In immunology

Immunology

Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...

, affinity maturation is the process by which B cell

B cell

B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...

s produce antibodies with increased affinity for antigen

Antigen

An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

 during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. A secondary response can elicit antibodies with several logfold greater affinity than in a primary response. The main principles of the in vivo affinity maturation namely mutation

Mutation

In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

 and selection

Selection

In the context of evolution, certain traits or alleles of genes segregating within a population may be subject to selection. Under selection, individuals with advantageous or "adaptive" traits tend to be more successful than their peers reproductively—meaning they contribute more offspring to the...

 are utilised for the biotechnological

Biotechnology

Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...

 approach of the in vitro affinity maturation.

In vivo affinity maturation

The process is thought to involve two interrelated processes, occurring in the germinal centers of the secondary lymphoid organs:

1. Somatic hypermutation
   Somatic hypermutation
   Somatic hypermutation is a mechanism inside cells that is part of the way the immune system adapts to the new foreign elements that confront it . SHM diversifies the receptors used by the immune system to recognize foreign elements and allows the immune system to adapt its response to new threats...
   
    (SHM): Mutations in the variable, antigen-binding coding sequences (known as complementarity-determining regions (CDR)) of the immunoglobulin genes. The mutation rate is up to 1,000,000 times higher than in cell lines outside the lymphoid system. Although the exact mechanism of the somatic hypermutation is still not known, a major role for the Activation-Induced (Cytidine) Deaminase
   Activation-Induced (Cytidine) Deaminase
   Activation-induced deaminase is a 24 kDa enzyme that creates deliberate mutations in DNA.AID removes the amino group from a cytidine base, turning it into a uridine...
   
    has been discussed. The increased mutation rate result in 1-2 mutations per CDR and cell generation. The mutations alter the binding specificity and binding affinities of the resultant antibodies.
2. Clonal selection
   Clonal selection
   The clonal selection hypothesis has become a widely accepted model for how the immune system responds to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens invading the body....
   
   : B cells that have undergone SHM must compete for limiting growth resources, including the availability of antigen. The follicular dendritic cells
   Follicular dendritic cells
   Follicular dendritic cells are cells of the immune system found in lymph follicles of secondary lymphoid organs and tertiary lymphoid organs. They are probably not of hematopoietic origin, though they look similar to true dendritic cells due to their filiform dendritic processes, but are of...
   
    (FDCs) of the germinal centers present antigen to the B cells, and only the B cell progeny with the highest affinities for antigen will be selected to survive. B cell progeny that have undergone SHM, but bind antigen with lower affinity will be out-competed, and be deleted. Over several rounds of selection, the resultant secreted antibodies produced will have effectively increased affinities for antigen.

In vitro affinity maturation

Like the natural prototype, the in vitro affinity maturation is based on the principles of mutation and selection. The in vitro affinity maturation has successfully been used to optimize antibodies, antibody fragments or other peptide

Peptide

Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 molecules like antibody mimetic

Antibody mimetic

Antibody mimetics are organic compounds that, like antibodies, can specifically bind antigens, but that are not structurally related to antibodies. They are usually artificial peptides or proteins with a molar mass of about 3 to 20 kDa...

s. Random mutations inside the CDRs are introduced using radiation

Radiation

In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...

, chemical mutagen

Mutagen

In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...

s or error-prone PCR. In addition, the genetical diversity can be increased by chain shuffling. Two or three rounds of mutation and selection using display methods like phage display

Phage display

Phage display is a method for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages to connect proteins with the genetic information that encodes them. Phage Display was originally invented by George P...

usually results in antibody fragments with affinities in the low nanomolar range.