BioSci 201: Lecture 33 - Immunology Flashcards
Gain an Overall Understanding of the Immune Response: Inflammation, AP, Clonal Expansion. Describe Key Molecules and Interactions: Ig Receptors, MHC, TCR. Understand the Origin of Diversity of Antigen Binding Receptors: V Region Fragments, Class Switching, Recombination, MHC Polymorphism.
Antigen receptor molecules include:
Antibody molecules (IgM, IgD, IgG, IgA, IgE).
T cell receptor molecules.
MHC molecules (class I and II).
Toll receptors.
Cancer: Multiple Myeloma
Uncontrolled B-cell clonal expansion.
Results in massive production of a single Ig type - a “monoclonal” antibody with random specificity.
Variability on the Light Chain V Region of Antibodies
HV1 HV2 HV3 (Hyper Variable).
These correspond to CDR1 CDR2 and CDR3 which are three loops at the antigen binding end of the antibody.
These are areas of differing amino acid sequence. (Other areas generally have the same amino acids).
Ig Binding Site
Consists of 3 light chain CDR loops and 3 heavy chain CDR loops
Heavy Chain Switching Ig Class or Isotype
B-cells produce Ig molecules with the same antigen binding specificity but different properties in this sequence:
IgM, IgD, IgG, IgA, IgE.
IgG is the most abundant.
Heavy chain constant regions determine class.
Switching of Antibody Class
Occurs by somatic recombination in activated B-cells
There is a sequence of different heavy chain C genes downstream of the numerous DNA segments that combine to make V regions.
The different C regions are expressed sequentially in an immune response.
Isotype Switching
Increasing deletions of heavy constant genes in activated B-cells during immune response.
Involves Introns/exons.
“Looping out” of genes resulting in deletion.
IgM
Has 4 C/H domains and forms a pentamer with J chain.
Binds C.
Important in early response and on surface of B-cell surfaces.
Is the first Ig on B-cells.
Can be secreted after activation of B-cells.
Secreted version is produced in primary immune response andforms pentameric complexes.
Existence of Secreted and Membrane Bound Forms of Ig Molecules
Is due to choice of poly-A site at the DNA level.
Structure of T-cell Receptor
Looks like the top arm of the Y on antibody molecules.
Consists of an alpha chain and a beta chain, both made of subunits (V and C) each of which is associated with a carbohydrate.
Chains are held into the membrane by cytoplasmic tails (one each - ++ for alpha + for beta) and these tails are held together by disulfide bonding.
Between subunits and transmembrane region there is a space called a hinge.
MHC Class I
Only has one cytoplasmic tail anchoring it to the membrane.
Is present on most cells (definitely on B and T cells, macrophages and other APCs).
Consists of an alpha chain (including parts 1 and 2 - antigen binding site and 3) and a separate beta-microglobulin molecule.
Functions as a surface display of peptide fragments originating from proteins made in the cytoplasm (monitor internal environment) requiring peptide processing and transport into the ER and then secretion of the MHC-Peptide Complex.
MHC Class II
Has 2 cytoplasmic tails anchoring it to the membrane.
Consists of alpha and beta chains (alpha 1 & 2 subunits and beta 1 & 2 subunits) with the 1 end forming the peptide binding cleft. Variability is only in the beta chain.
Present predominantly on B-cells and other APCs. Smaller number on T-cells and Macrophages.
Function as a surface display of peptide fragments of endocytosed proteins on APCs.
Possible Weak Points in the Immune System
Narrow clefts limit the kind of peptide fragments that the immune system can recognize.
Can pathogens evolve proteins that don’t fit the cleft.
Peptide production and transport machinery could also be vulnerable.
Class I cleft is capped. Peptide fragments are only ~8-10 AAs long.
(Need to be able to further explain these).
Some Arguments Against the Immune System Having Weak Points
MHC genes are polymorphic so there are many alleles in a population which allows for stability in terms of a population being able to cope with a large range of diseases.
MHC I variability maps to the binding cleft so allows for some variety in the ability of the immune system to cope with disease.
MHC II cleft is open ended so it fits longer peptides.
Peptide binding might not be so selective.
MHC Peptide Binding: Selectivity.
Most peptide-MHC bonds are to main chain atoms of peptide NOT side chains so allows to bind a wider range of peptides.
Multiple MHC alleles have evolved to deal with pathogens that escape MHC clefts.
