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Viral hypotheses for the aetiopathogenesis of autoimmune diseases are unproven. Indeed, a primary role for virus-induced autoimmune disease has yet to be fully established even in experimental systems. However new insights into virus-host interactions and improved technology justify fresh evaluation of these issues. We suggest modified Koch's postulates to test the viral hypothesis.

There are obvious difficulties in attempting to ascribe a viral aetiology to autoimmune diseases. Nevertheless, there are certain points relating to this issue which are generally recognized as fundamental, even if these are hard to resolve. Any theory must account for autoantigenic specificity and the polygenic factors conferring susceptibility to disease. The classical dogmas about loss of T or B cell tolerance or a combination of these cell populations are still valid, but the factors that lead to the breakdown of tolerance are more complex than was formerly envisaged. The complexities of host defense against viral infections are increasingly apparent. Furthermore, the classical, sharp distinction between innate or non-specific immunity and specific immunity is no longer tenable because these contribute to host defense in an integrated manner. The chain of events that lead from initial infection to sustained autoimmunity is likely to depend on quantitative factors, which can never be spelt out adequately in descriptive terms.

It has been considered by some workers that sister-chromatid exchange (SCE) frequencies are elevated in patients with scleroderma and systemic lupus erythematosus (SLE). However, these observations were based on limited numbers of patients. Other have postulated the presence of a defect in DNA repair in cells from patients with various connective tissue diseases, including scleroderma and SLE. We report our findings from a large survey of SCE frequencies in patients with connective tissue diseases. Their diagnoses are scleroderma, SLE, rheumatoid arthritis, juvenile chronic arthritis, Behcet's syndrome and polyarteritis nodosa. These patients had never received cytotoxic drugs. Healthy individuals, hospital patients with diagnoses other than connective tissue diseases and relatives of patients with scleroderma have been used as controls. The results have been analysed by generalized linear modelling, and we have shown that patients with SLE and Behcet's syndrome and controls with viral infections have elevated SCE frequencies, both before and after adjustments have been made for the effect on SCEs of an individual's age, smoking habits, sex and race. The SCEs of patients with scleroderma and their relatives were normal. SCE frequencies increased with age by 4% per decade and the SCE frequencies of smokers were approximately 12% higher than those of nonsmokers of similar age. The sec of an individual did not significantly affect SCEs but individuals from the Middle East were found to have lower counts than those originating from other parts of the world.

The proliferation of peripheral blood lymphocytes, cultured with Con A, can be inhibited by ionizing radiation. Lymphocytes from patients with conditions associated with autoimmunity, such as rheumatoid arthritis, systemic lupus erythematosus and polymyositis, are more radiosensitive than those from healthy volunteers or patients with conditions not associated with autoimmunity. The nuclear material isolated from the lymphocytes of patients with autoimmune diseases is, on average, lighter in density than the nuclear material from most healthy controls. This difference in density is not related to increased sensitivity to ionizing radiation but the degree of post-irradiation change in density (lightening) is proportional to the initial density, i.e. more dense nuclear material always shows a greater upward shift after radiation. The recovery of preirradiation density of nuclear material, 1 h after radiation exposure, taken as an indication of DNA repair, correlates with the radiosensitivity of lymphocyte proliferation (Con A response); failure to return to pre-irradiation density being associated with increased sensitivity of proliferative response. These results require extension but, taken with previously reported studies of the effects of DNA methylating agents, support the idea that DNA damage and its defective repair could be important in the aetio-pathogenesis of autoimmune disease.

It is suggested that thymus-dependent (T) lymphocytes play a key role in preventing autoimmunity, and that this is achieved by two mechanisms. First, T-lymphocytes are normally unresponsive to self-antigens, so that they do not cooperate with non-thymus-derived (B) cells in immune responses. B lymphocytes can, however, produce autoantibodies in several situations. Virus infection can lead to T-cell sensitisation, and through a carrier effect this can stimulate B cells to produce autoantibody. Attachment of a hapten to a self-constituent can achieve the same result. Non-antigen specific stimulation of T cells by adjuvants or by injections of allogeneic cells can overcome the need for antigen-specific stimulation of T cells and cooperation with B cells in the production of autoantibodies. Evidence is also presented that T cells can exert specific feedback control of autoantibody formation. Transfers of thymus cells from young to old mice reduces the incidence of autoimmune manifestations, and potentiation of autoantibody formation by administration of anti-lymphocytic serum occurs under conditions which suggest that control by T cells is overcome. Relaxation of T-cell control in ageing humans and experimental animals may be an important contributory factor in the development of autoimmunity.

This review outlines the principal methods available for separating mononuclear cells from human blood into different populations. It discusses the selection of appropriate techniques for different analytical purposes and gives the relevant references for practical details.

On the premise that somatic mutations may be involved in the pathogenesis of diseases such as systemic lupus erythematosus and rheumatoid arthritis, the proficiency of repair of 0 6 -methylguanine, a powerful, premutagenic, directly miscoding base lesion, was examined in the DNA of peripheral-blood mononuclear cells (mainly lymphocytes) from patients with such diseases. The capacity of lymphocytes to repair this lesion was impaired in many patients with autoimmune disease. In some healthy controls repair was also defective, whereas in other, non-autoimmune diseases, it was not. These findings support the hypothesis that this defect of repair was not simply a result of the disease state. It is therefore postulated that defective repair of 0 6 -methylguanine could be one of the factors determining the susceptibility to autoimmune diseases in genetically predisposed individuals.

Sister-chromatid exchange (SCE) frequencies have been measured in lymphocytes and fibroblasts of patients with systemic lupus erythematous (SLE) and healthy controls, and in lymphocytes of control patients with serum anti-nuclear antibodies (ANA) but no other disease manifestations of SLE. The SCEs of SLE lymphocytes were higher than those of the controls but the SCEs of the SLE fibroblasts did not differ from those of the controls. The SCEs of the controls with positive ANA did not differ significantly from those of the healthy controls. There was no correlation between SCE frequencies of the SLE lymphocytes and disease activity determined by many clinical and laboratory measurements. Primary and secondary DNA-repair defects in SLE cells are considered.

Cells with mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus may be detected in vitro by their resistance to the toxic effects of thioguanine. We have assessed HPRT mutants in peripheral blood lymphocytes of patients with connective tissue diseases who have been treated for long periods with cytotoxic drugs. The results from patients treated with cyclophosphamide were abnormal suggesting the presence of drug-induced mutations. The results from patients treated with chlorambucil or azathioprine did not differ from controls--either these drugs have not induced mutations or, more likely, the technique is not sufficiently sensitive to detect them. These possibilities are discussed. Specific mutations induced by cytotoxic drugs in patients with connective tissue diseases have not been previously recorded.

Food allergy can rarely be diagnosed by laboratory methods alone. The best approach is one which combines clinical observations with attempts to confirm the diagnosis by laboratory tests. In principle, the patient is put on a complete exclusion diet to see if the symptoms are thereby ameliorated. Attempts are made to provoke these by restoring items of diet in a planned sequence. It is usually necessary to intersperse these dietary items with placebo substances, that is, dummy foods so that both the doctor and the patient are free from bias in interpreting the results. The demonstration that disodium cromoglycate prevents this provocation provides additional evidence that a particular food is responsible for the disease symptoms. In addition, beneficial results with this drug indicate that the reaction is indeed allergic in nature.