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Molecular Mimicry


Molecular mimicry, also called epitopic and antigenic mimicry, is one of the leading theories that attempt to explain why the immune system turns on its own body in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes.

In essence, the theory is very simple. The signature that the immune system uses to recognise a specific foreign invader, such as a particular virus or bacteria, also occurs in the body’s own tissue. Thus as well as attacking the invader, the immune system also mistakenly attacks its own body giving rise to autoimmune diseases.

To understand how molecular mimicry is thought to work, it is necessary to understand a little of how the immune system identifies foreign invaders.

The body recognises viruses, bacteria and fungi (generically called pathogens) by their unique proteins. Proteins are long strands of basic building blocks called amino acids, strung together like beads on a string. The amino acid sequences, and thus the proteins, are directly coded for in an organism’s DNA. There are 20 amino acids found in animal proteins and still others found in plants, bacteria and fungi. Thus, because proteins can be anything from a handful to over five thousand amino acids long, the number of different potential proteins is virtually limitless. The different proteins manufactured by different organisms is not only the reason that they look and behave differently to each other, but it also gives the immune system a unique signature to recognise them by.

When the immune system is introduced to a new pathogen, it locates small sections (around 10 amino acids long) of the pathogen’s proteins as markers to recognise it by and remembers them. These small sections are known as epitopes. This means that when the immune system encounters the pathogen for a second time, it will recognise it straight away and deal with it efficiently. This explains why we only get chicken pox or measles once.

Each pathogen will generate multiple immuno-reactive epitopes, usually several per protein. This helps the immune system recognise a pathogen which has mutated slightly. Even if one changed protein means that one epitope will no longer work for that pathogen, some of the others probably still will.

The immune system uses a type of cell called a lymphocyte to identify and remember the epitopes. Lymphocytes are covered with little receptors that lock into specific epitopes like two pieces of a jigsaw puzzle. Each lymphocyte has around 100,000 receptors but all the receptors on a single lymphocyte are identical to each other so that any one lymphocyte is only capable of locking onto one specific epitope.

The immune system is potentially able to make about a thousand million million distinct receptors, although the actual number present in the body at any given time is estimated to be somewhere between a hundred million and ten thousand million.

There are two main types of lymphocyte, T cells and B cells. T cells themselves fall into two categories, killer T cells, which directly attack pathogens and inject toxins into them, and helper T cells, which orchestrate the immune response. B cells shed their receptors in a soluble form known as antibodies when activated by their target epitope. B cells can also engulf pathogens and break down their proteins into smaller sections called antigens. These antigens are presented to other lymphocytes, particularly helper T cells, for analysis. This is called antigen presentation.

The problem that the immune system faces is molecular mimicry. What if epitopes located on a pathogen resemble epitopes in the body’s own tissue? The risk is that the same mechanisms used for destroying harmful invaders will be used against self proteins. This is known as autoimmunity.

The problem of autoimmunity is usually solved by testing T cells in the gland responsible for maturing them, the thymus. Here they are tested against a range of the body’s own proteins and those T cells that react with these proteins are not released.

Because B cells aren't matured in a single location, the problem is slightly more complex. To solve it, the immune system uses antigen presentation to helper T cells. B cells will not release their antibodies or clone themselves unless they can present to a helper T cell with an equivalent receptor. When such a T cell also recognises the epitope, it sends a signal to the B cell to activate itself. This is called costimulation.

Preventing lymphocytes from attacking self proteins is called self tolerance.

So how does molecular mimicry come to happen, if indeed it does? The answer to this is not entirely clear. One possible solution is that not all the body's proteins are expressed in the thymus. The immune system would then be free to produce lymphocyes that target epitopes on these proteins. There is some evidence that this is indeed the case. For example, one protein in myelin, the insulating sheath around nerve cells in the central nervous system, called Myelin Oligodendrocyte Glycoprotein (MOG), has been shown not to be expressed in the thymus [Bruno et al].

Molecular mimicry has been demonstrated or hinted at experimentally on numerous occasions in multiple sclerosis and in its animal models. The problem is that several infective agents or food proteins have been suggested as sources for cross-reactive epitopes (also called mimetopes). The front runners, at this point in time, are Epstein-Barr virus (EBV), Human Herpes Virus-6 (HHV-6) and the milk protein, butyrophilin (it is suggested that the immune system cross-reacts with both dietary milk and myelin). Moreover, several myelin proteins have also been suggested as locations of the mimetopes including Myelin Oligodendrocyte Glycoprotein (MOG), Myelin Basic Protein (MBP), Proteolipid Protein (PLP) and Oligodendrocyte-Specific Protein (OSP).

Molecular mimicry is one of several rival theories that attempt to explain the cause of multiple sclerosis. It is yet to be accepted by everybody and some prominent researchers have yet to be convinced.

Here is a table of some of the studies that have indicated that molecular mimicry may be involved in the pathogenesis of multiple sclerosis:
Infective agent Myelin protein Disease References
Epstein-Barr virus (EBV - the virus that causes Infectious Mononucleosis)   MS Lang et al, Esposito et al
MBP Rodent models of MS Ufret-Vincenty et al
Human Herpes Virus-6 (HHV-6) MBP MS Tejada-Simon et al, Cirone et al
Butyrophilin (a protein in liquid milk)  MOG MS Kennel De March et al, Stefferlet et al, Winer et al
Herpes Simplex Virus-1 (HSV-1 - the virus that causes cold sores)   MS Cortese et al, Esposito et al
Multiple Sclerosis-associated Retrovirus (MSRV) and Human Endogenous Retrovirus-W (HERV-W)   MS Jolivet-Reynaud et al
Human Coronavirus 229E MBP MS Talbot et al
Measles Virus (MV) MBP MS Pette et al
Seven Viral and one Bacterial peptide MBP MS Wucherpfennig et al
  OSP MS Bronstein et al
Rubella (the virus that causes German Measles) MOG Rodent models of MS Besson Duvanel et al
Theiler's Murine Encephalomyelitis Virus (TMEV - a virus used to initiate animal models of MS) PLP Rodent models of MS Olson et al, Miller et al, Miller et al
Semliki Forest Virus (SFV) MOG Rodent models of MS Mokhtarian et al
Maedi Visna virus (MVV - a virus which causes demyelinating encephalitis in sheep) MBP A sheep model of MS Davies et al

Molecular Mimicry links:
Autoimmunity provoked by infection
Molecular Mimicry and Antigen-specific T Cell Responses in MS
Autoimmunity due to Molecular Mimicry as a cause of Neurological Disease
Antibodies Directed against Rubella Virus Induce Demyelination in Rats
Autoimmunity provoked by infection
Structural basis of molecular mimicry
HLA, molecular mimicry and multiple sclerosis
Viruses can silently prime for and trigger CNS autoimmune disease

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