The transcription factor T-bet

In the previous post I discussed tests for diseases. It is good to be able to get a high degree of certainty about whether an individual has a certain disease and this may have important implications for treatment. Under favourable circumstances a test may do more. Suppose that for a disease X there is a drug Y available which has the following properties. There is some, at least rough, quantitative measure for the severity of the disease at a given time. It is known that on average the severity of the disease is reduced by a significant percentage (e.g. 30%) when the drug is taken. It might, however, be that this average results from a few patients with a very large reduction in severity and a large number of patients with a small reduction in severity. Suppose that the drug is very expensive and has unpleasant side effects so that there is strong motivation not to prescribe it if it is not going to have a major benefit. Then it would be very useful to have a test which identifies those patients who are going to benefit before treatment is started.

A concrete example of the above is where the disease X is multiple sclerosis and the drug Y is one based on interferon . It has been suggested in a recent paper of Drulovic et. al. in the Journal of Neuroimmunology that the expression of a substance called T-bet in mononuclear cells in the blood may be prognostic for a good response to interferon treatment of MS patients. (A mononuclear cell means a white blood cell which is not a polymorphonuclear granulocyte.To say that T-bet is expressed in these cells means that they produce it.) Two other potential candidates for substances which might be prognostic, interferon and interleukin 17, do not give the same promising results.

So what is T-bet? The name, which was introduced in 2000, stands for ‘T-box expressed in T cells’. The name T-box denotes a class of genes which code for transcription factors. Note that the same name is often used for a gene and the protein it codes for. A transcription factor is a protein which binds to DNA and increases or decreases the extent to which certain genes are transcribed into RNA. It therefore influences the amount of the corresponding protein which the cell produces. Transcription factors are important for cell differentiation. All cells in the body have the same genes (almost – I do not want to get into exceptions here) and it is the expression of the genes in a given cell which determines which type of cell it is. As has been mentioned in previous posts T helper cells come in at least two types, Th1 and Th2, and a shift to a higher proportion of Th1 cells seems to be bad for MS. The substances T-bet and interferon are involved in the process of differentiation, pushing the cells towards Th1. In particular, T-bet seems to be the master regulator of this process. The details of the process are complicated. A recent paper by Edda Schulz, Luca Mariani, Andreas Radbruch and Thomas Höfer (Immunity 30, 673) has studied this both experimentally and theoretically.The theoretical part uses a mathematical (ODE) model. As mentioned in a previous post there is also another class of T cells called Th17. The difference between IL-17 and T-bet in MS indicated above seems to indicate that in that disease Th1 cells are more important than Th17 cells.

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