Structure of immunoglobulins (Ig) or antibodies: Immunoglobulins are glycoproteins made of heavy and light polypeptide chains. An antibody’s specificity is determined by its antigen-binding site, while its effector function is determined by the heavy chain.
Each antibody monomer is made of 4 chains:
Light chains in an antibody (Ig) molecule are either kappa or lambda. Both heavy and light chains are divided into constant © and variable (V) regions.
Heavy chains contain:
Each light chain contains:
The variable domains of the heavy and light chains have hypervariable regions at the amino terminals. Together, these hypervariable regions form the antigen-binding site.
The Ch regions determine the class (isotype) of the antibody and therefore its effector functions. Five classes (isotypes) of antibodies are seen:
They are classified according to the heavy chain they contain - alpha, delta, epsilon, gamma, or mu, respectively.
The carboxy terminal of the heavy chains forms the Fc fragment. When an antibody is treated with the enzyme papain, it is cleaved into:
Immunoglobulin genes and function in immune response: The antibody response to an antigen is diverse, with the body producing many different antibody molecules that have unique affinities and specificities for the antigen. Humans have an antibody repertoire > 100 billion.
The V region of light chains is coded by two DNA segments:
These segments join by somatic recombination to form a complete V region exon. The constant region is coded by the C gene. The V and C exons then join, followed by splicing, to form the final mRNA transcript for light chains.
Heavy chain V regions are coded by three types of gene segments:
They undergo a similar process as light chains (DNA rearrangement and recombination) to form the final mRNA transcript for heavy chains. The total number of V, D, J, and C gene segments that code for immunoglobulins is more than 100, and they are located on chromosomes 2, 22, and 14.
The genes coding for the heavy chain C region are arranged in a series, with each gene coding a different isotype. The first antibodies produced during an immune response are IgM, followed by “class switching,” which allows different isotypes of antibodies to be produced (such as IgG, IgE, and IgA).
There are repetitive DNA sequences called “switch regions” located between the gene clusters that code for immunoglobulins. During isotype switching, DNA recombines at the switch regions, and the intermediate DNA is excised out. The remaining regions are then transcribed as one of the isotypes, depending on what type of antigen or pathogen initiated the immune response.
In addition to recombination and gene rearrangement, immunoglobulin diversity is generated by:
P and N nucleotides are added with the help of RAG and TdT enzymes to further increase diversity.
Somatic hypermutation is the process of introducing point mutations in the rearranged V region genes of activated B cells. As a result, multiple clones of B cells are produced in response to the same antigen. B cells with greater affinity for the inciting antigen are preferentially selected and increase in number, a phenomenon called “affinity maturation.”
T cell receptor (TCR): The T cell receptor consists of a disulfide-linked heterodimer of either:
These heterodimers associate with CD3 and a homodimer of ζ chains to form the TCR complex. The intracellular tails of the CD3 complex act as ITAMs (immunoreceptor tyrosine based activation motifs) and are involved in signal transduction. When activated by phosphorylation, CD3 associates intracellularly with tyrosine kinases such as ZAP 70.
The structural diversity of the TCR is attributable to gene rearrangements. Each chain has a variable (V) region and a constant © region. The exon for the V region of the TCR is formed by:
These variable gene segments join by somatic recombination (gene rearrangement) during T cell development in the thymus. This is followed by transcription and splicing of the V exon to the exon for the C region, forming mRNA that is then translated into the corresponding TCR chain.
Structural diversity of TCRs is mainly caused by gene rearrangements between V, D, and J gene segments. This is accomplished by more than 100 types of gene segments available for rearrangement. Hypervariable regions on the TCR differ between TCRs and contribute to recognition and binding to a wide variety of peptides presented by MHC.
Nucleotides are added between the V and J segments by TdT (terminal deoxynucleotidyl transferase), which helps increase the diversity of TCRs.
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