Adaptive immune system Flashcards
General Features
Lymphocytes of the adaptive immune system have evolved to recognize a great variety of different antigens from bacteria, viruses, and other disease-causing organisms.
An antigen is any molecule or part of a molecule that is specifically recognized by the highly specialized recognition proteins on lymphocytes.
On B cells these are the immunoglobulins (Ig), which are produced by these cells in a vast range of antigen specificities, each B cell producing immunoglobulin of a single specificity. Membrane-bound immunoglobulin on the B-cell surfaces serves as the cell receptor for antigen (BCR). Immunoglobulin of the same antigen specificity is secreted as an antibody by terminally differentiated B cells-plasma cells.
The main effector function of B cells is the secretion of antibodies which bind pathogens or their toxic products.
Antibody functions
Antibodies bind and inactivate the antigens by:
- Neutralization (blocks viral sites; coats bacteria);
- Agglutination of microbes;
- Precipitation of the dissolved antigens
These three functions enhance phagocytosis. When the antibodies bind to the antigen, the phagocytic cell will have a receptor for the antibody and internalize it.
- Activation of the complement system (classical pathway) resulting in cell lysis.
Antibodies are highly specific receptors.
Antibodies
They consist of three equalized portions connected by a flexible tether.
Also, they have globular domains that have similar structures.
The structure of the antibody can be depicted as:
- The N-terminus for the recognition domain for the antigen.
- The C-terminus with a constant region.
The antibody will have 4 polypeptide chains, that are synthesized together from the beginning to the end:
2 identical heavy chains, and two identical light chains.
They are connected together by the disulfide bonds.
These antibodies will be very efficient, they have high affinity, but less avidity for the pathogen:
Avidity: total strength of interaction
Affinity: the strength of interaction between a single antigen-binding site and its antigen, it takes longer to be activated.
The variable region of the antibody is the recognition region, while the constant region is for the effector function.
There are two types of light chains:
Lambda (λ) and Kappa (κ)
Immunoglobulins (Ig)
There are 5 types of Immunoglobulins (Ig):
IgM, IgD, IgG, IgA, and IgE. They are released in this order during an infection.
IgG is predominant in serum, IgA in secretions, and IgE in tissues.
The structure of all 5 antibodies is very similar, with small differences.
IgG has 150kDa in total, the heavy chain is 50kDa, and the light chain - 25kDa, since there are two of each it equals 150kDa.
The class and effector function of an antibody is defined by the structure of his heavy chain.
For IgG, there are 4 different subtypes (1-4), and for IgA 2 subtypes (1-2), for the rest there is only one subtype.
Some flexibility is also found at the junction between the V and C domains, allowing bending and rotation of the V domain relative to the C domain.
Heavy and light chains
Each domain consists of a series of similar, although not identical, sequences about 110 aa long.
Light chain: 2 immunoglobulin domains
Heavy chain: 4 immunoglobulin domains
The antibody molecule can readily be cleaved into functionally distinct fragments, by enzymes.
For example, papain will cleave the antibody at the tether region, separating the antibody into three parts: Fc (constant region), and Fab (variables 1 and 2).
The functional differences between heavy chain isotypes lie in the Fc fragment
Pepsin is another proteolytic enzyme that cleaves the antibody at different levels in the constant region in the heavy chain. So we will have the different fragments pFc’ and F(ab’)2.
The V regions of any given antibody molecule differ from those of every other.
Sequence variability is not distributed evenly throughout the V region, it is concentrated in certain segments.
Haptens
Haptens: any small molecule/antigen that can be recognized by a specific antibody but cannot by itself elicit an immune response. They are about the size of a tyrosine side chain.
However, they have a lot of value in experimental research. Two identical hapten molecules joined by a short flexible region can link two or more anti-hapten antibodies, forming dimers, trimers, tetramers…
The flexibility at the hinge and the V-C junction enables the two arms of an antibody molecule to bind to sites some distance apart, such as the repeating sites on bacterial cell-wall polysaccharides.
Flexibility at the hinge also enables antibodies to interact with the antibody-binding proteins that mediate immune effector mechanisms.
There are differences in the basic structure of the V and C domains.
Each domain is constructed by two β sheets.
The sheets are linked by a disulfide bridge.
The flexible loops of the V domains form the antigen-binding site.
Combinatorial diversity
When the VH and the VL domains are paired in the antibody molecule, the three hypervariable loops from each domain are brought together, creating a single hypervariable site at the tip of each arm of the molecule.
This is the antigen binding site, which determines the antigen specificity of the antibody.
The six hypervariable loop are known as complimentary-determining regions (CDRs).
Combinatorial diversity: generation of antibodies with different specificities by generating different combinations of heavy- and light-chain V regions.
The aa sequence of the CDRs is different so too are the shapes and properties of the surfaces created by the CDRs
Antibodies bind ligands whose surface are complimentary to that of the antigen-binding site.
Epitopes
An antibody generally recognizes only a small region on the surface of a large molecule.
The structure recognise by the antibody is called an antigenic determinant or epitope.
Epitopes can be linear in the primary structure of the proteins, or they can discontinuous, meaning that the residues are not together in the primary, but in the secondary or tertiary sequences.
Most epitopes will be discontinuous, and they will be largely used in vaccines.
Antigen-antibody interactions
Antibody-antigen interactions involve a variety of forces.
These interactions can be disrupted by:
- High salt concentration
- Extremes pH
- Detergents
- High concentration of the pure epitope itself
- High temperatures.
Antibody-antigen interaction is reversible non-covalent.
Non-covalent forces involve electrostatic forces, hydrogen bonds, Van der Waals forces, hydrophobic forces, and cation-pi interactions.
Having non-covalent interactions means that it is going to be a stable interaction in our body, since it will not be disrupted by the mentioned factors.
Antigen recognition by T cells
The T cells will express the T cell receptors, and it looks the same as the Fab of an antibody. It is smaller compared to the B cell receptor, and is expressed only at the level of the plasma membrane, it is never secreted.
It has two polypeptide chains - alpha and beta, and they have globulin domains. The alpha and beta chain is bound by disulfide bonds, and they don’t have a domain for the effector function. They only have the recognition portion and a transmembrane domain. The antigen-binding site is located on the top of the T-cell receptor, and it has the particularity that it will recognise peptides from pathogens. These peptides will be loaded on the MHC molecules (which are expressed in almost all the cells in our body). Those cells don’t need to be infected to express the peptides. So the T cells don’t recognise pathogens in themselves, they recognise an ongoing infection.
T cells have about 30,000 identical antigen receptors on their surface.
The T cell receptor is glycosilated, which is important for some particular bindings.
T cells respond to short continuous amino acid sequences, so they can only recognise peptides.
These sequences are often buried within the native structure of the protein and cannot be recognized directly by T-cell receptors unless the protein is unfolded and processed into peptide fragments.
Peptides that stimulate T cells are recognized only when bound to an MHC molecule.
Ligands of T cell receptors are complexes of the foreign peptide and MHC molecule.
Besides the alpha and beta chains, T cells also carry a subset of these receptors: gamma and delta.
A minority of T cells express them
Bind heat-shock proteins and nonpeptide ligands, like mycobacteria lipid antigens.
They bind free antigen
Bind peptides presented by nonclassical MHC-like molecules.
MHC class I and class II molecules
MHC molecules are highly polymorphic and the major differences between the different forms are located in the peptide-binding cleft, influencing which peptides will bind and thus the specificity of the dual antigen presented to T cells.
These molecules look like the Fab of the T cell receptor, however one of the chains contains only a globular domain, and is not attached to the membrane but to the other polypeptide chain. The chains are called alpha and beta. On the top of the chains there will be some loops for the antigen binding, and they will also form a cleft (like a hotdog). The walls of the cleft will be alpha-helixes, and the floor will be formed of beta-sheets.
The Class II MHC molecules look very similar to those of class I, with the only difference that both globular domains spanthe membrane. They can accommodate longer peptides.
In both MHC class I and class II molecules, bound peptides are sandwiched between the two α-helixes, so T cell receptor interacts with both the MHC molecule and the peptide antigen.
MHC must be able to bind stably to peptides that are bound as an integral part of the MHC molecule.
MHC molecules are unstable when peptides are not bound.
MHC Class I:
Cluster of tyrosine residues interact with the peptide.The interaction is stabilized at both ends of the peptide-binding cleft. MHC class I molecules bind peptides in the ER.
MHC class II:
Bind peptides at least 13 aa long
Peptide is bound through hydrogen bonds and the ends are allowed to emerge from both ends.
In principle, there is no limit to the size of peptide the MHC can accommodate . However longer peptides are trimmed by peptidases to a length of 13-17 aa.
MHC II that lack bound peptide are unstable
The T cell receptor contacts are not symmetrically distributed over the MHC molecule. MHC indicate that the interactions between the T- cell receptor.
T cell receptor needs a co-receptor. The CD4 (an elongated receptor with multiple globular domains, a flexible hinge and transmembrane domain. The T cells expressing CD4 are called helper cells.) and CD8 (two polypeptide chains alpha and beta, have transmembrane domains and will be expressed by cytotoxic T cells) cell-surface proteins of T cells are required to make an effective response to antigen.
When CD4 - Helper T cel (only bind MHCII) receptor is present, the binding of the T cell receptor peptide: MHC is 100 times more sensitive.
The strength of binding of CD8 - killer T cell (only bind MHC1) to MHC class I molecule is influenced by the glycosylation state of the CD8 molecule.
MHCI and MHCII expression is regulated by cytokines and interferons. MHCI will be expressed by T cells, B cells, Macrophages, Dendritic cells, neutrophils. MHCII will be expressed by B cells, Macrophages, Dendritic cell, and epithelial cells of the body.
