B cells and T cells in autoimmunity
T cell theories of rheumatoid arthritis

The use of B cell depletion therapy in rheumatoid arthritis has taken some scientists and doctors by surprise. Many had assumed that rheumatoid arthritis was a "T cell disease". However, the vague idea that T cells are important in rheumatoid arthritis needs some more detailed thought. There are three different questions about T cells in rheumatoid arthritis. Firstly, is the disease initiated by a change in the behaviour of certain T cells? Secondly, is the disease dependent on T cells once it starts? Thirdly, is the inflammation in joints and other tissues directly caused by T cells? We would suggest that the answers to these questions are no, yes and no, and, as such, it is not very useful to call rheumatoid arthritis a T cell disease.

Fashionable theories about rheumatoid arthritis have tended to follow fashions in basic immunology research. Unfortunately, the solution to a problem which has been around for a hundred years is not particularly likely to be what was published in Nature last week. In the 1950s all that was known about immune responses was that there were antibodies. Autoimmunity came in to being as an idea because sufferers were found to have antibodies against themselves. However, it proved difficult to work out how the antibodies caused symptoms, so when T cells were discovered in the 1970s scientists shifted to studying T cells. Studies of T cells came to show that most B cells can only make antibody if "helped" by T cells. The idea grew up that T cells were in charge of the immune system, with B cells doing what they were told. This strengthened scientists view that T cells must be in charge of rheumatoid arthritis, although curiously they still saw B cells as in charge of the closely related disease, lupus.

By 1990 there was a further development in understanding of immunoregulation. It became clear that T cells were incapable of doing very much without the assistance of antibodies, produced by the plasma cell daughters of B cells. This meant that B cells were dependent on T cells but T cells were also dependent on B cells. The idea of some sort of cycle of two-way abnormal stimulation going on betwen T and B cells became fashionable in lupus, but the means by which it started remained a mystery. The hypothesis of a B cell driven cycle applying to all autoimmune disease developed at UCL against this backdrop. It was based on the concept that although both cells must be involved, a T cell initiation for autoimmunity never made any sense, but a B cell initiation might.

What were the arguments used by those who favoured a T cell drive for rheumaoid arthritis? Firstly, Stastny had found susceptibility to rheumatoid arthritis was linked to the tissue type genes known as HLA-DR or MHC class II. The only known function of MHC class II is to allow antigen to be presented to T cells to stimulate them to respond. Secondly, there were more T cells than B cells in the inflamed tissue. However, these arguments melt away on closer inspection. Stastny actually titled his paper "the association between rheumatoid arthritis and a B cell antigen", because MHC class II was first found on B cells. The involvement of MHC class II is just as important to the B cell as to the T cell and is usually essential for making antibodies. It means that the disease is dependent on T cells but tells us nothing about their role in initiation or in causing inflammation.

The presence of T cells in the inflamed tissues indicates nothing very much since T cells (of the TH1 type) are normally brought in to any inflamed tissue by mediators such as cytokines, whereas B cells are not. T cells have a job to do in inflammation but B cells do not. This means that the presence of T cells in the tissue tells us no more than the presence of phagocytes such as macrophages and granulocytes. More significantly, studies of very early inflammation in rheumatoid joints have shown over a period of forty years that the macrophages on the surface of the tissue get larger and increase in numbers before T cells arrive. That must mean that something else starts the inflammation going. Even when T cells do come in to the tissue they are in the wrong place to explain the activity of the macrophages on the tissue surface. Moreover, the surface macrophages do not show signs of being stimulated by T cell cytokines such as interferon gamma, nor is there much interferon gamma present in the joint.

These arguments led Zvaifler and Firestein to suggest that T cells play only a secondary role, if any, in the disease. However, the link with MHC class II is strong evidence that some sort of specific immune response is involved. That really means that the inflammation must be initiated by antibodies, a view that we had held for some twenty years without being able to make sense of what the antibodies were.

It is difficult to know why so many scientists were sure that rheumatoid factor antibodies were of no importance in rheumatoid arthritis, even though they were the main antibodies present and were the reason why the condition was considered autoimmune in the first place. It is somewhat bizarre that we should have discarded these antibodies and assumed that there must be an autoimmune response to something else that was more important, in the absence of any experimental evidence. In retrospect it appears completely illogical thinking. The problem was, of course, that nobody could see either what started off the production of rheumatoid factor or why it should cause inflammation specifically in joints. This led to the idea that there must be autoimmuity to a joint antigen even though this did not make sense in the context of the disease as a whole.

Throughout all this, no evidence for a consistent autoreactive T cell response was found. Moreover, treatment designed to remove T cells certainly removed them but had no beneficial effect on the arthritis. Perhaps the key sticking point for many people remained the idea that if antibody production was dependent on a specific T cell response then autoantibody production had to be driven by autoreactive T cells, which had lost tolerance to self. However, T cells reactive with IgG had not been found, despite the presence of antibodies to IgG (rheumatoid factors). Moreover, Roosneck and Lanzavecchia had been able to confirm the long recognised theoretical possibility that rheumatoid factors could be produced with the help of T cells recognising foreign, rather than self, antigens.

There remains a possibility, and even a probability, that the production of rheumatoid factors in rheumatoid arthritis depends on specific T cell responses, even if these are not truly autoreactive. The acquisition of T cell responses to foreign antigens constantly present in the body, such as Epsten Barr virus may be necessary for the generation of rheumatoid factor. There may also be a role for responses to antigens such as citrullinated peptides, which are neither self nor non-self, since they can be generated on a wide range of proteins.

Clinical trials of B cell depletion have shown that rheumatoid arthritis is almost totally B cell dependent. It is almost certainly T cell dependent as well, but the stochastic generation of B cells committed to IgG rheumatoid factor production seems to us to be the only viable explanation for the initiation of the disease and the subsequent inflammatory mechanism. We may be wrong, but are fairly sure that if we are the answer will not be that rheumatoid arthritis is a "T cell disease" but rather that the interaction between immunocompetent cells is even more subtle than we have suggested.