Expression of MHC Molecules

Major Histocompatibility Complex (MHC) molecules are surface proteins of cells. They present antigenic peptide to T cells. It is required for immune recognition of foreign antigen.

Expression of MHC molecules is different in different cells. MHC class I molecules are present on almost all nucleated cells. They are absent or very little present on non-nucleated cells like red blood cells (RBCs).

MHC class I molecules present endogenous antigen to CD8⁺ cytotoxic T cells. These antigen are produced inside the cell. It may be viral antigen, tumour antigen or other intracellular antigen.

MHC class II molecules are mainly present on professional antigen presenting cells (APCs). These cells include macrophages, dendritic cells, B lymphocytes and Langerhans cells.

MHC class II molecules present exogenous antigen to CD4⁺ helper T cells. These antigen are taken from outside and processed inside the antigen presenting cells.

Expression of MHC molecules is regulated by cytokines. Interferon-gamma (IFN-γ) increases the expression of both MHC class I and MHC class II molecules. It can also induce MHC class II expression on some cells which normally do not express it.

Some tumour cells may express MHC class II after stimulation by IFN-γ. This is called induced expression.

At genetic level, MHC expression is controlled by transcriptional regulators. NLRC5 (CITA) controls MHC class I gene expression. Class II Transactivator (CIITA) controls MHC class II gene expression.

Major Histocompatibility Complex (MHC)

Major Histocompatibility Complex (MHC) is a cluster of genes present on chromosome 6. It codes for special glycoproteins present on the cell surface. In human beings, these are called Human Leukocyte Antigen (HLA).

MHC molecules bind small peptide fragments. These peptide fragments are antigen. The antigen is then shown on the surface of cell. This is seen by T cells.

It is used by immune system to know self and non-self. Self means own normal body cells. Non-self means foreign agents like virus, bacteria and other pathogens. Altered body cells such as tumour cells may also be recognized.

There are two main types of MHC molecules. These are MHC class I and MHC class II.

MHC class I is present on almost all nucleated cells. It presents intracellular antigen to CD8⁺ cytotoxic T cells. These antigen are formed inside the cell.

MHC class II is present mainly on antigen presenting cells (APCs). These include macrophages, dendritic cells and B lymphocytes. It presents extracellular antigen to CD4⁺ helper T cells.

MHC genes are polygenic. It means many genes are involved. MHC genes are also highly polymorphic. It means many forms are present among individuals.

Because of this variation, MHC molecules can bind many types of peptide antigen. This helps in response against different pathogens.

Types of MHC Molecules Involved in Expression

There are three main types of Major Histocompatibility Complex (MHC) molecules involved in immune expression. These are MHC class I, MHC class II and MHC class III molecules.

1. MHC class I molecules

MHC class I molecules are glycoprotein molecules present on almost all nucleated cells of the body. These are not present on red blood cells (RBCs) because they have no nucleus.

In human, MHC class I molecules are encoded by HLA-A, HLA-B and HLA-C genes.

The structure of MHC class I molecule has one large alpha heavy chain. This chain is highly polymorphic. It is attached non-covalently with a small chain called beta-2 microglobulin.

MHC class I molecules bind endogenous antigen. These antigen are formed inside the cell. Viral proteins and tumour antigen are some examples.

The antigen is presented to CD8⁺ cytotoxic T cells. After recognition, the infected or abnormal cell may be destroyed by immune response.

2. MHC class II molecules

MHC class II molecules are not present on all body cells. Their expression is restricted. They are mainly present on professional antigen presenting cells (APCs).

The important APCs are dendritic cells, macrophages, B lymphocytes and Langerhans cells.

In human, MHC class II molecules are encoded by HLA-DR, HLA-DQ and HLA-DP genes.

The structure of MHC class II molecule has two polypeptide chains. These are alpha chain and beta chain. Both chains are almost similar in size and are attached non-covalently.

MHC class II molecules bind exogenous antigen. These antigen are taken from outside of the cell by engulfment and then processed inside the cell.

The processed antigen is presented to CD4⁺ helper T cells. These cells help in activation and regulation of other immune cells.

3. MHC class III molecules

MHC class III molecules are different from MHC class I and MHC class II molecules. They do not present antigen to T cells.

This region is gene rich region of MHC. It encodes different immune and inflammatory proteins.

The MHC class III region encodes complement proteins such as C4A, C4B, C2 and Factor B (FB).

It also encodes some important signaling and stress related proteins. These include Tumour Necrosis Factor-alpha (TNF-α), Tumour Necrosis Factor-beta (TNF-β) and Heat Shock Proteins (HSPs).

MHC class III molecules are mainly involved in inflammation, complement activation and regulation of immune response.

Cellular Distribution of MHC Molecules

The cellular distribution of Major Histocompatibility Complex (MHC) molecules is different for MHC class I and MHC class II. Some cells express them normally and some cells express them only after stimulation.

1. MHC class I molecules

MHC class I molecules are widely distributed in the body. They are present on almost all nucleated cells.

These molecules are found on the surface of body cells. Because most body cells are nucleated, MHC class I expression is broad.

They are absent or very poorly expressed on non-nucleated cells. Mammalian red blood cells (RBCs) are the important example because they do not contain nucleus.

2. MHC class II molecules

MHC class II molecules have restricted distribution. They are not present on all body cells.

They are mainly present on professional antigen presenting cells (APCs). These cells are specialized for antigen processing and antigen presentation.

The important cells normally expressing MHC class II are dendritic cells, macrophages, B lymphocytes and Langerhans cells.

Dendritic cells show strong expression of MHC class II molecules. They are important antigen presenting cells for activation of T helper cells.

Macrophages also express MHC class II molecules. They ingest antigen and present processed antigen to CD4⁺ T cells.

B lymphocytes express MHC class II molecules. They can present antigen which is bound by their surface receptor.

Langerhans cells are also included under professional antigen presenting cells. They express MHC class II molecules and present antigen in skin and mucosal region.

3. Inducible expression of MHC molecules

The distribution of MHC molecules is not always fixed. It can be changed by cytokine stimulation.

Interferon-gamma (IFN-γ) is an important cytokine which increases expression of MHC molecules. It mainly increases MHC class II expression on some cells.

Under inflammatory condition, some cells which normally do not express MHC class II may start expressing it. This is referred to as inducible expression.

These non-professional cells include fibroblasts, endothelial cells, epithelial cells, mesenchymal stromal cells and enteric glial cells.

After induction, these cells may act like non-professional helper antigen presenting cells. They present antigen to CD4⁺ T cells in local inflammatory condition.

Some tumour cells may also express MHC class II molecules after stimulation. This expression may occur inside tumour microenvironment and is called tumour-specific MHC class II (tsMHC-II) expression.

Expression of MHC Class I Molecules

The expression of MHC class I molecules occurs by endogenous pathway. In this pathway, antigen formed inside the cell is processed and shown on the cell surface. It is recognized by CD8⁺ cytotoxic T cells.

1. Protein degradation in cytosol

In this step, endogenous proteins are present in the cytosol of the cell. These may be viral proteins, tumour antigens or misfolded self proteins.

These proteins are first marked by ubiquitin. Then they are degraded by large enzyme complex called proteasome. Small peptide fragments are formed from this degradation.

2. Peptide transport into ER

The peptide fragments formed in cytosol are transported into endoplasmic reticulum (ER).

This transport occurs by a special transporter called TAP (Transporter Associated with Antigen Processing). TAP is present in the membrane of ER and it carries peptide from cytosol into ER lumen.

3. Synthesis of MHC class I molecule

At the same time, MHC class I heavy chain is synthesized in the ER.

The newly formed heavy chain is not stable at first. It is held by a chaperone protein called calnexin. This helps in initial folding of the heavy chain.

Then the heavy chain combines with β₂-microglobulin. After this binding, calnexin is released from the heavy chain.

4. Formation of peptide loading complex

The immature MHC class I molecule then joins with peptide loading complex (PLC).

This complex contains different chaperone proteins. These include calreticulin, ERp57 and tapasin.

Tapasin joins the MHC class I molecule with TAP transporter. So the peptide entering through TAP can be loaded into the peptide binding groove of MHC class I.

5. Peptide trimming and loading

The peptides entering into ER may be long in size. They are trimmed by ER enzyme such as ERAAP.

After trimming, peptide becomes suitable for binding with MHC class I molecule. Tapasin helps in keeping the peptide binding groove open.

A high affinity peptide then binds inside the groove of MHC class I molecule. This makes the MHC class I-peptide complex more stable.

6. Release and transport of MHC class I complex

After proper peptide binding, the chaperone proteins are released.

The stable peptide-MHC class I complex leaves the peptide loading complex. It then comes out from ER.

The complex passes through Golgi apparatus. Then it is carried by secretory vesicles towards the plasma membrane.

7. Presentation on cell surface

The loaded MHC class I molecule is finally expressed on the surface of the cell.

The bound peptide is displayed outside the cell. This peptide is recognized by T-cell receptor (TCR) of CD8⁺ cytotoxic T cells.

After recognition, the CD8⁺ T cell can destroy infected or abnormal cell. This is important in immune response against virus infected cells and tumour cells.

Biological Importance of Expression of MHC Class I Molecules

• Presentation of intracellular antigen – MHC class I molecules present intracellular antigen on the surface of cell. These antigen are formed inside the cell from virus, intracellular bacteria or tumour associated mutated proteins.
• Activation of cytotoxic immunity – MHC class I molecules present antigen to CD8⁺ cytotoxic T cells. After recognition by T-cell receptor (TCR), the CD8⁺ T cells become activated and kill infected or cancerous cell.
• Cellular surveillance – MHC class I molecules are present on almost all nucleated cells. So they help immune system to check internal proteins of most cells and detect abnormal peptide formed inside the cell.
• Regulation of Natural Killer cells – Natural Killer (NK) cells check the presence of MHC class I molecule on cell surface. When virus infected cells or tumour cells reduce MHC class I expression, NK cells detect this absence and destroy the abnormal cell.
• Self and non-self discrimination – MHC class I molecules act as cellular identity marker. They help the body to distinguish own tissue from foreign or altered tissue and they are important cause of graft rejection.
• Population level pathogen defence – Classical MHC class I genes are HLA-A, HLA-B and HLA-C. These genes are highly polymorphic, so different persons can present different peptide antigen from changing pathogens.
• Cross presentation – Some professional antigen presenting cells like dendritic cells take extracellular antigen and present them through MHC class I pathway. This process is needed for priming of naïve CD8⁺ T cells against virus and tumour antigen.
• Involvement in autoimmune disease – Some MHC class I variants are related with autoimmune diseases. HLA-B27 is associated with ankylosing spondylitis and reactive arthritis, due to molecular mimicry with bacterial protein or cellular stress by misfolded MHC class I molecule.

Expression of MHC Class II Molecules

The expression of MHC class II molecules occurs by exogenous pathway. In this pathway, antigen coming from outside the cell is processed and presented by professional antigen presenting cells (APCs).

1. Antigen uptake – In this step, exogenous antigen are taken inside the antigen presenting cell. These antigen may be bacteria, viral particles or other foreign proteins. The uptake occurs by endocytosis or phagocytosis in dendritic cells, macrophages and B cells.
2. Antigen degradation – After entry inside the cell, the antigen goes into endosomal vesicles. These vesicles slowly become acidic. In this acidic condition, enzymes like cathepsins and metalloproteases break the antigen into small peptide fragments of about 13 to 25 amino acids.
3. Synthesis of MHC class II molecule – At the same time, MHC class II molecule is formed in rough endoplasmic reticulum (ER). It is made up of two chains. These are alpha chain and beta chain.
4. Binding with invariant chain – The newly formed MHC class II molecule should not bind with intracellular peptide in the ER. So a chaperone protein called invariant chain (Ii or CD74) binds with it. This chain blocks the peptide binding groove of MHC class II molecule.
5. Transport to endosomal compartment – The MHC class II-invariant chain complex leaves the ER. It passes through Golgi apparatus. Then it enters into late endosomal compartment called MHC class II compartment (MIIC).
6. Cleavage of invariant chain – In the acidic MIIC, the invariant chain is digested by acid proteases. Only a small part remains in the groove. This small fragment is called CLIP (Class II-associated Invariant chain Peptide).
7. Removal of CLIP and peptide loading – HLA-DM binds with the MHC class II molecule and removes CLIP from the groove. HLA-DO may regulate this process. After removal of CLIP, suitable exogenous peptide binds into the open groove of MHC class II molecule.
8. Surface presentation – After peptide loading, the stable peptide-MHC class II complex is transported to the plasma membrane. It is expressed on the surface of the antigen presenting cell. The peptide is then recognized by T-cell receptor (TCR) of CD4⁺ helper T cells.

Biological Importance of Expression of MHC Class II Molecules

The following are the biological importance of expression of MHC class II molecules-

• Activation of CD4⁺ helper T cells – MHC class II molecules present exogenous antigen to CD4⁺ helper T cells. These antigen may come from bacteria, fungi, parasites or other extracellular pathogens.
• Coordination of adaptive immunity – After activation of CD4⁺ helper T cells, many immune responses are controlled. Th2 cells help B lymphocytes to produce specific antibodies. Th1 cells help macrophages and also support CD8⁺ cytotoxic T cells for killing of pathogen.
• Formation of immunological memory – MHC class II antigen presentation helps in formation of memory T cells. These memory cells remain in the body. When same pathogen enters again, the immune response becomes faster and stronger.
• Tumour surveillance – MHC class II molecules are usually present on antigen presenting cells. But some tumour cells may also express MHC class II molecule. This is called tumour-specific MHC class II (tsMHC-II) expression.
• Role in cancer immunity – Expression of tsMHC-II helps CD4⁺ T cell mediated immune pressure on tumour cells. It increases entry of T cells into tumour area and is related with better response to immune checkpoint inhibitor therapy.
• Self and non-self discrimination – MHC class II molecules help the immune system to recognize self and non-self antigen. It is important for tolerance to normal body tissue and response against foreign antigen.
• Involvement in autoimmunity – Sometimes regulation of MHC class II antigen presentation fails. Then autoreactive T cells may be activated against own tissue.
• Molecular mimicry – Some pathogen peptide may look similar to self protein. This is called molecular mimicry. In this condition MHC class II molecule may present such peptide and cause autoimmune reaction.
• Association with autoimmune diseases – Abnormal MHC class II presentation is linked with autoimmune diseases like Rheumatoid Arthritis, Type 1 Diabetes and Celiac Disease.

Genetic Regulation of MHC Molecule Expression

The following are the genetic regulation of MHC molecule expression-

• The expression of MHC genes is controlled by master transactivators. These proteins do not directly bind with DNA. They mainly work as scaffold and recruit other transcription factors for starting the transcription.
• Class II Transactivator (CIITA) is the master regulator of MHC class II gene transcription. It controls the expression of MHC class II genes. It also helps in increasing normal expression of MHC class I genes.
• NLRC5 (NLR Family CARD Domain-Containing Protein 5) is the main transactivator for MHC class I genes. It controls transcription of MHC class I genes and also some related antigen processing components.
• The promoter region of both MHC class I and MHC class II genes contains conserved SXY module. It is made up of W/S box, X1 box, X2 box and Y box sequences. This region gives place for binding of different transcription factors.
• On the SXY module, a multi-protein complex is formed which is called enhanceosome. This complex helps in proper arrangement of transcription factors required for MHC gene expression.
• RFX complex binds directly with the X1 box of the promoter. It is one of the important DNA binding factor. It is required for transcription of both MHC class I and MHC class II genes.
• CREB/ATF1 (Cyclic AMP response element-binding protein) associates with the X2 box. It helps in formation of transcriptional complex at the promoter region.
• NF-Y complex binds with the Y box. It is also a sequence specific DNA binding factor. These factors remain on promoter region and transcription starts when CIITA or NLRC5 joins with them.
• Interferon-gamma (IFN-γ) is an important cytokine which increases expression of MHC molecules. In non-immune cells, IFN-γ induces CIITA transcription through promoter IV (pIV). Then MHC class II expression is started.
• MHC expression is also controlled at chromatin level. When chromatin is open, transcription occurs easily. When chromatin is closed, expression of MHC genes becomes reduced.
• Hypermethylation of promoter region of CIITA or classical MHC genes decreases MHC expression. In this condition, methyl groups are added to DNA and transcription becomes suppressed.
• CIITA can recruit histone acetyltransferases (HATs). This opens the chromatin and increases active transcription. It can also recruit histone deacetylases (HDACs) which repress transcription and silence MHC genes.

Factors Affecting Expression of MHC Molecules

The following are the factors affecting expression of MHC molecules-

• Master regulators and genetic integrity – MHC gene expression needs proper regulator protein and normal gene structure. CIITA (Class II Transactivator) is required for MHC class II gene expression. NLRC5 is required mainly for MHC class I gene expression. They act with SXY enhanceosome complex. If deletion occurs in MHC locus or mutation occurs in CIITA and RFX genes, then expression of MHC molecules becomes low or absent.
• Cytokines – Cytokines have important role in MHC expression. Interferon-gamma (IFN-γ) is the strong inducer of MHC class I and MHC class II molecules. It activates CIITA promoter IV (pIV) and increases transcription. Other cytokines like IFN-α, IFN-β, GM-CSF, IL-4, TNF-α and IL-1β also increase expression. But TGF-β and IL-10 suppress expression of MHC molecules.
• Epigenetic modifications – This regulates the gene without changing the gene sequence. DNA methylation at promoter region of CIITA or classical MHC genes stops transcription. Histone acetylation by HATs such as CBP and p300 opens the chromatin and increases expression. Histone deacetylation by HDACs, EZH2 mediated methylation and H3K9me3 close the chromatin and reduce MHC gene expression.
• Cellular signaling pathways – Some cell signaling pathway also control MHC expression. RAS/MAPK pathway and Toll-like receptor 2 (TLR2) pathway can suppress MHC class II expression. Progesterone receptor activation decreases MHC class I expression by blocking STAT1 phosphorylation and signaling.
• Viral evasion – Some viruses reduce MHC molecule expression for escaping from T cell response. HIV-1 Nef protein sends MHC class I molecules like HLA-A and HLA-B to lysosome for degradation and also delays MHC class II movement to surface. SARS-CoV-2 ORF6 blocks nuclear entry of NLRC5 and stops MHC class I transcription. HHV8 and EHV1 remove MHC class I from surface by endocytosis. BHV1 stops new synthesis of MHC class I by shutting host translation.
• Bacterial interference – Some bacteria also decrease expression of MHC molecules. Antigen of Mycobacterium tuberculosis induces repressive histone methylation like H3K9me3. Due to this CIITA and MHC class II expression becomes decreased.
• MicroRNAs – Some microRNAs (miRNAs) act after transcription and reduce MHC expression. miR-200a-5p, miR-125a-5p and miR-148a-3p can suppress mRNA of MHC heavy chain or TAP transporter. So proper MHC molecule formation becomes reduced.
• Post-translational regulation – CIITA activity is controlled after its formation. It is regulated by phosphorylation, ubiquitination and acetylation. Kinases like PKA, ERK1/2 and GSK3 change its activity, nuclear localization and oligomerization.
• Protein degradation and physical masking – In some cancer cells, SND1 oncoprotein binds with MHC class I molecule and sends it for lysosomal degradation. Sometimes glycosphingolipids get accumulated on cell surface. They physically cover MHC molecules and prevent proper recognition by T cells.

Role of Interferons in MHC Expression

The following are the role of interferons in MHC expression-

• Upregulation of MHC molecules – Interferon-gamma (IFN-γ) increases the expression of MHC class I and MHC class II molecules on cell surface. It makes more number of MHC molecules available for antigen presentation.
• Induction on non-professional cells – MHC class II molecules are normally present on professional antigen presenting cells. But IFN-γ can induce MHC class II expression on cells which normally do not express it. These cells include fibroblasts, epithelial cells, endothelial cells, enteric glial cells and mesenchymal stromal cells.
• Tumour-specific MHC-II expression – In tumour microenvironment, IFN-γ can induce tumour cells to express tumour-specific MHC class II (tsMHC-II). This helps in activation of infiltrating CD4⁺ T cells. These activated cells again release more IFN-γ, so the anti-tumour immune response becomes increased.
• CIITA activation – IFN-γ increases MHC class II expression by activating Class II Transactivator (CIITA). It mainly stimulates CIITA promoter IV (pIV). After this, CIITA acts as master regulator and starts transcription of MHC class II genes.
• Epigenetic effect – IFN-γ also changes chromatin condition for active transcription. It increases acetylation of histone H3 and histone H4 at promoter region of MHC class II genes, such as HLA-DRA. Due to this chromatin becomes open and transcription is increased.
• Type I interferons – IFN-α and IFN-β are type I interferons. They are generally produced by virus infected cells. These interferons can also increase MHC expression by activating JAK-STAT signaling pathway.

Expression of MHC Molecules During Antigen Presentation

MHC molecules are required for antigen presentation. T cells cannot recognize whole antigen directly. The antigen is first processed into short peptide fragments. Then these peptides are expressed on the cell surface with MHC molecules.

There are two main pathways for this process. Endogenous antigen are presented by MHC class I molecules. Exogenous antigen are presented by MHC class II molecules.

Expression through MHC class I pathway

In MHC class I pathway, antigen are formed inside the cell. These antigen may come from replicating virus, intracellular bacteria or mutated tumour protein.

The cytosolic proteins are first tagged by ubiquitin. Then they are broken by proteasome into small peptide fragments. These peptides are usually 8 to 16 amino acids long.

The peptide fragments are transported into endoplasmic reticulum (ER). This transport is done by TAP (Transporter Associated with Antigen Processing).

At the same time, MHC class I heavy chain is synthesized in the ER. It is folded and stabilized by chaperone proteins like calnexin, calreticulin and ERp57.

The MHC class I molecule joins with peptide loading complex (PLC). Tapasin keeps MHC class I near TAP. Then suitable peptide enters into the binding groove of MHC class I molecule.

After peptide loading, the stable peptide-MHC class I complex leaves the ER. It passes through Golgi apparatus. Then it reaches cell surface and is expressed for recognition by CD8⁺ cytotoxic T cells.

Expression through MHC class II pathway

In MHC class II pathway, antigen come from outside the cell. These antigen may be circulating bacteria, toxins or extracellular foreign proteins.

The antigen are taken by professional antigen presenting cells (APCs). These cells are dendritic cells, macrophages and B cells. The uptake occurs by endocytosis or phagocytosis.

The engulfed antigen enters endosomal compartments. These compartments become acidic slowly. In this acidic condition, cathepsins degrade the antigen into peptide fragments.

At the same time, new MHC class II molecules are formed in the ER. The peptide binding cleft of MHC class II is blocked by invariant chain (Ii or CD74). This prevents binding of wrong cellular peptides inside the ER.

The MHC class II-invariant chain complex moves through Golgi apparatus. Then it reaches late endosomal compartment called MIIC.

In MIIC, the invariant chain is degraded. Only a small fragment remains in the groove. This fragment is called CLIP.

HLA-DM removes CLIP from the binding groove. Then a suitable exogenous peptide binds with MHC class II molecule.

The loaded peptide-MHC class II complex moves to plasma membrane. It is expressed on the surface of APC. It is recognized by CD4⁺ helper T cells.

Cross-presentation

In some cases, professional APCs take exogenous antigen but present them by MHC class I molecules. This is called cross-presentation.

It connects exogenous antigen uptake with MHC class I presentation. This helps in activation of CD8⁺ T cells against virus infected cells and tumour cells.

Role of MHC Expression in T Cell Activation

The following are the role of MHC expression in T cell activation-

• Antigen recognition – T cells do not recognize free antigen. The antigen first become short peptide. Then it is shown on cell surface with MHC molecule. T-cell receptor (TCR) binds with this peptide-MHC complex. This is the first signal for T cell activation.
• Co-receptor binding – Only binding of TCR is not enough. T cell co-receptor also binds with MHC molecule. CD8 binds with α3 region of MHC class I. CD4 binds with β2 region of MHC class II.
• CD8⁺ T cell activation – MHC class I presents intracellular antigen. These antigen may be viral protein or tumour protein. It activates CD8⁺ cytotoxic T cells. After activation, these cells kill infected cell or cancerous cell.
• CD4⁺ T cell activation – MHC class II presents extracellular antigen. It is present on antigen presenting cells (APCs). It activates CD4⁺ helper T cells. These cells secrete cytokines and help B cells, macrophages and other immune cells.
• Three signal activation – MHC gives the first signal by showing peptide antigen. Full activation also need co-stimulatory signal and cytokine signal. CD80/CD86 on presenting cell binds with CD28 on T cell and gives second signal. Cytokines give third signal.
• Strength of response – The amount of MHC molecule on cell surface controls the strength of T cell activation. More MHC expression gives strong response. Low or absent MHC expression gives weak response and helps virus infected cell or tumour cell to escape from immune system.

Abnormal or Altered Expression of MHC Molecules in Disease

The following are the abnormal or altered expression of MHC molecules in disease-

A. Malignancies and cancer

1. Loss of MHC class I – In many tumour cells, MHC class I expression becomes reduced or absent. Due to this the tumour peptide is not presented properly to CD8⁺ cytotoxic T cells. This helps the tumour cell to escape from immune response. It is found in melanoma, non-small cell lung cancer and renal cell carcinoma. Mutation in β2-microglobulin (β2m) gene and DNA hypermethylation are important causes.
2. Loss of MHC class II in lymphoma – In Diffuse Large B-Cell Lymphoma (DLBCL) and Primary Mediastinal Large B Cell Lymphoma (PMBCL), MHC class II expression is often lost. It is associated with poor survival. The loss occurs due to deletion, rearrangement or loss of function mutation of CIITA gene and RFX transcription factor complex.
3. Epigenetic silencing – In some tumours, MHC genes are silenced at chromatin level. Here the gene is present but expression is low. DNA hypermethylation of CIITA promoter stops MHC class II transcription. EZH2 mediated histone methylation also decreases MHC class I and MHC class II expression.

B. Autoimmune diseases

1. Ankylosing spondylitis – Ankylosing Spondylitis (AS) is related with HLA-B27 molecule. It is a MHC class I molecule. The heavy chain of HLA-B27 folds abnormally in endoplasmic reticulum (ER). It forms abnormal homodimers. This produces unfolded protein response. IL-23 and IL-17 are increased and chronic inflammation of joint occurs.
2. Rheumatoid arthritis – Rheumatoid Arthritis (RA) is related with HLA-DRB1 gene. It is a MHC class II gene. Some HLA-DRB1 alleles contain shared epitope region. These molecules bind citrullinated peptides. These peptides are then presented to T cells and autoantibody formation takes place. Immune tolerance is lost.
3. Celiac disease – In Celiac Disease, most of the patients have HLA-DQ2 or HLA-DQ8. These are MHC class II molecules. They bind deamidated gluten peptide in intestine. This peptide is presented to T cells. Then inflammatory reaction occurs and intestinal tissue is damaged.

C. Viral infections

1. HIV-1 immune evasion – HIV-1 Nef protein changes the transport of MHC molecules inside cell. It sends MHC class I molecules like HLA-A and HLA-B to lysosome for degradation. HLA-C and HLA-E are not removed in same way. So the infected cell avoids both CD8⁺ T cells and NK cells. Nef also slows the surface movement of MHC class II molecules.
2. Epstein-Barr virus – Epstein-Barr Virus (EBV) forms gp42 glycoprotein. This binds with HLA-DR and MHC class II-peptide complex on cell surface. It blocks proper binding of T-cell receptor (TCR). So activation of antiviral CD4⁺ helper T cells becomes reduced.
3. SARS-CoV-2 – SARS-CoV-2 ORF6 protein blocks the nuclear entry of NLRC5. NLRC5 is required for MHC class I gene transcription. So new formation of MHC class I molecule becomes less. Antigen presentation to CD8⁺ T cells is reduced.

D. Primary immunodeficiency

1. Bare lymphocyte syndrome – Bare Lymphocyte Syndrome (BLS) type II is a severe inherited immunodeficiency. It is caused by mutation in CIITA gene or RFX complex. These factors are needed for transcription of MHC class II genes. So MHC class II molecules are absent on cell surface. CD4⁺ T cell activation becomes defective.

Clinical Significance of MHC Molecule Expression

The following are the clinical significance of MHC molecule expression-

• Organ and tissue transplantation – In human, MHC molecules are called Human Leukocyte Antigen (HLA). These molecules help in self and non-self recognition. When donor and recipient HLA are not matched, the graft is taken as foreign. It causes transplant rejection. In bone marrow transplantation, donor immune cells may attack recipient tissue. This is called Graft-versus-Host Disease (GVHD).
• Tumour immune evasion – Many malignant cells reduce or lose MHC class I or MHC class II expression. Due to this tumour antigen is not shown properly to T cells. So tumour cell escapes from immune response.
  • a. In Diffuse Large B-Cell Lymphoma (DLBCL) and Primary Mediastinal Large B Cell Lymphoma (PMBCL), MHC class II expression may be lost. This may occur due to CIITA mutation and is related with poor patient survival.
• Predictive marker for immunotherapy – Tumour-specific MHC class II (tsMHC-II) expression is a useful clinical marker. High tsMHC-II means more T cells are present in tumour area. It is related with better survival and good response to immune checkpoint inhibitor therapy like anti-PD-1 and anti-PD-L1.
• Personalized cancer therapy – Some cancer therapies depend on the HLA type of the patient. The tumour peptide must be presented by a suitable HLA allele. This is called HLA-restricted therapy. T-cell receptor (TCR) therapy, T-cell engagers and personalized cancer vaccines are made on this basis. Example is HLA-A*02:01 restricted antigen presentation.
• Viral immune escape – Some viruses change MHC expression for escaping from immune response. HIV-1 Nef protein sends HLA-A and HLA-B to lysosome for degradation. So CD8⁺ T cells cannot recognize infected cell properly. But HLA-C, HLA-E and HLA-G remain on surface, so Natural Killer (NK) cells are not strongly activated.
• Autoimmune susceptibility – Some MHC alleles are strong genetic risk factor for autoimmune disease. It may occur due to molecular mimicry or abnormal peptide binding. In molecular mimicry, microbial peptide looks like self peptide and immune response may attack own tissue.
  • a. Ankylosing Spondylitis (AS) is associated with HLA-B27. It may present bacterial peptide from Klebsiella or Yersinia, which mimic self tissue. HLA-B27 may also misfold in endoplasmic reticulum (ER) and causes cellular stress with severe joint inflammation.
  • b. Rheumatoid Arthritis (RA) is linked with HLA-DR4 and HLA-DRB1 alleles having shared epitope. These molecules bind citrullinated peptides strongly. These peptides may form due to smoking or oxidative stress and then autoantibody formation occurs.
  • c. Celiac Disease is associated with HLA-DQ2 and HLA-DQ8. These molecules bind deamidated gluten peptide in intestine. The peptide is presented to T cells and inflammatory attack occurs on gut mucosa.

Regulation of MHC Molecule Expression

The following are the regulation of MHC molecule expression-

• Master transcriptional regulators – MHC gene expression is controlled by master transactivator proteins. These proteins do not bind directly with DNA. They act as scaffold for other transcription factors. CIITA (Class II Transactivator) controls MHC class II gene transcription. NLRC5 (NLR Family CARD Domain-Containing Protein 5) controls MHC class I gene transcription.
• SXY enhanceosome module – The promoter region of MHC class I and MHC class II genes contain conserved SXY module. It has W/S box, X1 box, X2 box and Y box. RFX complex, CREB/ATF1 and NF-Y complex bind on these regions. These proteins form enhanceosome. Then CIITA or NLRC5 joins with it and starts transcription.
• Cytokine upregulation – Some cytokines increase expression of MHC molecules. Interferon-gamma (IFN-γ) is the strong inducer of both MHC class I and MHC class II molecules. It stimulates CIITA transcription through specific promoters. Other cytokines like IFN-α, IFN-β, GM-CSF, IL-4, TNF-α and IL-1β also increase MHC expression.
• Cytokine suppression – Some cytokines decrease expression of MHC molecules. TGF-β and IL-10 are immunosuppressive cytokines. They inhibit MHC expression and reduce antigen presentation.
• Epigenetic modulation – MHC gene expression is also regulated by chromatin condition. DNA hypermethylation at promoter region of CIITA or classical MHC genes stops transcription. Histone acetylation opens chromatin and increases transcription. Histone deacetylation by HDACs and EZH2 mediated histone methylation close the chromatin and repress MHC gene expression.
• Post-translational control – CIITA is controlled after its formation also. Its activity, movement into nucleus, oligomer formation and degradation are regulated by post-translational modifications. These include phosphorylation, ubiquitination and acetylation.
• MicroRNA regulation – Some microRNAs (miRNAs) act after transcription. miR-200a-5p, miR-125a-5p and miR-148a-3p suppress mRNA of MHC heavy chain or peptide transporter like TAP. Due to this proper MHC complex formation becomes reduced.
• Intracellular signaling pathways – Some signaling pathways suppress MHC expression. RAS/MAPK pathway and Toll-like receptor 2 (TLR2) pathway can decrease MHC class II expression. Progesterone receptor activation decreases MHC class I expression by inhibiting STAT1 phosphorylation and signaling.

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