1242
intracardiac autonomic-nerve fibres is secondary to microvascular disease. Clearly, the best hope of saving diabetics from early cardiac death lies in prevention. There is increasing evidence that strict control of blood-glucose reduces the risk of long-term complications, and the control of hypertension, obesity, hyperlipidasmia, and smoking seems particularly important in diabetic patients.
ENTEROBACTER, B27, AND ANKYLOSING SPONDYLITIS
ABOUT 97% of patients with ankylosing spondylitis (A.S.) have the B27 histocompatibility antigen in their tissue typel and A.S. is extremely uncommon in B27-negative individuals. This is by far the strongest of all the associations between tissue type (HLA) and disease to have been reported,2 so it may be the best place to look for clues to the relationship. The molecular mimicry hypothesis,3 which is one of many hypotheses advanced, postulates antigenic similarities between presumptive pathogenic agents and the HLA antigen in question. Such similarity might lead to disease if the susceptible patient was slow to eliminate the pathogen, so allowing time for the latter to do damage. Alternatively, the host’s immune response to the pathogen might incidentally be self-damaging. Since only 20% of B27-positive people ever get the symptoms of A.S.4 it seems likely that additional factors, genetic5 or environmental, are involved in the pathogenesis of the disease. The finding by Ebringer and co-workers6 of antigen cross-reactivity between B27 and several gram-negative bacteria including Klebsiella pneumonix prompted them to test A.S. patients for these organisms. The frequency with which klebsiella/enterobacter species were isolated from the fseces of A.S. patients with active disease proved to be raised, so a longer-term study, the results of which have lately been reported,7 was undertaken. The most interesting finding was a correlation between the appearance of klebsiella species in the faeces of A.S. patients during remission and a subsequent relapse of the disease. Klebslellx were isolated more often from the faeces of patients with active disease, and less often from those with persistently inactive disease, than from the controls. Overall the frequency with which klebsiella/enterobacter species were recovered from A.S. patients either in or out of remission was no greater than in controls, so A.S. patients do not seem incapable of controlling the bacteria. Ebringer and co-workers’ findings could provide the molecular mimicry hypothesis with more secure experimental support than has previously existed. There are other mechanisms which could account for HLA/disease associations, including those suggested by defective in-vitro tests for cell-mediated immune responses in A.S.8 and multiple sclerosis.9 The search for disease-associated 1. Brewerton, D. A., et al. Lancet, 1973, i, 907. 2. Svejgaard, A., et al. Transplant. Rev. 1975, 22, 3. 3. Snell, G. D. Folia Biol. 1968, 14, 335. 4. Brewerton, D. A. Arthritis Rheum. 1976, 19, 656. 5. van der Linden, J. M. J. P., et al. Lancet, 1975, i, 520. 6. Ebnnger, A., Cowling, P., Ngwa Suh, N., James, D. C O., Ebringer, R. W. in HLA and Diseases (edited by J. Dausset and A. Svejgaard). INSERM,
Paris, 1976. 7. Ebnnger, R. A., Caldwell, D. R., Cowling, P., Ebringer, A. Ann. rheumat Dis.
8. 9.
1978, 37, 146.
Nikbm, B., et al. ibid. 34, suppl. 49. Ciongoli, A. K., et al. Lancet, 1973, ii, 1147.
tissue types was, in the first place, at least partly prompted by the recognition of inbred strains of mice whose ability to respond to certain synthetic antigens was inherited with particular tissue types. The immuneresponse genes, which control these responses in mice, map inside the mouse major histocompatibility complex on chromosome 17.10 Recent observations have modified previous views on the cellular basis of immune-response gene action. Injection of antigen with macrophages from responder mice into non-responders stimulates an immune response in the latter." The lack of response in non-responders seems to result from preferential stimulation of a specialised suppressor type of T lymphocyte by the animals’ macrophages. Why macrophages from non-responder animals should preferentially elicit a suppressor response by their own (or responder-strain) T lymphocytes is unclear. There are other examples of inherited constraints on immune responses which may operate through macrophages" or, independently of tissue type, through antibody affinity. 14 HLA types ’are easy to determine and they have been remarkably productive of disease associations, even outside the sphere of immunopathology. 15 Despite the difficulties of investigation, inherited but non-HLA-linked immunopathological disorders may prove to be at least as common.I
LONG-TERM SAFETY OF RECEPTOR-BLOCKING DRUGS
latest communication on beta-adrenoceptor blocking drugs from the Committee on Safety of Medicinesl6 is reassuring but cautious. The C.S.M. is still receiving reports of rashes or dry eyes associated with all the available drugs in this group, but the signs and symptoms appear to be reversible and reactions as severe as those associated with practolol have not been described for any other beta-blocker. Nevertheless, the C.S.M. urges doctors to continue to report all untoward events in patients on these drugs. Rightly so, for, despite the intensive adverse-effects studies on beta-blockers which were initiated when the practolol syndrome was recognised, new, or apparently new, unwanted effects THE
continue
to be reported. A surprisingly high frequency of visual hallucinations and illusions has been described by Flemingerl7 in patients who had recently had their daily dose of propranolol increased. As Fleminger pointed out, patients may not complain of these troubles spontaneously because they do not connect the symptoms with the drug, and it required a semistructured interview, including a check list for psychological and somatic symptoms, to uncover this problem. Another potentially important effect of several betablockers which has lately been described is a small but significant increase in fasting plasma-triglyceride concentrations after four weeks of drug treatment when
(17.5%)
10. Benacerraf, B., McDevitt, H. O. Science, 1972, 175, 273. 11. Benacerraf, B., Germain, R. N. Immun. Revs, 1978, 38, 78. 12. Debré, P., Kapp, J. A., Benacerraf, B. J. exp. Med. 1975, 142, 1436. 13. Paswell, J. H., Steward, N. W., Soothill, J. F. Clin. exp. Immun. 159. 14. Kim, Y. T., Siskind, G. W. Immunology, 1978, 34, 669. 15. Svejgaard, A., Ryder, C. P. Lancet, 1976, ii, 547. 16. Lancet, 1978, i, 1109. 17 Fleminger, R Br med. J. 1978, i, 1182.
1974, 17,
intracardiac autonomic-nerve fibres is secondary to microvascular disease. Clearly, the best hope of saving diabetics from early cardiac death lies in prevention. There is increasing evidence that strict control of blood-glucose reduces the risk of long-term complications, and the control of hypertension, obesity, hyperlipidasmia, and smoking seems particularly important in diabetic patients.
ENTEROBACTER, B27, AND ANKYLOSING SPONDYLITIS
ABOUT 97% of patients with ankylosing spondylitis (A.S.) have the B27 histocompatibility antigen in their tissue typel and A.S. is extremely uncommon in B27-negative individuals. This is by far the strongest of all the associations between tissue type (HLA) and disease to have been reported,2 so it may be the best place to look for clues to the relationship. The molecular mimicry hypothesis,3 which is one of many hypotheses advanced, postulates antigenic similarities between presumptive pathogenic agents and the HLA antigen in question. Such similarity might lead to disease if the susceptible patient was slow to eliminate the pathogen, so allowing time for the latter to do damage. Alternatively, the host’s immune response to the pathogen might incidentally be self-damaging. Since only 20% of B27-positive people ever get the symptoms of A.S.4 it seems likely that additional factors, genetic5 or environmental, are involved in the pathogenesis of the disease. The finding by Ebringer and co-workers6 of antigen cross-reactivity between B27 and several gram-negative bacteria including Klebsiella pneumonix prompted them to test A.S. patients for these organisms. The frequency with which klebsiella/enterobacter species were isolated from the fseces of A.S. patients with active disease proved to be raised, so a longer-term study, the results of which have lately been reported,7 was undertaken. The most interesting finding was a correlation between the appearance of klebsiella species in the faeces of A.S. patients during remission and a subsequent relapse of the disease. Klebslellx were isolated more often from the faeces of patients with active disease, and less often from those with persistently inactive disease, than from the controls. Overall the frequency with which klebsiella/enterobacter species were recovered from A.S. patients either in or out of remission was no greater than in controls, so A.S. patients do not seem incapable of controlling the bacteria. Ebringer and co-workers’ findings could provide the molecular mimicry hypothesis with more secure experimental support than has previously existed. There are other mechanisms which could account for HLA/disease associations, including those suggested by defective in-vitro tests for cell-mediated immune responses in A.S.8 and multiple sclerosis.9 The search for disease-associated 1. Brewerton, D. A., et al. Lancet, 1973, i, 907. 2. Svejgaard, A., et al. Transplant. Rev. 1975, 22, 3. 3. Snell, G. D. Folia Biol. 1968, 14, 335. 4. Brewerton, D. A. Arthritis Rheum. 1976, 19, 656. 5. van der Linden, J. M. J. P., et al. Lancet, 1975, i, 520. 6. Ebnnger, A., Cowling, P., Ngwa Suh, N., James, D. C O., Ebringer, R. W. in HLA and Diseases (edited by J. Dausset and A. Svejgaard). INSERM,
Paris, 1976. 7. Ebnnger, R. A., Caldwell, D. R., Cowling, P., Ebringer, A. Ann. rheumat Dis.
8. 9.
1978, 37, 146.
Nikbm, B., et al. ibid. 34, suppl. 49. Ciongoli, A. K., et al. Lancet, 1973, ii, 1147.
tissue types was, in the first place, at least partly prompted by the recognition of inbred strains of mice whose ability to respond to certain synthetic antigens was inherited with particular tissue types. The immuneresponse genes, which control these responses in mice, map inside the mouse major histocompatibility complex on chromosome 17.10 Recent observations have modified previous views on the cellular basis of immune-response gene action. Injection of antigen with macrophages from responder mice into non-responders stimulates an immune response in the latter." The lack of response in non-responders seems to result from preferential stimulation of a specialised suppressor type of T lymphocyte by the animals’ macrophages. Why macrophages from non-responder animals should preferentially elicit a suppressor response by their own (or responder-strain) T lymphocytes is unclear. There are other examples of inherited constraints on immune responses which may operate through macrophages" or, independently of tissue type, through antibody affinity. 14 HLA types ’are easy to determine and they have been remarkably productive of disease associations, even outside the sphere of immunopathology. 15 Despite the difficulties of investigation, inherited but non-HLA-linked immunopathological disorders may prove to be at least as common.I
LONG-TERM SAFETY OF RECEPTOR-BLOCKING DRUGS
latest communication on beta-adrenoceptor blocking drugs from the Committee on Safety of Medicinesl6 is reassuring but cautious. The C.S.M. is still receiving reports of rashes or dry eyes associated with all the available drugs in this group, but the signs and symptoms appear to be reversible and reactions as severe as those associated with practolol have not been described for any other beta-blocker. Nevertheless, the C.S.M. urges doctors to continue to report all untoward events in patients on these drugs. Rightly so, for, despite the intensive adverse-effects studies on beta-blockers which were initiated when the practolol syndrome was recognised, new, or apparently new, unwanted effects THE
continue
to be reported. A surprisingly high frequency of visual hallucinations and illusions has been described by Flemingerl7 in patients who had recently had their daily dose of propranolol increased. As Fleminger pointed out, patients may not complain of these troubles spontaneously because they do not connect the symptoms with the drug, and it required a semistructured interview, including a check list for psychological and somatic symptoms, to uncover this problem. Another potentially important effect of several betablockers which has lately been described is a small but significant increase in fasting plasma-triglyceride concentrations after four weeks of drug treatment when
(17.5%)
10. Benacerraf, B., McDevitt, H. O. Science, 1972, 175, 273. 11. Benacerraf, B., Germain, R. N. Immun. Revs, 1978, 38, 78. 12. Debré, P., Kapp, J. A., Benacerraf, B. J. exp. Med. 1975, 142, 1436. 13. Paswell, J. H., Steward, N. W., Soothill, J. F. Clin. exp. Immun. 159. 14. Kim, Y. T., Siskind, G. W. Immunology, 1978, 34, 669. 15. Svejgaard, A., Ryder, C. P. Lancet, 1976, ii, 547. 16. Lancet, 1978, i, 1109. 17 Fleminger, R Br med. J. 1978, i, 1182.
1974, 17,
