑ-chain and β2 microglobulin molecule. These two chains are associated with non-covalent bonds. The association of ɑ-chain and β2 microglobulin molecule is necessarily required for the expression of class I MHC molecule on the surface of the cell membrane.

Fig: Class I MHC molecules

Functions of class I MHC molecules

The primary function of class I MHC molecules is to bind with the peptide antigens and present them to CD8+ T cells. CD8 ⁺ T cells are those which possess a glycoprotein called CD8. The MHC I binds with the endogenous antigen and displays it to the T cells. These molecules are commonly found on the surface of all nucleated cells.

Fig: Functions of class I MHC molecules

CD8⁺ T cells

In MHC class I restricted T cells, CD8 ⁺ T cells are a crucial subset that function as adaptive immunity mediators. They include two types of cells, cytotoxic T cells, and suppressor T cells. The cytotoxic T cells are essential for killing cancerous cells and virally infected cells. On the other hand, suppressor T cells are used to restrain certain types of immune responses.

Class II MHC molecules

The class II MHC molecules are described as the glycoprotein molecules that are found on the antigen-presenting cells, such as dendritic cells, macrophages, and B-cells. These molecules are composed of two different polypeptide chains, ɑ chain, and β chain. Both chains are associated via non-covalent interactions.

Fig: Class II MHC molecules

Functions of class II MHC molecules

The primary function of class II MHC is to bind with the peptide antigen and display it to the CD4 T cells. The MHC II molecules activate B cells to produce antibodies. These molecules have a significant role in graft versus host response. This is because, in humans, the immune response gene is identical to MHC II molecules. They play a role in antigen presentation, T and B cell cooperation and macrophage - B cell cooperation. 

Fig: Functions of class II MHC molecules

CD4 T cells

The CD4 T cells have a variety of functions, including the activation of the cells of the innate immune system, B lymphocytes, cytotoxic T cells, and nonimmune cells. They also play a significant role in the inhibition of immune response.

Class III MHC molecules

The class III MHC molecules are a diverse group of secretory molecules that are involved in a wide variety of functions in the immune system. These molecules are not considered as markers on the cell surfaces. They include complements like C2 (second component of the complement system) and C4 (fourth component of the complement system), factor B, two steroid 21-hydroxylase enzymes, the inflammatory cytokines, tumour necrosis factors α and β, and two heat shock proteins. 

Functions of class III MHC

The class III MHC molecules are involved in the complement activation. These molecules are also involved in the inflammatory response that occurs due to various factors such as cytokines and tumour necrosis factors. They are not involved in antigen presentation like MHC class I and class II molecules. 

MHC class IV molecules 

These are proteins encoded by genes present in the telomeric end of the Class III MHC region in humans. They are present on the T cells of leukaemia (Tla) and on the immature thymocytes. It is a minor class of MHC molecules. 

Difference between MHC I and MHC II

HLA (Human Leukocyte Antigen)

It is the major histocompatibility complex present in man. HLA stands for human leukocyte antigens that are described as proteins or markers present in most of the cells of our body. The immune system uses these HLA molecules to differentiate the self and foreign or non-self molecules.

Fig: Discrimation between self and nonself antigens

Location of HLA in human beings

The HLA complex of man is located on the short arm of chromosome 6 and it possesses six loci. Loci is considered as the location of genes on a chromosome. They are named as A, B, C, D, S and Tla. The loci D is further divided into DR, DQ and DP. The loci S is further divided into C2, C4 and Bf (Factor B). Tla is located adjacent to A. S is located between B and D.

Fig: Short arm of chromosome number 6 in humans showing the HLA

HLA genes in human beings

The HLA genes in human beings are grouped as follows:

Class I genes

Loci A, B and C are called class I genes. They are responsible for the production of antigens located on the surface of nucleated cells. They cause transplantation reactions normally and hence they are also called transplantation genes. It possesses three major groups and III minor groups of genes. 

Major groups of class I genes

Major groups of class I genes are as follows:

• HLA-A
• HLA-B
• HLA-C

Minor groups of class I genes

Minor groups of class I genes are as follows:

• HLA-E
• HLA-F 
• HLA-G

Class II genes

Loci DQ, DR and DP belong to class II antigens. They produce immune associated antigens (la). These antigens are associated with the regulation of immune responses. They are present on B-cells, macrophages, monocytes, antigen presenting cells and activated T cells. 

Class III genes

They are located on loci S of the short arm of chromosome 6. They are responsible for the levels of complement components such as C4, C2 and factor B in the body. 

Class IV genes

Loci Tla is commonly called class IV genes. It is located adjacent to A and is seen associated with antigens present on T cells of leukaemia. 

HLA Test

Human leukocyte antigen (HLA) typing or HLA test is a medical test used to match patients (recipients) and donors for bone marrow or cord blood transplants. HLA is important for organ transplants otherwise the transplant may be rejected by the recipient’s immune system. Patients undergoing procedures like stem cell transplants may experience problems due to HLA antigen sensitisation. 

Method of HLA test

For conducting HLA tests, from the potential donors and recipients (patients) blood samples or the swabs from the cheek are taken. The blood samples or cheek swabs are then tested in a laboratory to figure out the HLA type. The following methods are commonly used in a laboratory for HLA tests. 

• Cellular methods
• Serological methods
• Biochemical methods
• DNA based methods - Examples include SSO (sequence-specific oligonucleotide), SSP (sequence-specific primer), and RFLP-PCR (restriction fragment length polymorphism polymerase chain reaction) and sequence-based typing (SBT).

Fig: HLA test

Functions of MHC

The MHC is responsible for the following functions

Production of HLA

The MHC genes control the production of antigens located on the nucleated cells such as lymphocytes. They are commonly called transplantation antigens, human leukocyte antigens or graft rejection antigens. 

Graft rejection

The MHC is responsible for intense graft rejections. When the graft tissue dies in the recipient. It is called graft rejection. This is mainly mediated by lymphocytes.

Antigen recognition of T cells

T cells normally recognise the foreign antigens only in the presence of class I and class II MHC molecules. 

Production of immune associated antigens

The MHC genes control the production of immune associated antigens (la) located on the surface of B cells, macrophages, antigen presenting cells, monocytes and activated T cells. 

Controlling the levels of complement components

The MHC genes control the levels of complements like C4, C2 of the classical pathway and factor B of the alternative pathway. 

Non immunological functions

MHC is also responsible for certain non immunological functions like controlling the body weight in mice, egg production in hens etc. 

MHC restriction

The presentation of antigens by macrophages to T cells appears to be specific. The macrophages that present antigens to T helper cells need class II MHC molecules on the surface. Macrophages that present antigens to T cytotoxic cells need class I MHC molecules on the surface. When the macrophages bear a different MHC molecule on the surface it cannot cooperate with T cells and thus antigen presentation cannot occur. This phenomenon is called MHC restriction. 

Significance of MHC in immunity

The following are the major significances of MHC in immunity:

• MHC molecules play a crucial role in the immune system because they enable T lymphocytes to identify cells that have ingested infectious bacteria, such as macrophages. 
• Class I and class II MHC (major histocompatibility complex) proteins are essential components of the adaptive immune system. 
• The function of displaying peptides on the cell surface for identification by T lymphocytes is performed by both groups MHC proteins.

Practice Problems

Q1. MHC is abbreviated as ___________________.

A. Multiple histocompatibility complex
B. Major histocompatibility complex
C. Minor histocompatibility complex
D. Major histological catalyst

Solution: MHC or a major histocompatibility complex is described as a group of genes located on the short arm of chromosome 6 in humans that code for certain proteins that are present on the surfaces of the cells. It is called human leukocyte antigen in humans and H-2 complex in mice. It is mainly responsible for immune response, formation of transplantation antigens and proteins of the complement system. Hence, the correct option is b.

Q2. MHC is described as a tight cluster of linked __________.

A. Proteins
B. Genes
C. Lipids
D. Carbohydrates

Solution: MHC or a major histocompatibility complex is described as a group of genes located on the short arm of chromosome 6 in humans that code for certain proteins that are present on the surfaces of the cells. It is called human leukocyte antigen in humans and H-2 complex in mice. It is mainly responsible for immune response, formation of transplantation antigens and proteins of the complement system. Hence, the correct option is b.

Q3. What is the other name of MHC in humans?

A. HLA
B. H2
C. Adjuvants
D. Haplotypes

Solution: MHC or a major histocompatibility complex is described as a group of genes located on the short arm of chromosome 6 in humans that code for certain proteins that are present on the surfaces of the cells. It is called human leukocyte antigen in humans and H-2 complex in mice. It is mainly responsible for immune response, formation of transplantation antigens and proteins of the complement system. Hence, the correct option is a.

Q4. Who discovered the major histocompatibility complex molecules?
Answer: George Snell first discovered MHC while studying the process of rejection of the transplants in mice in the 1940s.

FAQs

Question 1. What is the MHC test?
Answer: MHC test is used to locate the human leukocyte antigens (HLAs). These are present on practically every cell surface in the human body. The surface of white blood cells contains a significant quantity of HLAs. They aid the immune system in distinguishing between self substances and foreign substances.

Question 2. Do platelets have class I MHC molecules?
Answer: The class I MHC molecules are found on the surface of all nucleated cells. The platelets have a nucleus and therefore, they also possess MHC molecules.

Question 3. What is the difference between MHC and HLA?
Answer: MHC and HLA perform essentially the same functions despite having a few minor differences. The MHC in humans is called HLA. HLA is only present in humans, whereas MHC is present in a wide variety of species.

Question 4. What is MHC disease?
Answer: Major histocompatibility complex (MHC) genes or human leukocyte antigen genes (HLA) in human beings are considered as the main contributors of genetic susceptibility to diseases such as multiple sclerosis, Type 1 diabetes, and rheumatoid arthritis. 

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