Objectives and Vocabulary for Week Three Flashcards
Know the four tenants of the clonal selection theory
1) Each lymphocyte bears a single type of receptor with a unique specificity.
2) Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with a high affinity leads to lymphocyte activation.
3) The differential effector cells derived from an activated lymhpocyte will bear receptor of identical specificty to those of the parental cell from which that lymphocyte was derived.
4) Lymhpocytes bearing receptors specific or ubiquitous for self molecules are deleted at an early stage in lymphoid cell development are are therefore absent from the repertoire of mature lymphocytes.
Differentiate between Ehrlichs side chain theory and the clonal selection theory
Ehrlich’s side chain theory was one that proposed that each cell contained many receptors which linked to antigens like a key in a lock, and once the receptor—the “side chain”–was triggered by an antigen the cell would produce excess amounts of soluble receptor to neutralize said antigen.
The clonal selection theory is a theory which leads to the idea that there are numerous populations of B/T cell clones who each posses immunoglobulins which bind to different antigens with varying levels of specificity. Once a particular cell has encountered a particular antibody that cell then undergoes proliferation and a clonal expansion. These cells shall then produce the antibodies which destroy pathogens. This theory further states that immune cells that have immunoglobulins which bind to the cells of the host body will be destroyed early on in their development.
Be able to describe how antibody structure leads to function
Antibodies are essentially formed from two different molecules. These molecules are referred to as the heavy chain and the light chain. Both heavy chain and light chain contain regions which are constant—ie common to all immunoglobulin/antibodies—and regions which are variable between antibodies. Variable regions can be composed of an infinite number of amino acid sequences that allow binding of an equally high variety of antigens. The constant region, takes on of only four or five possible forms and confers effector function. There are four framework regions which form beta sheets, whereas areas of high variability (HV regions) form the outer loops. The V regions, especially those which are hypervariable, are the particular part of the V domain that localize to particular regions on the surface of the antigen it will bind. An antibody does not recognize the entirety of a molecule, rather due to it’s structure, it can only recognize a small section of the antigen, it’s epitope. Due to this, if an antigen becomes denatured, the antibody may not recognize the antigen in question, but it may be the case that the antibody can access and recognize an otherwise inaccessible section of the antigen. Due to the fact that an antibody has a Y shape, it has a hinge region which allows flexibility when binding to two determinants. The regions of H and L chains are paired, and therefore the combination of H and L chain CDRs determine antigen specificity, and this plays a role in combinatorial diveristy—wherein variability is produced by different H and L chain combinations.
Define the mechanisms leading to lymphocyte diversity and how the lymphocyte repertoire is generated.
There are four mechanisms which lead to the generated diversity seen in lymphocytes. There mechanisms are, combinatorial diversity, junctional diversity, different combinations of H and L chains that pair to the Ag binding site, and somatic hypermutation. Combinatorial diversity refers to the use of different gene segments for V(D)J and VJ recombination. Junctional diversity refers to the addition or subtraction of nucleotides at joining segments by TdT. The mechanism of somatic hypermutation entails inducing point mutations in the rearranged V region genes, leading to enhanced binding of antigens. There are multiple copies of the V, D, and J regions on each chromosome. There is a radom selection of one gene segment for each type, and this number of different V and J regions at the L chain locus promotes diversity. The combination of combinatorial diversity and junctional diversity combined can potentially create 1.3x108 combinations.
Discuss how somatic recombination occurs in B lymphocyte lineage genetic segments
Somatic recombination in B lymphocytes occurs through the process of combining different regions of DNA to form a single transcript and single protein chain that combines and acts as the B cell receptor. This process is carried out through the use of several enzymes and DNA sequences themselves. The enzymes are as follows, VDJ recombinase, RAG-1 and RAG-2, Ku70 and Ku 80, DNA-Pk, Artemis, TdT and DNA ligase. The signal spacer is referred to as an RSS, which is a conserved block of seven nucleotides with twelve or twenty-three base pair spacer followed by a conserved block of nine nucleotides. These spaces give rise to the 12/23rule, which states that a gene segment flanked by the twelve base pair spacer can only be joined to a gene segment flanked by a twenty-three base pair spacer. This orientations preludes direct V to J joining in the heavy chain. So, to begin, RAG1/2 complex binds to each of the RSS sequences. RAG makes single stranded DNA breaks, making two separate joints and are ligated to form hairpin structures. Then, Ku70/80 binds to the DNA ends after cleavage, recruits DNA-PK and Artemis which opens the hairpin structure. TdT adds more nucleotides randomly to the ends of the V and J regions, and DNA ligase joins the two ends, joining together the VDJ/VJ regions.
) Identify the four mechanisms in place that contribute to lymphocyte receptor diversity
1) Combinatorial Diversity, 2) Junctional Diversity, 3) Different combinations of H and L chains that pair to form the Ag binding site, and 4) Somatic hypermutation.
Clonal Selection Theory
A fundamental tenent of the immune system (no longer a hypothesis) stating that every individual possess numerous clonally derived lymphocytes, each clone having arisen from a single precursor, expresses one antigen receptor, and is capable of recognizing and responding to a distinct antigenic determinant. When an antigen enters, it selects a specific preexisiting clone and activates it.
Side Chain Theory
Theory proposed by Paul Ehrlich to explain the immune response in living cells. Where side chains link with a particular toxin “like a key in a lock.” These side chains would then break off and become antibodies which would circulate throughout the body. The thought was that the cell would then become activated and then produce more of the antibodies its side chain encountered.
Naive Lymphocyte
: Mature T or B cells which have not been exposed to an antigen. Some of these cells circulate through the lymphatic system When these cells encounter an antigen, or an antigen is presented to them through an APC, the cell then becomes activated and undergoes a clonal expansion.
Effector Cell
The cells that perform effector functions during an immune response, such as secreting cytokines (ie helper T cells), killing microbes, killing microbe-infected host cells, or secreting antibodies
Proliferation
The increase in the number of cells due to some facet of the immune response, often due to cytokines or antigens activating lymphocytes
Clonal Deletion
A mechanism of lymphocyte tolerance in which an immature T cell in the thymus or an immature B cell in the bone marrow undergoes apoptotic death as a consequence of recognizing a self-antigen
Heavy Chain
The large polypeptide subunit of an antibody. The heavy chain defines the isotype of an antibody and are composed of one variable domain, one diversity domain, and several constant domains.
Light Chain
The small polypeptide subunit of an antibody, of which there are two types kappa and lambda chains. These are encoded on chromesome 2 and 22 respectively. Light chain class remains fixed for the life of the B lymphocyte.
Constant (C) Region:
: The portion of Ig or TCR polypeptide chains that does not vary in sequence among different clones and is not involved in antigen binding.
