Precommitment hypothesis

The precommitment hypothesis postulates that the precursor of an antibody-forming cell is already committed to produce antibody of a single specificity prior to contact with antigen. Basic to the precommitment hypothesis are the following assumptions ... 

The precommitment hypothesis is considered throughout this review in its strict sense, thus as precommitment to synthesis of a single species of antibody molecules. It will be referred to as strict precommitment. Where it would be experimentally undistinguishable from precommitment to form a small number of different specificities, it will be referred to as quasi precommitment. 

In obtaining experimental evidence for the precommitment hypothesis, the basic problem is to distinguish whether a cell, at the time when it is exposed to antigen, is yet uncommitted or already committed. 

The term uncommitted cell is ambiguous. For opponents of the precommitment hypothesis it may mean a pluripotential or totipotential cell which may gain its antibody-synthesizing capacity as a consequence of contact with antigen. Proponents of the precommitment hypothesis accept that immature uncommitted cells do exist, but they postulate that uncommitted cells cannot be triggered by antigen. 

This bears directly on the precommitment hypothesis, which predicts not only that a cell has to possess receptors of the same specificity as the antibody produced, but that no immunoglobulin receptors of other specificity should be present on the cell surface. Raff et al. (1973) designed an experiment to test whether or not this is true. Because of the fundamental importance of this experiment for the subject of this review, I am going to describe the experiment and discuss its significance in some detail. 

Hence it can be concluded that the above experiments strongly support the precommitment hypothesis. It is not possible to distinguish between strict precommitment and quasi precommitment (see Introduction) because the method is insufficiently sensitive. 

In spite of the overwhelming body of evidence in favour of the precommitment hypothesis we have to be aware of several experimental findings which are (or seem to be) incompatible with the precommitment hypothesis. 

The magnitude of the antibody response is usually not considered to be relevant for the precommitment hypothesis. If, however, a large number of antibody-forming cells were to appear early in the antibody response in the absence of cell division, then a considerable fraction of cells must have participated in the initiation of the antibody response. This might be incompatible with the precommitment hypothesis. 

Although the RNA transformation experiments are often considered to be arguments against the precommitment hypothesis, I believe that in fact they are irrelevant to the subject. First of all, it is not surprising that a cell equipped with a functional protein synthetic machinery would be able to translate RNA to protein if the former could enter the cell intact. It has recently been shown that RNA, injected into amphibian eggs, will be readily translated into myeloma polypeptide chain (Stevens and Williamson, 1972). I suggest the RNA transformation experiments should be disregarded in the present context as they probably do not reflect normal in vivo processes. 

The precommitment hypothesis entails the intrinsic assumption that the repertoire of the antibody-forming capacity in any individual cannot be larger than the number of lymphocytes the individual possesses. If a tadpole with a very small number of lymphocytes is able to respond by antibody production to any tested antigen, the following possibilities are implied ... 

Thus, I suggest that the evidence on the antibody response in small animals is as yet inconclusive. Nevertheless, the issue discussed above is probably the most significant impediment for accepting the precommitment hypothesis. 

I have defined the precommitment hypothesis as follows when a precursor of an antibody-forming cell meets an antigen for the first time, the cell is already committed to formation of antibody of a single specificity. 

The experimental evidence in favour of the precommitment hypothesis was based on the following findings ... 

The reported studies have supported the precommitment hypothesis at least in respect to B lymphocytes. No attempt has been made in this review to analyze the evidence for precommitment of T lymphocytes. There are many experiments showing that different subpopulations of T cells respond to different antigens (Salmon et al., 1971 Zoschke and Bach, 1971) and a thorough analysis of this evidence may well show that the precommitment hypothesis is as valid for T cells as for B cells. 

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