Antibody Genes Flashcards
What is cross-reactivity?
Cross-reactivity occurs when the CDR region of an antibody for one antigen also binds to another antigen to a detectable degree. CDRs can be extremely specific (Ka up to 10^15 L/mol), but they remain simple combinations of AAs with set charges and hydrophobicities/philicities. Thus, one produced to defend the body may also attack an self-epitope within the body somewhere.
What is one beneficial product of cross-reactivity and one toxic product of cross-reactivity?
A beneficial property is the production of antibodies to the harmless tetanus toxoid (used in vaccinations) that cross-react with the deadly tetanus toxin during an actual infection. A toxic product is the antibodies to streptococcal bacteria may cross-react with laminin in heart valves. While this is a low affinity reaction, there may be enough signal to trigger an autoimmune response. This leads to a destructive, complement mediated inflammatory process called rheumatic heart disease.
What is the clonal selection theory?
The clonal selection theory (a Darwinian theory) states that all antibodies expressed by B and T cells are pre-determined and exist in a huge variety in each person. An antigen that enters a body interacts with millions of these antibodies until it encounters the one that has sufficient affinity to activate its related cell and produce an immune response. This theory is opposed to the Lamarckian theory that stated that all antibodies were essentially formless and were instructed by the antigen to form to its shape.
What is allotypic exclusion?
The lambda, kappa, and H chain genes are all located on different chromosomes, and we have two copies of each. In order to not produce multiple copies of each gene (and thus multiple different antibodies), B-cells silence one of the heavy chain genes and three of the lambda and kappa light chain genes in a manner similar to X-inactivation. Thus, they may only express one of each. This also explains why a cell that switches heavy chains never switches light chains.
How is the variable domain gene region organized?
The V domain gene region is subdivided into ‘mini genes’ . On the heavy chain, the V region consists of V, D, and J gene segments. On the light chain, the V region consists of V and J segments. Thus, the shorthand V(D)J is used to generically refer to all segments of the variable region.
In what order are the V(D)J segments spliced and what enzyme does the splicing?
The DNA of the D and J segments are spliced first, with a random selection of each being included. The DNA of the V and DJ segments are then spliced together. The result is then transcribed into RNA extending downstream to include the constant regions and mu and delta segments. This is achieved by RAG-1 and RAG-2 enzymes. Without these enzymes neither T not B cells are created. (Omenn Syndrome)
What are “N” regions and what are the advantages and disadvantages of them?
“N” regions are found at the splice sites of the V D and J regions. During DNA recombination, some of the nucleotides are removed and others inserted at the margins of these segments. This produces very random segments of genes, as there is no template to determine the nucleotide. This greatly increases the number of V(D)J regions that are possible, enhancing immunity. It also has a heavy price because 2/3 of the results will create frameshift mutations and nonsense codons.
How does a B cell attempt to recover from an errant frameshift mutation?
It undergoes another round of allotypic exclusion, reactivating another copy of the gene (either the other heavy chain, or one of the other three light chains) and inactivates the frame shifted copy. If the RAG enzymes are still active, it may also rearrange the V(D)J region it already was expressing. This is called receptor editing.
Do the changes in the V(D)J region occur in the germ line or in somatic cells?
They occur in both. There are slight differences in the V D and J regions that are heritable and occur in the germ line. But the rearrangements that occur within each cell occur somatically.
What is somatic hypermutation and what does it lead to?
Each time a B-cell divides after antigenic stimulation, there is a chance that one of the daughters will make a slightly different antibody due to normal mutation rates of dividing cells. Some of these mutations will make the antibody increased binding affinity for the antigen, leading to selective pressure for that cell line. This is called affinity maturation.
What is class switching?
Class switching occurs when a B cell changes its DNA to stop producing IgM or IgD and begin producing IgA, IgG, or IgE. The V domain remains the same, and the DNA is recombined to exclude the M and D regions (which are discarded) and produce whichever other class the cell chooses. It can only happen in one direction, as the intervening DNA is no longer in the genome for a reversion to IgM or IgD. The order of the genes is Mu, Delta, Gamma (1&2), Epsilon, and Alpha. (M, D, G, E, A)
