Chronic myelocytic leukemia. Origin of some lymphocytes from leukemic stem cells.

In three patients with chronic myelocytic leukemia who were heterozygous at the X-linked glucose-6-phospháte dehydrogenase locus, lymphocytes were studied to determine if they had the same stem cell origin as the leukemic myeloid cells. Normal tissues such as skin had both B and A glucose-6-phosphate dehydrogenase isoenzymes, but the leukemic myelogenous cells displayed only one isoenzyme type, consistent with their clonal origin. A population of cells with undoubted thymus-derived (T)-lymphocyte characteristics had both isoenzymes. Presumably, then, these T cells did not arise from the leukemic stem cell, either because they antedated the development of leukemia in that stem cell or, more likely, because they arose from progenitors not involved by the disease. In contrast, another population of lymphocytes showed only one isoenzyme type, suggesting that it arose from the chronic myelocytic leukemia stem cell. However, although this population contained many cells with the characteristics of bone marrow-derived (B) lymphocytes, it is not certain that the single enzyme produced by the cells over all can be attributed to B lymphocytes rather than to contaminating non-B-lymphoid cells.

Malignancies induced by chlorambucil.

There is a high incidence of acute myeloid leukaemia in patients who have been treated with chlorambucil. This appears at least in part to be directly due to the drug itself and cannot be attributed to the disease processes for which the drug is given. Patients with connective tissue diseases may be more sensitive to this leukaemogenic effect of chlorambucil than patients with other non-malignant conditions.

Viruses and autoimmune diseases--adapting Koch's postulates.

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.

Endothelial prostacyclin release in systemic lupus erythematosus.

The ability of sera from patients with SLE to stimulate endothelial cell prostacyclin production was studied using a standardized assay system for testing the effects of serum on cultured human endothelial cell monolayers. The effects of 20 normal and 32 SLE sera on endothelial prostacyclin production were measured. No differences between the rates of prostacyclin production were seen between the two groups, either basally or when prostacyclin release was stimulated with thrombin or bradykinin. In the SLE samples there was no correlation between anticardiolipin IgG or IgM titres and their ability to stimulate basal or agonist-induced prostacyclin release. These results suggest that the elevated risk of thrombosis in SLE patients is not associated with inhibition of endothelial cell prostacyclin synthesis.

What is clinical immunology?

The clinical and laboratory details of 10 patients with predominantly immunological problems were circulated to selected physicians in different forms of hospital practice. In general, these physicians would prefer to select their own immunological tasks and could get these performed in their clinical pathology laboratories or regional immunology centres. Immunologists are seen predominantly as laboratory-based advisers rather than clinicians responsible for the care of such patients.

Sister-chromatid exchange frequencies in fibroblasts and lymphocytes of patients with systemic lupus erythematosus.

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.

Sister-chromatid exchange frequencies in lymphocytes of controls and patients with connective tissue diseases.

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 disease 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 sex 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.

Infectious arthritis in primary disorders of immunoglobulin synthesis.

Disorders of immunoglobulin synthesis are of great interest to rheumatologists. At the diagnostic level, such disorders not uncommonly mimic commoner rheumatic diseases, so it is important that the diagnostic possibility of immunodeficiency be kept in mind. Infections often complicate immunodeficiency and may present in an atypical manner. From the theoretical standpoint, the interactions between infectious agents and patients with impaired immunity suggest ways in which the same or similar agents could be responsible for arthritis of unknown etiology. Furthermore, many immunodeficiency disorders predispose to autoimmunity; establishing the mechanism of this association may offer good insights into the factors that trigger autoimmune disorders in patients with seemingly normal immune competence.

Immunosuppression and the rheumatic diseases.

Ignorance of the basic nature of rheumatoid arthritis precludes the introduction of rational schemes for using cytotoxic drugs. It is still plausible that the autoimmune and other immunological abnormalities which accompany this disease are the secondary effects of persistent antigen, for example, related to microbial infections. In this event, cytotoxic drugs may diminish the inflammatory response but their effects on immune responses would be irrelevant or even undesirable. Should rheumatoid arthritis prove to be a primary immunoproliferative disorder, cytotoxic drugs may prove to be of value not because of their conventional immunosuppressive effects but because of their selective action on the proliferating cells. Indeed, current evidence suggests that these drugs enhance rather than depress conventional immune responses, at least in the doses given to patients with rheumatic disorders.

[The aetiology of rheumatoid arthritis (author's transl)]. / Die atiologie der chronischen Polyarthritis

An ineffective aetiology for rheumatoid arthritis and other connective tissue diseases has been frequently postulated but never proven. Despite the failure to obtain firm evidence of viral infection in most patients with these disorders for several reasons this theory should not be discarded. Firstly several mechanisms have been discovered by which virus infections can persist in lymphocytes and other tissue thereby provoking inflammation without the production of complete readily detectable virus particles. Secondly there are numerous ways in which host resistance to virus can be subverted with the perpetuation of an ineffective or inappropriate immune response. Thirdly the immunopathological features of these diseases are entirely compatible with an infective aetiology. The main problem is likely to prove the difficulty in attributing a primary pathogenetic role to any isolated virus rather than regarding it as a passenger virus which has been non-specifically activated by the disease process. However preoccupation with a viral aetiology should not blind one to other possibilities since many environmental allergens can produce immunopathological disease of highly protean nature.

The viral theory of connective tissue diseases: a review.

For many years evidence for a viral aetiology of connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis has been sought by a variety of methods, including attempts at direct isolation, the study of rheumatoid synovial cells, ultrastructural examination of pathological material and assays of anti-viral antibody. No convincing proof has yet been obtained. However, a better understanding of the mechanisms of viral persistence, and the ways in which host defences can be subverted by viral infections has prompted other ways of approaching this problem. A viral aetiology for this group of diseases remains an attractive but unsubstantiated hypothesis.

Spontaneous production of B cell growth factors by SLE lymphocytes.

Systemic lupus erythematosus blood lymphocytes produce B cell growth factors (BCGF) spontaneously to an extent comparable with pokeweed mitogen-stimulated lymphocytes from normal donors. BCGF production by SLE lymphocytes is not increased by PWM and these cells are refractory to exogenous BCGF. Production requires B cells and irradiated T cells but not accessory cells. The properties of spontaneously synthesized BCGF differ in some respects from those induced by PWM. These findings suggest that the abnormal B cell proliferation characteristic of SLE may result, at least in part, from autostimulatory growth factors.