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Somatic hypermutation
 
 
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Somatic hypermutation (or SHM) is a mechanism inside cells
Cell (biology)

The cell is the structural and functional unit of all known Life organisms. It is the smallest unit of an organism that is classified as living, and is often called the building bricks of life....
 that is part of the way the immune system adapts
Adaptive immune system

The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic challenges. Thought to have arisen in the first Gnathostomata, the adaptive or "specific" immune system is activated by the ?non-specific? and evolutionarily older innate immune system ....
 to the new foreign elements which confront it (for example, microbes). SHM diversifies the receptors that the immune system uses to recognize foreign elements (antigen
Antigen

An antigen is a substance that prompts the generation of antibodies and can cause an immune response. The word originated from the notion that they can stimulate antibody generation....
s), and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation
Mutation

In biology, mutations are changes to the nucleotide sequence of the genetic material of an organism. Mutations can be caused by copying errors in the genetic material during cell division, by exposure to ultraviolet or ionizing radiation, chemical mutagens, or virus , or can be induced by the organism, itself, by cellular processes such as s...
 affecting the variable regions of immunoglobulin genes.






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Somatic hypermutation (or SHM) is a mechanism inside cells
Cell (biology)

The cell is the structural and functional unit of all known Life organisms. It is the smallest unit of an organism that is classified as living, and is often called the building bricks of life....
 that is part of the way the immune system adapts
Adaptive immune system

The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic challenges. Thought to have arisen in the first Gnathostomata, the adaptive or "specific" immune system is activated by the ?non-specific? and evolutionarily older innate immune system ....
 to the new foreign elements which confront it (for example, microbes). SHM diversifies the receptors that the immune system uses to recognize foreign elements (antigen
Antigen

An antigen is a substance that prompts the generation of antibodies and can cause an immune response. The word originated from the notion that they can stimulate antibody generation....
s), and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation
Mutation

In biology, mutations are changes to the nucleotide sequence of the genetic material of an organism. Mutations can be caused by copying errors in the genetic material during cell division, by exposure to ultraviolet or ionizing radiation, chemical mutagens, or virus , or can be induced by the organism, itself, by cellular processes such as s...
 affecting the variable regions of immunoglobulin genes. Unlike many other types of mutation
Mutation

In biology, mutations are changes to the nucleotide sequence of the genetic material of an organism. Mutations can be caused by copying errors in the genetic material during cell division, by exposure to ultraviolet or ionizing radiation, chemical mutagens, or virus , or can be induced by the organism, itself, by cellular processes such as s...
, SHM affects only individual immune cells, and the mutations are not transmitted to offspring
Offspring

In biology, offspring is the product of reproduction, a new organism produced by one or more parents.Collective offspring may be known as a brood or progeny in a more general way....
.

Mistargeted somatic hypermutation is currently under investigation as a possible mechanism in the development of B-cell lymphoma
B-cell lymphoma

The B-cell lymphomas are types of non-Hodgkin lymphoma affecting B cells. It develops more frequently in immunocompromised individuals ...
s.

Targets

When a B cell
B cell

B cells are lymphocytes that play a large role in the humoral immunity . The principal functions of B cells are to make antibody against antigens, perform the role of Antigen Presenting Cells and eventually develop into memory B cells after activation by antigen interaction....
 recognizes an antigen, it is stimulated to divide (or proliferate). During proliferation, the B cell receptor locus
Locus

The word locus is Latin for "place". It can mean:...
 undergoes an extremely high rate of somatic
Somatic

The term somatic refers to cells of the body, rather than gametes . In humans, somatic cells contain two copies of each chromosome , whereas eggs and sperm only contain one copy of each chromosome ....
 mutation, that is at least 105-106
SI prefix

An SI prefix is a name or associated symbol that precedes a basic unit of measure to form a decimal multiple . The abbreviation SI is from the French language name Syst?me International d?Unit?s ....
 fold greater than the normal rate of mutation across the genome. The mutations that occur are mainly single base substitutions, with occasional insertions and deletions and occur at “hotspots” located throughout DNA
DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetics instructions used in the development and functioning of all known living organisms and some viruses....
 that encodes the immunoglobulin variable region. This directed hypermutation allows for the selection of B cells that express immunoglobulin receptors possessing an enhanced ability to recognize and bind a specific foreign antigen
Antigen

An antigen is a substance that prompts the generation of antibodies and can cause an immune response. The word originated from the notion that they can stimulate antibody generation....
.

Mechanism

Cytosine Chemical Structure
Uracil Chemical Structure
Experimental evidence supports the view that the mechanism of SHM involves deamination
Deamination

Deamination is the removal of an amine group from a molecule.In the human body, deamination takes place in the liver. Deamination is the process by which amino acids are broken down when too much protein has been taken in....
 of cytosine
Cytosine

Cytosine is one of the five main bases found in DNA and RNA. It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ....
 to uracil
Uracil

Uracil is a common and naturally occurring pyrimidine derivative. Originally discovered in 1900, it was isolated by hydrolysis of yeast nuclein that was found in bovine thymus and spleen, herring, sperm, and wheat germ....
 in DNA by an enzyme called Activation-Induced (Cytidine) Deaminase
Activation-Induced (Cytidine) Deaminase

Activation-Induced Deaminase is a 24 kDa enzyme that removes the amino group from the cytidine base in DNA.AID is currently thought to be the master regulator of secondary antibody diversification....
, or AID. A cytosine:guanine
Guanine

Guanine is one of the five main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, thymine, and uracil. In DNA, guanine is paired with cytosine....
 pair is thus directly mutated a to a uracil:guanine mismatch. Uracil residues are not normally found in DNA, therefore, to maintain the integrity of the genome most of these mutations must be repaired by high-fidelity DNA mismatch repair
DNA mismatch repair

DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion and mis-incorporation of bases that can arise during DNA replication and Genetic recombination, as well as repairing some forms of DNA damage ....
 enzyme
Enzyme

Enzymes are biomolecules that catalysis chemical reactions. Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called Substrate , and the enzyme converts them into different molecules, the products....
s. The uracil bases are removed by the repair enzyme, uracil-DNA glycosylase. Error-prone DNA polymerases are then recruited to fill in the gap and create mutations.

The synthesis of this new DNA involves error-prone DNA polymerase
DNA polymerase

A DNA polymerase is an enzyme that catalyze the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best-known for their role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
s, which often introduce mutations either at the position of the deaminated cytosine itself or neighboring base pair
Base pair

In molecular biology, two nucleotides on opposite complementarity DNA or RNA strands that are connected via hydrogen bonds are called a base pair ....
s. During B cell division the immunoglobulin variable region DNA is transcribed
Transcription (genetics)

Transcription is the synthesis of RNA under the direction of DNA. RNA synthesis, or transcription, is the process of transcribing DNA nucleotide sequence information into RNA sequence information....
 and translated. The introduction of mutations in the rapidly-proliferating population of B cells ultimately culminates in the production of thousands of B cells, possessing slightly different receptors and varying specificity for the antigen, from which the B cell with highest affinities
Affinity

Affinity, in etymology affinity is the opposite of infinity . These two words have the same root coming from the Latin: finis = end....
 for the antigen can be selected. The B cells with the greatest affinity will then be selected to differentiate into long-lived plasma cell
Plasma cell

Plasma cells, also called plasma B cells or plasmocytes, are White blood cells of the immune system transported by the blood plasma and the lymphatic system....
s producing antibody
Antibody

Antibodies are gamma globulin proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacterium and viruses....
 and memory B cell
Memory B cell

Memory B cells are a B cell sub-type that are formed following primary infection....
s contributing to enhanced immune responses upon reinfection.

The hypermutation process also utilizes cells that auto-select against the 'signature' of an organism's own cells. It is hypothesized that failures of this auto-selection process may also lead to the development of an auto-immune response.

See also

  • Affinity maturation
    Affinity maturation

    In immunology, affinity maturation is the process by which B cell produce antibodies with increased affinity for antigen during the course of an immune response....
  • Anergy
    Anergy

    Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte immune tolerance....
  • Immune system
    Immune system

    An immune system is a collection of biological processes within an organism that protects against disease by identifying and killing pathogens and tumour cells....
  • V(D)J recombination
    V(D)J recombination

    VJ recombination is a mechanism of genetic recombination that occurs in vertebrates, which randomly selects and assembles segments of genes Genetic code specific proteins with important roles in the immune system....


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