From the National Magazine

Regulation of Antibody Production in Lupus Patients and Their Relatives

Dr Myer Salaman, Dept of Immunology, Imperical College School of Medicine, St Mary's Campus, Norfolk Place, London W2 1PG

As many of you will know, most of the problems suffered by people with SLE can be blamed on a group of proteins known as antibodies or immunoglobulins. The proper function of antibodies is to bind to invading infectious organisms and bring about their destruction. Unfortunately antibodies are sometimes made which can bind to components of a person's own cells - the so-called autoantibodies. In SLE such autoantibodies, for example those directed against DNA, may bind to material from dying cells circulating in the blood. The 'immune complexes' so formed overwhelm the normal procedure for their disposal and are deposited at various sites in the body such as the skin, joints or kidney, leading to inflammation and tissue damage. The autoantibodies may also cause problems by binding directly to components in the tissues.

Although all antibodies are related in structure they belong to five distinct immunoglobulin (Ig) classes. In lupus most attention is focussed on the classes known as IgM and IgG. IgM is the first class of antibody to be made when an immune response gets going. A switch later to IgG production is normal, but this switch in patients has special significance because it is the IgG autoantibodies that are particularly unwelcome.

About ten years ago in News & Views I described a study carried out with David Isenberg and Martin Seifert in which we looked at the level of normal and auto-antibodies in the blood of lupus patients and their healthy close relatives.We found that patients and relatives have a particular ability to make IgG responses. Sometimes relatives even made low levels of IgG autoantibodies, which is rare in healthy people. Almost certainly the reason for these findings is the existence of a genetic trait for high IgG response that is shared by both patients and relatives. This would be one of the genetic factors which contributes to the development of the disease.

With the assistance of Amy Kennell, Matthew Green and Maggie Larche, we have now completed a second family study looking not only at immunoglobulins but also at the white blood cells known as lymphocytes. We are most grateful to LUPUS UK for providing funds for this project. A low level of blood lymphocytes is a characteristic finding in patients with SLE. Although all types of lymphocyte may be reduced in number, particularly hard hit is the group of lymphocytes known as natural killer or NK cells. The term 'natural killer' reflects the ability of these cells to kill other cells, for example virus-infected cells. However, we now recognise that these cells release factors (cytokines) which are important in influencing the activity of other cells of the immune system. We confirmed the low numbers of NK cells in patients and also found a reduction in some relatives. As well as the numbers being reduced, the functional activity of the remaining cells was diminshed. As in the previous study high levels of IgG were found in many patients and relatives. There did not, however, appear to be any link between an abnormally low level of NK cells and an abnormally high level of IgG antibodies.

But when we looked at a much smaller population of lymphocytes known as NKT cells we had a surprise. These cells have attributes of both NK cells and the most numerous of the lymphocyte populations (T cells) and are thought to have the ability, like NK cells, to affect immune responses. Whenever IgG was raised in patients or relatives, NKT cells were low. It was as if NKT cells were needed to prevent IgG levels going up.

It seems then that we may have identified a group of cells with responsibility for regulation of IgG production. But even this small NKT population is a mixture of cells with different functions, and further work will be needed to identify precisely the cell type involved and how regulation takes place. This will best be studied in the laboratory using cell culture techniques. By use of blood samples from relatives the regulatory defect can be studied free of complications arising when patients' samples are tested, as the latter are likely to have been affected by changes in the body resulting from the disease and the drugs that are given. Regulation in any case is likely to be complex, involving not only NKT cells but NK cells,T lympocytes and, of course, the cells that actually produce antibodies - B lymphocytes.

A possible spin off from this work could be a new treatment for SLE based on increasing the activity of NKT cells so as to reduce the level of those undesireable IgG autoantibodies. This would have advantages over current therapy that relies on general suppression of the immune system, a process that may encourage infection.

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