Immunology Flashcards
What are the 2 mechanisms of human defence?
Innate immunity
Adaptive immunity
Where do antibodies come from?
Synthesised and secreted by B lymphocytes
Before birth, they’re produced in the foetal liver
After birth- produced in the bone marrow from haematoitic stem cells
Outline the development of B cell sin the bone marrow
Bone marrow stroma provides the microenvironment for B lymphocytes to mature AND differentiate
Useful cells- exported to the periphery
Self- reactive B cells are disposed of
Ensures that each cell only has 1 specificity
Describe the T cell- independent responses
B cells (B-1) reside in the marginal zone of speed and are activated by polysaccharide and lipid antigens
Majority of B cells are follicular B cells (B-2) because they circulate through the follicles of lymphoid organs
Follicular B cells make the bulk of T-cell dependant class switches
They have a high-affinity antibody responses to protein antigens an give rise to long-lived plasma cells
Describe the 6 stages of B cell activation
- Membrane bound Ig recognises and binds to the microbe
- Receptor is non-covalently associated with 2 proteins: Ig alpha and beta
- Ig-alpha and Ig- beta contain conserved immunoreceptor tyrosine based activation motifs
- Signals initiated by binding to antigen receptor are transduced by recpetor-associated proteins
- Net result= Activation of transcription factors such as myc, NF-kb or AP-1
- Transcription factors switch on genes whose proteins are involved in cell proliferation and antibody synthesis
Describe the basic structure of an antibody
Glycoproteins
Range in size from 150kDa-900kDa
2x Heavy chains and 2x Light chains
N terminal= antigen binding site
C- terminal= Fc region
What are heavy chains?
Encoded by a single locus on human chromosome 14
Type of heavy chain present defines class of antibody
Distinct heavy chains differ in size and amino acid composition
What are light chains?
Encoded by 2 gene loci
Kappa locus is on human c-some 2
Lambda locus on human csome 22
Molecular weight of each light chain is approx 25kDa
Determine the specificity of antigen binding
2 identical light chains are either bases on either kappa or lambda
Describe the structure and function of immunoglobulins
Immunoglobulins are bifunctional proteins:
Thye must interact with a small number of specialised molecules- Fc receptors on cells- main classes include Fc alpha, Fc. , Fc gamma
They complement proteins
They’re intracellular cell signalling molecules whilst recognising an infinite array of antigenic determinants at the same time
Cell surface antigen receptor of B cells- Allows b cells to sense their antigenic environment
Secreted antibody- Neutralises toxins or microbes
Used for agglutination of viruses or immune complexes
Used to arm or recruit effector cells
Describe immunoglobulin G
Most abundant serum antibody and makes aprox 80% of total serum antibodies
Consists of 2 heavy chains and either 2 kappa/ lambda light changing
4 subclasses: 1-4
Longest half-life of all antibodies- aprox 23 days
What are the functions of IgG?
Major antibody of secondary immune system
IgG 3 &4 readily cross the placenta= important roles in the neonatal protection
IgG3 is the most effective activator of compliment
IgG4 does activate complement
IgG1/3 binds wiht a high affinity to Fc receptors on phagocytotic cells and thus mediates opsonisation
IgG aids immobilising bacterial threats and neutralises toxins and viruses
Describe immunoglobulin M
Largest Ig
Memebrane bound form is ALWAYS monomeric
Aprox 1000kDa
Found intravascularly
Aprox 10% of plasma Ig’s
Describe immunoglobulin A
Aprox 15% of plasma Ig
Major tissue Ig found lining mucosal surfaces: GI tract, Respiratory tract and Urogenital tract
The SC protect IgA from degradation by gastric acid and digestive proteolytic enzymes
Often found as a dimer
Key in neutralising antibody in the mucosal compartment
Exists in two subclasses and differs between 2 compartments where it is found- blood and mucosal secretions
Blood IgA is monomeric
Mucosal IgA is almost always dimeric
Describe immunoglobulin D
180kDA
Delta H chains= 70 kDa
Rarely detected in blood
Two classes: 1 and 2
Plays an important role in maturation and proliferation of B cells
Describe immunoglobulin E
200kDa
Epilson chains of approx 73 kDa
IgE constitutes 0.3% of serum Ig
Major immunoglobulins in mediating allergic and anti-parasitic responses
Cross-link to the FC epilsonR on mast cells
Triggers the release of histamine, tryptase and proteolytic enzymes by mast cells
How do antibodies interfere with HIV?
A. Virus- target cell interaction blocked
B. Post attachment stages blocked
C. Virus- cell fusion inhibited
D. Virus uncoating prevented, viral assembly and maturation interrupted and virus budding inhibited
E. Infectious virions aggregated
What are the stages of complement action?
- Pattern recognition acts as trigger
- Protease cascade amplified
- Inflammation, phagocytosis or membrane attack
What is RAG1 and RAG-2?
2 DN shuffling enzymes that are encoded by recombination activating genes aka V(D)J
B and T cells express enzymes here during development and maturation
They initiate the molecular processes that lead to lymphocyte receptor formation by V(D)J segment recombination
Nonsense mutation in RA1/2 cause the most profound immunodeficiency, sever recombined immunodeficiency (SCID)
Describe central tolerance
The processes of eliminating and developing T/B lymphocytes that are auto reactive
Bone marrow stromal cells and blood plasma provide ncomplete encyclopaedia of self antigens to train B cells
Any B cell that binds strongly to these self antigens are either deleted/ recycled
What is peripheral tolerance?
When auto reactive B cell are released into peripheral lymphoid organs and they’re silenced by several mechanisms
A major mechanism being- B anergy in which auto reactive B cells are maintained in an antigen unresponsive state
Describe the principles of cellular co-operation
Antibody production is improved when T cells are present
“Purified” lymphocytes were shown to produce immune responses in vitro to antigens
Contaminated with macrophages, when truly purified with little response, therefore macrophages are important- seen to have another role in antigen presentation
What is MHC?
MAJOR HISTOCOMBATABIITY COMPLEX= Special structre cells used to present antigen to lymphocytes
B cells recognise antigen without MHC- surface bound antibody referred to as B cell Receptor
These can act as antigen presenting cells (APCS)
T cells can only “see” antigen presented on MHC
What are T cells?
Lymphoid cels of adaptive immune system
Formed from lymphoid stem cells, produced in the bone marrow
Mature in the thymus where they produce a T cell receptor (TCR)
2 main subsets of T cells:
1. Helper T cells- Produce proteins to act as messengers for the rest of the immune system, in the form of cytokines
2. Killer T cells- cause infected cells to apotose
Once triggered hey can kill a cell in an antigen specific manner
A 3rd subset has been characterised recently: Regulatory T cells= Keep other T cells under control
What are APC’s?
Antigen presenting cells
Professional APCs deliver antigen to CD4+ T cells
Dendritic cells, macrophages and B cells
All APCs require class II MHC molecules in addition to other co-stimulatory molecules on their surface
What is the function of dendritic cells?
Main function in periphery= act as ‘gatekeepers’
They capture foreign material and transport them to secondary lympoid tissues
Immature DCs halve pattern recognition receptors (PRRs)
During migration to the lymphoid tissue they mature
Describe MHC class I
Made up of an alpha chain and a light chain of Beta2 microglobulin (encoded on c-some 15)
There are 3 domains on the alpha chain, with a peptide binding cleft between alpha-1 and alpha-2
Peptide binding region is closed at both ends
MHC class I peptide cleft binds peptides of 8-10 amino acids length
Individuals can possess up to 6 different HLA class I molecules on their cells, with the possibility of 2A, 2B and 2C antigens
Therefore a restricted number of clas I molecules can present and bind a range of different foreign peptides
Describe MHC class II
Made up of an alpha and beta chain- both encoded by MHC
Peptide binding cleft between alpha 1 and beta 1 region
Can accommodate larger peptides of between 15-30amino acids
Fundamental difference between the clefts of class 1 and II molecules;
Peptide binding left of class II molecules is open at both ends
Cleft in class I is closed
Class II molecules can present significantly larger peptides
An individual possesses a restricted number of different class II MHC molecules
MHC class II molecules interact with a co-recpetor molecule, the CD4 expressed on helper T cell populations
CD4 interacts wiht the beta 2 domain of the constant part of the molecules
T helper cells are clas II MHC restricted
What are co-receptor molecules?
T cells bind to MHC antigen via their TR and a co-recprtor
T- cells are subdivided into 2 major populations depending upon which co-receptor molecule is expressed on the cell surface, CD4/ CD8
Which T cells express the CD4 receptor?
T helper cells
Which T cells express the CD8 receptor?
Cytoxic T cells
Describe TAP transporters and how they work
The endogenous peptides gain access to the ER lumen and MHC class I molecules through:
2 proteins in the ER membrane are responsible for transporting peptide into the ER
Memebers of the family of proteins known as the ATP-binding cassette proteins (ABC)
Transporters asscotiated with he Antigen Processing-1 and 2 (TAP-1 and 2) is encoded by genes within the MHC
After, two TAP proteins form a heterodimer, link the cytoplasm of the cell with the lumen of ER
How are peptides generated in cytosol?
Proteins within cells re continually being degraded and replaced wiht newly synthesis proteins
Degradation is carried up by a multi catalytic protease complex named proteasome
Large cylindrical omelet of 28 sub-units that are arranged into 4 stacked rings
Proteins to be degraded are introduced into the core and are broken don into smaller peptide fragments
2 sub-units (LMP1 and 2) of the proteosome are endowed within the MHC, close to the TAP-1 and 2 genes
Outline the process of MHC class I presentation
Newly synthesised MHC class I alpha chains rapidly bind to an 88kD Calnexin (CNX)
A chaperone protein retains MHC class I molecule in a partially folded state wihtin the ER, until it binds to the Beta 2 micro globulin
Binding of Beta2M to MHC class I heavy chain causes dissociation from CNX
CNX is replaced by another chaperones Calreticulin and ERp57
MHC class I interact with TAP via tapasin to form the PLC
TAP molecules actively transport endogenous peptides into the lumen of the ER
Tapain helps select the best fitting peptide
Binding of a suitable peptide to partially folded MHC class I molecules alows it to be released from the PLC
MHC-1 peptide complex transits the Golgi apparatus to cel surface
Describe Class II MHC presentation
Newly synthesised mMHC class II molecules are held within the ER by and invariant chain (li)
Li chain directs class II out off the ER to acidified endosome
Within the acidified endosome the invariant chain is digested in the low pH environment
The peptides are free to bind to MHC class II binding site
Class III MHC + peptide is expressed on the cell membrane
The competed MHC Class II peptide complex is then directed towards the cell surface
List the different tissues in which lymphocytes can be found
Slpeen
Lymph nodes
Bone marrow
Blood
Skin
Intestines
Liver
Lungs
What is tolerance?
Under normal circumstances the immune system it does not react with the host’s own potentially antigenic substances – so called self antigens
This unresponsiveness to self is called immunological tolerance
Failure in tolerance results in autoimmune diseases such as
Rheumatoid arthritis (RA)
Describe alpha-beta TCRs
<95% of T cells express these receptors
Each T cell has approx 30,000 surface receptors
Only one antigen specificity per cell
Develops in the thymus in a similar manner to B cell receptors but without somatic mutation
α-chain: similar rearrangements to light chain Ig
β-chain: similar rearrangements to heavy chain Ig
Cannot signal on it’s own
Describe the CD3 T cell receptor complex
Series of proteins which allow signalling
Associated with TCR in membrane
Essential role in function and mutual association required for TCR and CD3 expression in the membrane
Also associated with CD4/8 molecule allowing MHC interaction
