All the genetic information needed to make millions of different antibodies actually fit into a limited number of genes, and this is made possible because antibody genes are pieced together from widely scattered bits of DNA, and the possible combinations are nearly endless. As this gene forms, it assembles segments that will determine the variable-V, diversity-D, joining-J, and constant-C segments of this antibody molecule, a typical IgM heavy chain.
Variable (V), and constant regions (C) are genetically encoded. As the immune system needs to be capable of responding to something in the region of over 1000 antigens, there is a need for an enormous number of genes to provide for this. The amount of DNA that this would involve would therefore be enormous too, but nature has solved this problem in a very clever and unique way. (see under Antibodies)
In the germline DNA, the V genes encoding the antigen combining sites need to combine with the C constant region genes. Diversity of specificity is produced by additional interposed or linking genes. For eg: ....
An immunoglobulin (Ig) molecule consists of two light chains, and two heavy chains. Light chains (L chains) exist in two classes, lambda and kappa. In light chains, the "linking genes" are the J genes, which link V to C; so this produces a combination of V-J-C. Joining is imprecise, causing further variation, or combination diversity. (see under antibodies)
In the case of Heavy chains, (H Chains) there is yet another region interposed between V and J, this is the D (for diversity), gene segment. Thus in H chains, there is V-D-J-C, again with combination diversity. If then, a light chain variable region consists of 25 lambda V (variable) genes, and 5 J (link) genes, then there are already 125 possible combinations, disregarding imprecision of joining.
For kappa light chains, there are 5 V genes and 70 J genes, yielding 350 combinations. For Heavy chains, there are 100 V genes, 50 D genes, and 6 J genes, giving 30,000 combinations.
L=light chains are separated from H=heavy chains by disulphide (S-S) links.
Intrachain S-S links divide H and L chains into domains which are separately folded.
Thus, an IgG molecule contains 3 H heavy chain domains, written CH1, CH2 and CH3. Between CH1 and CH2, there are many cysteine and proline residues.
This is known as the hinge region and confers flexibility to the Fab arms (the area of the molecule, where antibody joins with an antigen) of the Ig molecule.
This is used when antibody interacts with antigen.
Disregarding combination diversity, this yields more than 109 combinations. Multiply this by joining imprecision, plus a heightened mutation rate of genes in the hypervariable region, it can be seen that from 261 genes, this process can exceed at least 1018 variations. (See Antibodies)
Genetic factors can affect an individual's immune system and its responses to foreign antigens in several ways.
Genes determine the variety of MHC molecules that individuals carry on their cells, and genes also influence the potential array of T-cell receptors present on T cells.
Regulatory Complement Proteins. (RCP's)
The Functions of RCP's.
1) Switch genes on /off
2) Regulate the genetic information from DNA, ( the grey area in the picture)
3) Convert the genetic information into a strand of RNA. (the brown area in the picture)
4) They release Neutrophils from the bone marrow. (see neutrophils)
RNA's in turn translate that genetic information from DNA, into protein structures. (the yellow area in the picture) Most genes are expressed as proteins.
RCP's bind to specific regulatory sequences of DNA, and act to switch genes on and off, and thereby regulate the transcription of genes; ie:-
RCP's convert the genetic information in a strand of DNA, into a strand of RNA , especially messenger RNA. (see yellow area of picture)
DNA, which stands for deoxyribonucleic acid, is the long-chain molecule that contains the genetic material (encoded hereditary characteristics) in living organisms. (De-oxy-rye-bon-new-clee-ic) acid, is a long linear polymer (see definition below) found in the nucleus of a cell, formed from nucleotides, and shaped like a double helix. It is associated with the transmissionion of genetic information. DNA, is The "king" of molecules.
RNA, which stands for ribonucleic acid, is also a long linear polymer (a long-chain) of nucleotides, found in the nucleus, but mainly in the cytoplasm of a cell, where it is associated with microsomes. It transmits the genetic information from DNA, to the cytoplasm, and controls certain chemical processes in the cell.
The function of RNA is to translate the genetic material stored in DNA, into protein structures. RNA essentially carries out the instructions of DNA.
Most genes are expressed as proteins. The synthesis within a cell of a particular protein can be detected by antibodies able to bind to that protein.
Any step of gene expression may be modulated, from the DNA -RNA Transcription step, to post-transational modification of a protein.
Definition of a Polymer: ( A polymer is a naturally occurring compound, consisting of large molecules
made up of a linked series of repeated simple monomers. (it can be made artificially too)
The Major Histocompatibility Complex (MHC)
(A synonym for human leukocyte antigens. )
MHC's are a large gene family and play an important role in the immune system, autoimmunity, and reproductive success. In humans, these genes are referred to as human leukocyte antigen (HLA) genes, although people often use the abbreviation MHC to refer to HLA gene products.
To clarify the usage, some of the biomedical literature uses HLA to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule; however this convention is not consistently adhered to.
MHC molecules are important components of the immune response. They allow cells that have been invaded by an infectious organism to be detected by cells of the immune system called T lymphocytes, or T cells.
The MHC molecules do this by presenting fragments of proteins (peptides) belonging to the invader on the surface of the cell. The T cell recognizes the foreign peptide attached to the MHC molecule and binds to it, an action that stimulates the T cell to either destroy or cure the infected cell. In uninfected healthy cells the MHC molecule presents peptides from its own cell (self peptides), to which T cells do not normally react. However, if the immune mechanism malfunctions and T cells react against self peptides, an autoimmune disease arises.
Genes in the MHC region are the subset that encodes cell-surface antigen-presenting proteins. The most intensely-studied HLA genes are the nine so-called classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1,HLA-DP1 HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1.
In humans, the MHC is divided into three regions: Class I, II, and III.
The A, B, and C genes belong to MHC class I,
The six D genes belong to class II.
The proteins encoded (to specify the genetic code for a protein molecule) by the MHC's, are expressed on the surface of cells and display both self antigens (peptide fragments from the cell itself) and nonself antigens (e.g. fragments of invading microrganisms) to a type of white blood cell called a Tcell. This Tcell has the capacity to kill or co-ordinate the killing of pathogens, infected or malfunctioning cells. (see link and HLA's) here... http://en.wikipedia.org/wiki/Major_histocompatibility_complex
The subsequent steps depend in part on which co-stimulatory molecules interact and how well they interact. Because these interactions are so critical to the response of the immune system, researchers are intensively studying them to find new therapies that could control or stop the immune system attack on self tissues and organs.
This same group of genes are also known as HLA's, Human Leukocyte Antigens. A group of molecules that are located on the surface of cells and are unique in each organism, enabling the body to distinguish self from nonself. (see quote below)
Human Leukocyte Antigens (HLA)
This group of genes (also known as MHC's ) control key steps in the immune response, especially those related to recognition by T cells of specific antigens
presented to them by antigen-presenting cells, such as the phagocytes=
macrophages, and Dendritic cells .
The MHC region is divided into three subgroups called MHC class I, MHC class II, and MHC class III.
The major HLA antigens are essential elements in immune function, and the different classes of HLA's, have different functions.
1) class I antigens (A, B & C) -Present peptides from inside the cell (including viral peptides if present.) These are self antigens, which are recognised and usually ignored. (An autoantigen is any constituent of the body's own tissues, capable of stimulating autoimmunity)
2)class II antigens (DR, DP, & DQ) -Present phagocytosed antigens from outside of the cell to T-lymphocytes. (These are self antigens which present fragments of non-self, antigens, to Tcells) Class II proteins are found only in the membranes of lymphocytes and phagocytic antigen presenting cells.
3)class III -Encodes for other immune components, such as complement components ( C2, C4, factorB) and some that encode cytokines.
The MHC proteins display fragmented pieces of an antigen on the host cell's surface. These antigens may be self or nonself. If they are nonself, there are two ways by which the foreign protein can be processed and recognized as being "nonself".
If the host is a leukocyte such as a monocyte or neutrophil, it may have engulfed the particle (be it bacterial, viral, or particulate matter), broken it apart using lysozymes, and displayed the fragments on Class II MHC molecules.
On the other hand, if a host cell was infected by bacteria or a virus, or was cancerous, it may have displayed the antigens on its surface with a Class I MHC molecule.
In particular, cancerous cells and cells infected by a virus have a tendency to display unusual, nonself antigens on their surface.
These nonself antigens, regardless of which type of MHC molecule they are displayed on, will initiate the "specific immunity" of the host's body.
It is important to note that cells constantly process endogenous proteins and present them within the context of MHC I.
Immune effector cells are trained not to react to self peptides within MHC, and as such are able to recognize when foreign peptides are being presented during an infection or cancer.
The MHC region is being scrutinized by immunologists for its pivotal role in the immune system, the MHC has also attracted the attention of many evolutionary biologists, due to the high levels of allelic diversity found within many of it's genes. Much theory has been devoted to explaining why this particular region of the genome harbors so much diversity, especially in light of its immunological importance .
HLAs (MHC's) also have a role in:
1) disease defence,
2) reproduction (may be involved in mate selection)
3) cancer (may be protective or fail to protect),
4) human disease,
5) in autoimmunity, (known to mediate many autoimmune diseases,)
6) as antigens, (are responsible for organ transplant rejection.)
Apart from the genes encoding these 6 major antigens, there are a large number of other genes, many involved in immune function located on the HLA complex. Diversity of HLA in human population is one aspect of disease defence, and, as a result, the chance of two unrelated individuals having identical HLA molecules on all loci is very low. (see link below)
Human leukocyte antigen - Wikipedia, the free encyclopedia
Genetic Polymorphisms, are a genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered. Polymorphisms arise through mutation. The mutation may be due to a change from one type of nucleotide to another, an insertion or deletion (collectively known as indels), or a rearrangement of nucleotides. (See under antibodies ) Once formed, a polymorphism can be inherited like any other DNA sequence, allowing its inheritance to be tracked from parent to child. (read Genetics Encyclopedia polymorphisms in links below)