细胞生物学
variable used in lambda1987年诺贝尔生理学或医学奖
“抗体多样性的遗传学原理”
获奖者：利根川进
   
the genetic principle for generation of antibody diversity
Susumu Tonegawa
The Nobel Prize in Physiology or Medicine 1987
"for his discovery of the genetic principle for generation of antibody diversity"
Massachusetts Institute of Technology (MIT) 
Summary
Man is surrounded by viruses, bacteria and other microorganisms which constitute a threat to life and health. When these contagious agents enter the body they are recognized and attacked by the immune defence. Important tools in the recognition of this large variety of intruders are the antibodies. They are produced by white blood cells called B lymphocytes. The parts of the microorganisms against which antibodies react are called antigens. The number of different antigens that the body may encounter is enormous. We are dealing with hundreds of millions of substances, all of them with their specific structure. Strangely enough our immune defense have at hand antibodies which can identify all these molecules and start to counter attack - that is, hundreds of millions of different antibodies which are ready in the body already in advance before they have seen the antigen against which they can react!
This fabulous capacity to vary of antibodies is known since a couple of decades. The genetic background allowing this variation has, however, been an unsolved puzzle. The structure of the antibodies is determined by genes but as the human genome only contains about 100 000 genes it seemed unreasonable that they could allow the producti
on of maybe a billion different antibodies.
The man who explained this mystery is the Japanese Scientist Susumu Tonegawa. In a pioneering study published in 1976 Tonegawa could through a series of ingenious experiments show how parts of the genome of the cell (DNA) is redistributed under its differentiation from an embryonic cell to an antibody producing B lymphocyte. During the following two years Tonegawa completely dominated this area of research. He could in increasingly greater detail clarify how those parts of the genome which gives rise to antibody are moved around in order to allow each B lymphocyte to produce its own unique antibody.
Tonegawas discoveries have increased our knowledge about structure of our immune defense. They also open up possibilities to increase the immune response against pathogenic microorganism through vaccination - and also to improve inhibition of unwanted immune reactions.
The antibody, a molecule with many faces
The antibody is a protein where the building stones - amino acids normally form four chains. Two of these chains (polypeptides) are long and identical. The other two are short and are likewise identical. Together the four polypeptide chains form a Y-like symmetric molecule (Figure 1).
Figure 1. A picture of an antibody molecule with two long (T) and two short (L) polypeptide chains which are kept together by sulphur bridges (-S-S). The variable parts of a long chain (V,D, and J) and a light chain (Y and J) together form the antigen binding area of the antibody.
In man there are five different types of long chains which have been given letters M, D, G, A and E. The naming of the long chains forms the bases for the names of the five so called immunoglobulin classes: IgM, IgD, IgG and so on. The short chains are of two types: kappa or lambda. Each antibody molecule has - regardless of class - either two kappa or two lambda chains.
Towards the base of the Y there is a constant part where the sequence of amino acids is t
he same in all antibodies belonging to the same class. In the outer ends of the two arms of the Y, however, there exist a significant variation in the amino acid sequence when comparing different antibodies. In this variable part there are three areas where variation is very large. These areas constitute the walls in a "pocket" where the foreign substance, the antigen, will fit and can bind. You can make the analogy of an antibody molecule with a lobster where the claws of the lobster correspond to the antigen binding parts of the antibody.
Through its Y-form the antibody accordingly is endow two identical antigen binding areas. These areas have a more or less good fit to a particular antigen. The better the fit the harder to grip of the antigen and the more efficient the defense. As we are continuously confronted within an enormous variety of antigens we also have to have a large number of molecules there the variable parts do fit to different antigens.
The constant part of the antibody does also contain important biological functions. After the binding of the antibody to an antigen on the surface on for example a virus (Figure 2) t
he antibody molecule is changed in such a way that its constant part will activate important parts of the immune defense. Among these is the complement system which can directly make holes in bacteria and other microorganism and which also attract white blood cells such as macrophages ("big eaters") and granulocytes to the battle ground.

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