Major Histocompatibility Complex Reviewer PDF

**MAJOR HISTOCOMPATIBILITY COMPLEX** **MHC MOLECULES** - named as **HUMAN LEUKOCYTE ANTIGENS** or **HLA** by [Dausset] because its [gene products are originally in WBC or leukocyte ] - they are the **most polymorphic system found in humans**. It allows for an [immune response to d...

**MAJOR HISTOCOMPATIBILITY COMPLEX** **MHC MOLECULES** - named as **HUMAN LEUKOCYTE ANTIGENS** or **HLA** by [Dausset] because its [gene products are originally in WBC or leukocyte ] - they are the **most polymorphic system found in humans**. It allows for an [immune response to diverse immunogens] - **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.] - These molecules are **now known as MHC molecules** because they [determine whether transplanted tissue is histocompatible] and thus accepted or recognized as foreign and rejected. **Main function of MHC MOLECULES** - **main function** is to [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**. - example in kidney transplant, 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. Therefore, the organ transplantation is not successful **CHARACTERISTCS** - **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**, resulting 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]). It means that the set of MHC genes located on **one chromosome (either maternal or paternal)** is inherited **together.** It 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, or if immunocompetent cells transplanted on the donor tissue target the foreign cells of the recipient for elimination. **3 Classes of MHC MOLECULES** **Class I, II, II** - usually, the [most common] is the **class I and II** **CLASS 1 MOLECULES** - Located in three different loci: HLA-**A** HLA-**B** HLA-**C** **[(Classical Class 1)]** - expressed on all nucleated cells (not present in RBC) - Utilized to present [endogenous antige]n to **cytotoxic T lymphocytes** or the **CD8+ T cells**, triggering a **cytotoxic reaction** - **FUNCTION:** 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 express 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**) - Loci: **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] (regulate the interaction between helper **T cells** & **ANTIGEN-PRESENTING CELLS** (APCs) - **FUNCTION**: molecules associate with foreign antigens taken into the cell [from the outside] (**exogenous antigen presentation**) **CLASS 3 MOLECULES** - **different structure** from the class 1&2 - code for the **C4A, C4B, C2, and B complement proteins** as well as **cytokines** such as [tumor necrosis factor (TNF)] - **Secreted proteins** that have an [immune function], but they are [not expressed on cell surfaces], as are class 1&2 **CLASS I 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 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** - Role in [successful organ transplantation] - **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** 1\. Plasma membrane (nucleated cell) \- [controls the entrance and exit of molecules] \- inside the cell is **RER**, **Golgi complex**, **Proteosomes** \- outside the cell is **ECF** \- **ICF** (inside the cell) **Mechanism:** \- the **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 **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 bind (complete structure), it will release the [two chaperone molecules] **(ERp57 and calreticulin)** \- 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 \- The [**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 i**n rer will produce **mhc class 2 molecules** \- In mhc class 2 has a protein **(invariant chain) Ii** \- 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]