MHC (HLA) System and Immune Response

Major Histocompatibility Complex

• Also known as HUMAN LEUKOCYTE ANTIGENS or HLA, named by Dausset
• Gene products are originally in WBC or leukocyte
• It is the most polymorphic system in humans
• Allows for an immune response to diverse immunogens
• It is the molecular basis for T cell discrimination of self from non-self
• Found on the short arm of chromosome 6 at band 21
• Second only to the ABO antigens in influencing the survival or graft rejection of transplanted organs
• It determines whether transplanted tissue is histocompatible and thus accepted or rejected
• MHC molecules bring antigen in the body to the surface of cells for recognition by T cells
• T-cell activation will occur only when antigen is combined with MHC molecules on the surface of other cells
• The genes that encode these cell-surface molecules are the system of genes known as the MHC
• In kidney transplants, the organ transplant should be compatible in the donor and recipient
• If not the same molecules, the kidney will be treated as a foreign by the body, and the organ transplantation is not successful

Characteristics

• Polymorphism refers to the presence of two or more different genetic compositions among individuals in a population
• Polymorphism in MHC means that different individuals in a population have different MHC alleles
• This results in variation in how the immune system recognizes and responds to pathogens
• Alleles refer to the different variations of MHC molecules that determine how the immune system recognizes and presents antigens
• Inherited in a haplotype (combination of inherited trait either maternal or paternal)
• The set of MHC genes located on one chromosome (either maternal or paternal) is inherited together
• This is a group of closely linked alleles on a single chromosome
• Transplanted tissue may trigger a destructive mechanism, rejection, if the recipient's cells recognize the MHC protein products on the surface of the transplanted tissue as foreign
• Immunocompetent cells transplanted on the donor tissue target the foreign cells of the recipient for elimination

3 Classes of MHC Molecules

• Class I, II, and III
• Classes I and II are the most common

Class 1 Molecules

• Located in three different loci: HLA-A, HLA-B, and HLA-C (Classical Class 1)
• Expressed on all nucleated cells, and are not present in RBC
• Utilized to present endogenous antigen to cytotoxic T lymphocytes or the CD8+ T cells, triggering a cytotoxic reaction
• These molecules associate with foreign antigens, such as viral proteins, synthesized WITHIN a host cell (endogenous pathway for antigen presentation)
• Non-Classical Class 1: HLA-E, HLA-F, HLA-G
• (E and F are not expressed in cell surfaces while G are found in fetal cells or trophoblast cells)

Class 2 Molecules

• Only found on B cells, monocytes, macrophages, dendritic cells, and thymic epithelium (antigen presenting cells)
• Located in the D region
• Major class 2 molecules: HLA-DP, HLA-DQ, HLA-DR
• Non-classical class 2 molecules: HLA-DM, HLA-DN, HLA-DO
• Antigen presenting cells with MHC 2 molecules present antigens to T helper cells or the CD4+ T cells, which are helper cells involved in antibody production
• They regulate the interaction between helper T cells & ANTIGEN-PRESENTING CELLS (APCs)
• These molecules associate with foreign antigens taken into the cell from the outside (exogenous antigen presentation)

Class 3 Molecules

• Structure differs from Classes 1 and 2
• Code for the C4A, C4B, C2, and B complement proteins as well as cytokines such as tumor necrosis factor (TNF)
• Secreted proteins have an immune function and are not expressed on cell surfaces, as are classes 1&2

Class 1 Restriction

• Class I molecules mainly present peptides that have been synthesized within the cell
• They present it to CD8+ (CYTOTOXIC) T CELLS
• If the antigen is recognized as being foreign, cytokines are released causing destruction of the target cell

Class II Restriction

• Class II molecules mainly bind exogenous peptides (taken from the outside and degraded.)
• They present these to CD4+ HELPER T CELLS which then secrete cytokines that cause an antigen activated b cell to proliferate and produce plasma cells to make antibodies against the antigen
• Significant in bacterial infections or in the presence of other material that is endocytosed by the cell

Main Role

• The main role of CLASS I and CLASS II is ANTIGEN PRESENTATION
• They bind peptides within cells and transport them to the plasma membrane, where T cells can recognize them
• T cells can only see and respond to antigens when they are combined with MHC molecules
• BACTERIA: ATTACK CELLS FROM THE OUTSIDE
• VIRUSES & OTHER INTRACELLULAR PATHOGENS: ATTACK CELLS FROM THE INSIDE

Clinical Significance

• Plays a role in successful organ transplantation
• It is used in Paternity testing for exclusion or non-exclusion
• HLA Typing is also useful in forensic medicine, anthropology and basic research in immunology

Pathways of Antigen Presentation

• Endogenous Pathway: Class 1
• Plasma membrane (nucleated cell)
• Controls the entrance and exit of molecules
• The inside of the cell consists of the RER, Golgi complex, and Proteosomes
• The outside of the cell is ECF
• ICF (inside the cell)
• Mechanism
  • A virus will enter the cell
  • The virus will produce its own Ag or Ag protein
  • The Ag protein will enter the proteosomes (it degrades the antigenic protein into smaller substances) (the smaller substances are called peptides)
• In the RER has attached ribosomes (synthesize MHC Class 1 molecules)
• (Incomplete structure)
• The MHC class 1 molecules will bind to calnexin (act as a chaperone molecules)
• (Allows the binding of incomplete mhc class 1 molecules into beta 2 microglobulin)
• Once the b2 microglobulin binds (complete structure), it will release the Erp57 and calreticulin chaperone molecules
• The main function of ERp57 and calreticulin is to close or block the antigenic binding site of mhc class 1 molecules and also stabilizes the structure of mhc class 1 molecules
• Once the mhc has been stabilized, it will leave the RER by (TAPASIN protein)
• The peptides from the proteosomes will be transported by transporters associated with antigen presentation/processing into the mhc class 1 molecules
• (Once the mhc is close to the peptides, the Erp57 and calreticulin and tapasin will be destroyed)
• The mhc together with peptide will travel to GA and the GA have vesicles which will be the pathway of mhc with peptide (mhc class 1 molecules with peptides complex) to be presented to the cell surface where it will be presented with the CD8+ T cells
• The CD8+ has its own specific receptor (T cell receptor and CD8+ receptor, this 2 will confirm if the complex is mhc class 1 molecules)
• Once confirmed it will trigger the cytokines to cleave the virus

Exogenous Pathway: Class 2

• Plasma membrane (APC) ex. Macrophage
• Bacteria will not directly infect the cell
• For the bacteria to enter the cell, it must undergo phagocytosis by engulfment of macrophages (bacteria)
• Through fusion of phagosome and lysozyme it will produce phagolysosome Inside the cell is rer and gc

Mechanism

• The ribosome in rer will produce mhc class 2 molecules
• In mhc class 2 has a protein (invariant chain) li
• The Invariant chain stabilizes or protects the binding site of mhc class 2 molecules
• The phagolysosomes will be degraded to form peptides
• The peptides will be transported in the vesicles
• The mhc class 2 molecules with invariant chain will go out of the rer and travel through the golgi complex to meet the peptides
• Once they meet, the invariant chain will be degraded
• Once degraded, the invariant chain will form the clip fragment
• The clip fragment blocks the antigenic binding site of mhc class 2 molecules
• The clip fragments will exchange location with the peptide for the mhc class 2 molecules and peptide to combine
• Once they combine, they will be presented to the cell surface where it meets the cd4+ cell or T helper
• The cd4+ has its own receptor (t cell receptor and cd4 receptor)
• These two will confirm the mhc class 2 molecules
• Once confirm, the cd4+ will release cytokines to trigger activation of b cells to produce plasma cell to produce antibody that will bind and kill antigen

Explore the Major Histocompatibility Complex (MHC), also known as the Human Leukocyte Antigen (HLA) system, its polymorphism, and its critical role in T-cell activation. Understand MHC haplotypes in organ transplantation and the consequences of MHC mismatch. Learn about the impact of different MHC alleles on immune responses and other antigens influencing graftrejection.