Case 17- Immunity Flashcards
Adaptive immunity
Relies on T and B lymphocytes. Derived from haematopoietic stem cells in the bone marrow and are activated in secondary lymphoid organs. Antigens are presented on MHC molecules. System has high specificity and responds to individual pathogens
Antigen presenting cells
Dendritic cells, Macrophages and B cells. They present antigens on the MHC class 2 molecules to CD4 T cells. T cells activation produces a specific adaptive immune response and can activate the innate immune system.
Attributes of the innate immune system
Response time- fast: minutes/hours Low specificity Key cells- Macrophages, Neutrophils, Basophils and Eosinophils Immunological memory- none Low diversity
Key attributes of the adaptive immune system
Response time- slow:days
High specificity
Key cells- T cells, B cells and antigen presenting cells
Immunological memory
Diversity- high diversity due to genetic recombination
Major histocompatibility complex (MHC)
Cell surface molecules that present peptide fragments to naive T cells in order to activate them and make effector T cells. They allow the identification of both self and non-self peptides by T cells, allowing cells to present foreign pathogens or cancer proteins to the immune system
Human leukocyte antigen (HLA)
The complex of genes that encodes the production of the human MHC molecule
MHC class 1 molecule
MHC class 1 molecules are found in the surface of all nucleated cells. They tend to present peptides originating from intracellular pathogens, such as viruses. They activate cytotoxic T cells that express CD8 on their surface. These cytotoxic T cells then induce apoptosis in the infected cells.
MHC class 2 molecules
MHC class 2 molecules are found on APC’s such as dendritic cells, B cells and Macrophages. Class 2 molecules tend to present peptides from extracellular pathogens that have been ingested such as types of bacteria. They activate naïve T cells that express CD4 T cells such as T helper cells.
Key attributes of MHC class 1 molecules
Structure- 3 domain membrane bound alpha chain and a single domain beta chain, heterodimer
Found on- all nucleated cells
Size of peptide- 8-10 amino acids
Type of T cell activated- CD8+ T cell i.e. cytotoxic T cell
Type of pathogen- intracellular pathogen i.e. viruses
Site of peptide loading- endoplasmic reticulum
Key attributes of MHC class II molecules
Structure- 2 domain alpha chain and 2 domain beta chain that are both membrane bound, heterodimer
Found on- professional APC’s such as dendritic cells, Macrophages and B cells
Size of peptide= 14-18 amino acids
Type of T cell activated= CD4 T cells i.e. helper T cells
Type of pathogen= extracellular pathogen i.e. bacteria
Site of peptide loading= specialised vesicle
MHC rejection in transplants
If MHC molecules are not matched then the graft will be rapidly rejected. Even if the MHC loci are genetically identical, graft rejection will occur over time due to differences at other loci which encode minor histocompatibility antigens. Due to the certainty of mismatch in minor histocompatibility antigens transplantation requires the use of powerful immunosuppressive drugs.
The 3 types of rejection response which can lead to the loss of a graft
- Hyperacute: occurs within hours as a result of preformed antibodies (type II hypersensitivity reaction)
- Acute: takes several days to develop (type IV hypersensitivity reaction
- Chronic: occurs months to years after transplantation due to a variety of mechanisms (no treatment options)
Antigen processing
1) Antigens need to be processed within the cell before they can complex with an MHC molecules, which has been pre-assembled in the endoplasmic reticulum.
2) Proteosomes brake down viral proteins to create viral peptides, they join self-peptides from normal cellular proteins.
3) They travel to the ER where they come in contact with the transporter TAP. TAP transports protein fragments from the cytosol to the ER lumen. Here they bind to MHC1.
Formation of an MHC1 molecules
1) MHC1 consists of a heavy chain and a B2 microglobulin (soluble subunit) and a peptide fragment from either self or viral proteins.
2) The assembly of MHC1 starts with the folding of alpha chain assisted by the molecular chaperone Calnexin and an associated enzyme ERp57.
3) ERp57 catalyses the formation of disulphide bonds.
4) There is subsequent binding of the Beta 2 microglobulin to the heavy chain which creates a peptide binding groove.
5) The peptide binding groove is needed for entry into the Peptide loading complex (PLC).
6) In the PLC Calnexin is replaced with Calreticulin which connects to ERp57.
7) The remaining parts of the PLC is the TAP and Tapasin.
Role of Tapasin
1) Tapasin and the ERp57 play a big role in the stability of the PLC.
2) Tapsin also stabilises TAP to allow for protein entry into the peptide binding groove.
3) Tapsin may widen the peptide binding groove.
4) High affinity peptides which fit the binding groove cause a confirmational change. Tapsin responds to this change by dissociating causing the disassembly of the PLC.
MHC class 1 presentation
1) MHC class I α chains bind to calnexin in the ER until β2-microglobulin binds to the α chains. MHC class I complex is released from calnexin.
2) MHC class I then binds to a complex of chaperone proteins: stabilising and positioning the MHC class I molecule. Also connects it to TAP (a transporter protein involved in antigen processing). This forms the peptide loading complex.
3) Non-self (e.g. viral) or self (e.g. from mutant tumour cell) proteins in the cytosol of cells are degraded by large multi-catalytic protease enzyme into peptide fragments. These peptide fragments can enter the ER via TAP. The peptide fragments are between 8-10 amino acids long.
4) Binding of a peptide fragment to MHC class I causes the release of the chaperone complex and TAP and the subsequent export of MHC class I:antigen complex to the surface of the cell membrane. This process occurs in all nucleated cells.
MHC class 2 presentation
1) MHC class II molecules are found in the endoplasmic reticulum (ER) attached to an invariant chain. This invariant chain functions to stop peptide fragments from binding to the MHC molecule in the ER.
2) The invariant chain also causes the MHC class II molecule to leave the ER in a vesicle. This vesicle then enters the endocytic pathway and becomes more acidic.
3) The drop in pH cleaves the invariant chain (class II associated invariant chain protein, a small protein still bound to MHC cleft). Endocytosed molecules (molecules that have been internalised) are broken down into peptide fragments of about 14-18 amino acids in length (by hydrolytic enzymes); however, CLIP stops these fragments binding to MHC class II.
4) HLA-DM binds to MHC. This functions to remove CLIP so that an antigen can bind to MHC class II and the MHC:antigen complex can then be expressed on the cell surface.
Role of the invariant chain
A portion of the invariant chain binds into the protein binding groove of the MHC class II molecules. Prevents proteins present in the ER from binding. The invariant chain guides the MHC class II complex out of the ER and through the golgi apparatus into a vesicle. Progressive acidification of the endocytic vesicle activates proteases that cleave the invariant chain leaving the class 2 invariant chain peptide (CLIP) bound to the MHC class 2 complex.
Structure of a T cell receptor
- T cell receptors consist of one α (alpha) and one β (beta) chain, with CD3 molecules either side
- T cells also express a co-receptor, either CD4 or CD8, which bind to MHC (major histocompatibility complex) molecules to enhance signalling via the TCR.
- Both the α and β chains contain the antigen recognition site; this is where the antigen will bind to the TCR to produce a response.
- This antigen recognition site is highly specific and will only bind to one antigen.
VDJ recombination
V(D)J (variable, junction) recombination of alpha and beta chains allows us to create a unique B-cell receptor. The genes to make these chains have multiple segments, these segments are then combined randomly.
