75

complete blood-counts. White-blood-cell counts have ranged from 1350 to 5620 per c.mm. and absolute lymphocyte-counts from 200 to 2248 per T and B cell proportions were studied using c.mm. rosette techniques at 3 and 9 days of age: T cells were 44% and 46%, respectively (control 50% on

four of six

both occasions), and B cells were 43 % and 19 % (control 32% and 35%). In-vitro lymphocyte stimulation with concanavalin A (con A) and P.H.A. at 3 days of age was diminished with stimulation indices of 6-3 and 6-4 for con A and P.H.A., respectively, as compared with control stimulation of 23-4 and 23-3. Immunoglobulin levels at 20 days of age were within normal limits (mg. per 100 ml.): IgG 750, IgA 0, IgM 5-4. Karyotype analysis of P.H.A.-stimulated peripheral blood performed on the tenth day revealed only XY cells. R.B.C. and lymphocyte A.D.A. studies were performed on samples taken at 9 days of age. No A.D.A. activity could be detected in R.B.C.S in the first week of life. A.D.A. activity could also not be detected using a prolonged incubation assay which can detect as little as 1-5 nmol per mg. Hb per hour or 1-5% of normal R.B.C. activity. In contrast, residual A.D.A. activity could be detected in mononuclear-cell/platelet preparations obtained after centrifugation of blood on a’HypaqueFicoll’ gradient. The child’s mononuclear-cell/platelet preparation contained only 0-865 nmol per mg. protein per minute as compared with 150±42 in normal

mononuclear-cell/platelet preparations.

finding of residual A.D.A. activity in the mononuclear-cell/platelet preparation has been previously The

observed in another child with classical S.C.I.D. and R.B.C.-A.D.A. deficiency 13 In the present case this residual activity did not represent chimxrism with maternal cells because all of the cells responding to P.H.A. had The presence early in life of both a male karyotype. peripheral-blood lymphocytes responsive to P.H.A. and con A as well as maternal antibodies probably accounts for the relative normality of this and similar children during the early weeks of life. We have demonstrated in this report the ability accurately to identify heterozygotes for A.D.A. deficiency and to diagnose the affected fetus in utero. These techniques will lead to more satisfactory genetic counselling in these families and will offer the option of selective abortion of affected fetuses or adequate preparation for therapy of an affected child. This work was aided by grants from the National Institutes of Health (Al 10343 and GM 19443) and the National Foundation. R. H. is a recipient of N.I.H. research career development

The ability to detect heterozygotes with 90% confidence has been reported in a study of a large kindred in which a child had previously been born with R.B.c.A.D.A. deficiency and S.C.I.D.3,l1 In the family reported here, in which a child had died with S.C.I.D. but whose A.D.A. status was unknown, we have identified the parents and other members as heterozygotes for A.D.A. deficiency. Accurate identification of carriers was made possible by the study of three generations, the use of two different methods for assay of R.B.C.-A.D.A. activity, and determination of the phenotypes of the electro-

phoretic A.D.A. polymorphism. The prenatal diagnosis of the homozygous state of A.D.A. deficiency was unambiguous and was confirmed by findings in the child after birth. The amniotic cells of the child at risk contained less than 15% of the A.D.A. activity seen in normal amniotic cells. The range of A.D.A. activity in the normal amniotic cells was large but appeared to be characteristic for the individual amniotic-cell culture. It will be of importance to compare the A.D.A. activity in fibroblasts derived from this child with that found in the amniotic cells, since we have found that fibroblasts of occasional affected children may have as much as 20% residual A.D.A. activity.12 Electrophoresis of fibroblast extracts containing such residual activity has revealed an electrophoretically altered tissue isozyme, probably representing a mutant enzyme 13 Variation in the amount of residual fibroblast A.D.A. activity may represent genetic heterogeneity which, if reflected in amniotic-fluid cell cultures, could lead to difficulty in distinguishing affected from carrier fetuses.

to

R. H.

REFERENCES

Rosen, F. S., Merler, E. in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, and D. S. Frederickson); p. 1643. New York, 1972. 2. Giblett, E. R., Anderson, J. E., Cohen, F., Pollara, B., Meuwissen, H. J. Lancet, 1972, ii, 1067. 3. Scott, C. R., Chen, S.-H., Giblett, E. R. J. clin. Invest. 1974, 53, 1.

1194. 4.

5. DISCUSSION

award Al 70254.

Requests for reprints should be addressed

6. 7.

8. 9. 10. 11. 12.

Hirschhorn, R., Levytska, V., Meuwissen, H. J., Pollara, B. Nature new Biol. 1973, 246, 200. Hirschhorn, R. J. clin. Invest. (in the press). Hirschhorn, R., Beratis, N. G. Lancet, 1973, ii, 1217. Hopkinson, D. A., Cook, P. J. L., Harris, H. Ann hum. Genet. 1969, 32, 361. Hirschhorn, R., Levytska, V. Cell. Immun. 1974, 12, 387. Spencer, N., Hopkinson, D., Harris, H. Ann. hum. Genet. 1968, 32, 9. Chen, S.-H., Scott, C. R. Am. J. hum. Genet. 1973, 25, 21a. Chen, S.-H., Scott, C. R., Giblett, E. R. ibid. 1974, 26, 103. Hirschhorn, R., Levytska, V., Parkman, R. J. clin. Invest. 1974, 53, 33a.

13.

Parkman, R., Rosen, F. S., Gelfand, E., Sanderson, A., Hirschhorn, R. Unpublished.

Hypothesis LOW-RENIN HYPERTENSION : NEPHROSCLEROSIS ?

J. D. SWALES Department of Medicine, General Hospital, Leicester LE5 4PW

A substantial group of patients with essential hypertension have abnorrenin levels which respond poorly to stimulow mally lation. Important differences in response to therapy and in prognosis have been described between these and other hypertensive patients. It is suggested that the vascular changes of nephrosclerosis, which may be seen in both hypertensive and normal subjects, result in a reduction of afferent arteriolar distensibility, with impairment of basal renin secretion and responsiveness. This hypothesis accords with both the known clinical characteristics of low-renin hypertension and with the known effect of arterial changes upon the activity of other baroreceptors.

Summary

76 INTRODUCTION

ThE belief that renin metabolism is normal in essential- hypertension has been widely discarded in recent years with the development and extensive use of sensitive assay procedures. One of the most widely investigated phenomena has been the existence of a substantial minority of hypertensive patients (203O %) with subnormal plasma-renin levels, which are not associated with aldosterone excess nor elevated by normal stimuli for renin secretion.1- This subgroup assumed more than academic interest with the claim that such patients have a low incidence of vascular complications.s At the same time there is substantial evidence to support the belief that the blood-pressure of these patients shows an unusually favourable response to diuretics.6 The sequence of events which leads to renin suppression in these circumstances has been keenly debated and can only be understood in relation to the normal physiology of renin secretion.

Renin Secretion The most important source of renin is the juxtaglomerular apparatus (J.G.A.) of the kidney. Important stimuli for renin secretion include extracellular volume depletion, reduction of renal perfusion pressure, potassium depletion, hyponatrxmia, and beta-adrenergic stimulation.’ The major renal baroreceptor responsible for the control of renin release is situated on the afferent arteriole, and is believed to respond, amongst other things, to changes in transmural pressure gradient, increased renal sympathetic activity, increased vasomotor tone, and changes in the elastic components of the arteriolar wall.’ An additional chemoreceptor, situated in the macula densa of the distal tubule,8 is probably important but not essential in the control of renin release. Thus, renin secretion still responds to hxmorrhage and reduced renal perfusion pressure even when glomerular filtration is prevented.9 Renin Secretion in Low-renin Hypertension In low-renin hypertension an abnormal stimulus might suppress juxtaglomerular renin secretion, or the defect might reside in the juxtaglomerular apparatus. Both hypotheses have been entertained. Thus extracellular-fluid expansion might be responsible for low renin values in this condition just as in primary aldosteronism.1O Although it has been suggested that an abnormal mineralocorticoid is secreted in some patients with low-renin hypertension," there are other possible reasons for extracellular and plasma-volume expansion. For instance, salt ingestion might be high or renal sodium excretion defective.12 According to this view, low-renin hypertension is a qualitatively different disease from hypertension in which renin levels are high. This provides the basis for Laragh’s classification of hypertension into subgroups where volume and vasoconstrictor factors predominate. 12 Unfortunately, the evidence for such volume expansion in low-renin hypertension is unconvincing. Two studies 3,13 in which a difference in volume (extracellular or sodium spaces) between low-renin and other hypertensives has been demonstrated are open to criticismand are indeed inconsistent with each other. Other studies have failed to demonstrate any difference in the relevant isotope spaces.14,15 Current evidence is clear on

point: fluid retention of the degree encountered primary aldosteronism is not seen in low-renin hypertension. There is even less evidence for interruption of the pathways which lead to renin secretion.*’ one

in

An alternative view is that the low-renin

state

is

a

phase in the evolution of hypertension. Plasma-renin levels are inversely correlated with age in patients with essential hypertension."* ’ However, even when due is made for age, allowance low in low-renin

renin levels

are

still abnor-

hypertension. It is therefore in addition that hypertensive patients show a greater than normal fall in renin secretion with time,’-, perhaps as a result of increased pressure in the afferent arteriole. 18 It still remains to be explained why only In addia minority of patients show low renin levels. have shown of that whilst the studies tion, majority are somewhat with low-renin patients hypertension mally suggested

older than the other subgroups,",’9 this has not been universally the case;=° and the observed differences in age are comparatively small. The following hypothesis attempts to reconcile the clinical features of lowrenin hypertension with known pathological changes in the kidney. THE HYPOTHESIS

Arteriolar nephrosclerosis renders the pressure receptor situated in the afferent arteriole less distensible and therefore relatively insensitive, thus impairing both basal renin secretion and the renin response to stimulation. Evidence in favour of this stems from several sources.

Nephrosclerosis Hypertension is associated with hyalinisation of the afferent arteriolar wall. This change begins in the subendothelial region and then extends to the mediae In .

the present context the relevant characteristic is that nephrosclerosis is patchy and proceeds at an irregular rate, and indeed may be absent altogether.22,23 Conversely, the lesion occurs in normotensive individuals and its incidence rises with age.24 Thus 16-5 % of normal individuals over the age of 50 exhibit this lesion.2’ There is a close analogy with renin secretion. Renin levels decline with age.26 Amongst normotensive individuals an impaired response to renin stimulation is largely confined to the over-50s and reaches 33% in the eighth decade.

Reversal

ofChanges Nephrosclerotic changes are not irreversible, and regression sometimes occurs in the presence of sustained hypertension 23 or even with a terminal fall in blood-pressure 23 Renin responsiveness may likewise return spontaneously in a significant proportion of patients with low-renin hypertension 2’ Treatment of such patients may also be associated with a return of responsiveness.28 ,

Baroreceptor Activity It is unfortunately impossible to record afferent-fibre activity of individual J.G.A.S. However, activity of the carotid and aortic arch baroreceptors can be studied. Rabbits with renal hypertension show a decreased baroreceptor activity and decreased sensitivity of the receptors to pressure change.29 Calciferol intoxication and experimental atherosclerosis also reduce such

77

sensitivity in rabbits."," In all these situations it was possible to demonstrate a reduction in distensibility of the appropriate vessel wall. It is unlikely that atheroma would play a role at the arteriolar level, but it seems probable that more diffuse vascular disease of the type found in nephrosclerosis might well influence juxtaglomerular baroreceptor activity. IMPLICATIONS

Differences in the natural history of the renin-

subgroups of hypertension are readily comprehensible, since selection of patients with low-renin hypertension will automatically select individuals who have benign nephrosclerosis. Additionally, patients may be diluted by borderline hypertensives who have nephrosclerosis due to ageing rather than hypertension. The factors which determine this lesion are complex and uncertain,23 but it may be related to duration, lability, and severity of hypertension as well as the patient’s age. However, patients with fibrinoid necrosis of the vessel wall due to malignant hypertension are likely to belong to a different renin subgroup unless they have previously passed through a phase of " benign " essential hypertension. The exceptionally good response to diuretic therapy is readily understood. Studies with angiotensin inhibitors indicate that elevation of circulating-renin levels plays an important role in maintaining bloodpressure in the face of sodium depletion both in man. and in the laboratory animal.’ When this response is impaired, it is therefore reasonable to anticipate that more profound fall in blood-pressure would take place. "

"

This need not indicate that fluid retention is responsible for the hypertension. Demonstration of a specifically beneficial effect of spironolactone, as compared with other diuretics, might constitute evidence against the present hypothesis. This claim is, however, unsubstantiated.6 REFERENCES 1. Helmer, O. M. Can. med. Ass. J. 1964, 90, 221. 2. Crane, M. G., Harris, J. J., Johns, V. J. Am. J. Med. 1972, 52, 457. 3. Jose, A., Crout, J. R., Kaplan, N. M. Ann. intern. Med. 1970, 72, 9. 4. Kuchel, O., Fishman, L. M., Liddle, G. W., Michelakis, A. ibid. 1967, 67, 791. 5. Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F. T., Krakoff, L. R., Bard, R. H., Buhler, F. R. New Engl. J. Med. 1972, 286, 441. 6. Dunn, M. J., Tannen, R. L. Kidney Int. 1974, 5, 317. 7. Davis, J. O. Am. J. Med. 1973, 55, 333. 8. Thurau, K. W. C., Dahlheim, H., Grüner, A., Mason, J., Granger, P. Circulation Res. 1972, 30-31, suppl. 2, p. 182. 9. Blaine, E. H., Davis, J. O., Prewitt, R. L. Am. J. Physiol. 1971, 220, 1593. 10. Chobanian, A. V., Burrows, B. A., Hollander, W. J. clin. Invest. 1961, 40, 416. 11. Melby, J. C., Dale, S. L., Wilson, T. E. Circulation Res. 1971,

28-29, suppl. 2, p. 143. Laragh, J. H. Am. J. Med. 1973, 55, 261. Woods, J. W., Liddle, G. W., Stant, E. G., Michelakis, A. M., Brill, A. B. Archs intern. Med. 1969, 123, 366. 14. Lebel, M., Schalekamp, M. A., Beevers, D. G., Brown, J. J., Davies, D. L., Fraser, R., Kremer, D., Lever, A. F., Morton, J. J., Robertson, J. I. S., Tree, M., Wilson, A. Lancet, 1974, ii, 308. 15. Schalekamp, M. A., Lebel, M., Beevers, D. G., Fraser, R., Kolsters, G., Birkenhager, W. H. ibid. p. 310. 16. Birkenhager, W. H., Schalekamp, M. A. D. H., Krauss, X. H., Kolsters, G., Schalekamp-Kuyken, M. P. A., Kroon, B. J. M., Teulings, F. A. G. Eur. J. clin. Invest. 1972, 2, 115. 17. Tuck, M., Williams, C. H., Cain, J. P., Sullivan, J. M., Dluhy, R. G. Am. J. Cardiol. 1973, 32, 637. 18. Brown, J. J., Lever, A. F., Robertson, J. I. S., Schalekamp, M. A. Lancet, 1974, ii, 320.

12. 13.

ROLE OF Fc RECEPTORS IN HERPES SIMPLEX VIRUS INFECTION ALAN S. RABSON JOSE C. COSTA Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.

It is suggested that Fc receptors which Sum ary appear on the surface of cells infected by herpes-simplex virus confer a biological advantage on the virus—perhaps by binding immunoglobulin

molecules or surface, thus

antigen-antibody complexes on the cell blocking viral antigenic sites, or by consuming antibody directed at surface viral antigen or by modifying replication of the virus. RECEPTORS for the Fc portion of immunoglobulins the surface of cells have been known for some time, but their precise biological function and significance in some of the cell types in which they are readily demonstrable are still unclear. In 1964 Watkins reported that sheep red blood-cells (R.B.C.) coated with anti-sheep R.B.c. antibody adsorbed to herpes-simplex virus (H.S.v.) infected cells but not to uninfected cells.l Later Yasuda and Milmgrom showed that this haemadsorption was mediated through a bond between the Fc fragment of the antibody coating the R.B.c. and an Fc receptor site which developed on the surface of the H.s.v.-infected cell.2 This development of an Fc receptor takes place early in the infectious cycle and may be due to uncovering of a cell receptor or the inserting of a viralcoded protein with receptor properties into the cell membrane. What is the biological significance of an Fc receptor in an H.s.v.-infected cell? When a cell supports replication of H.s.v. particles, virus-specific antigens appear on the cell membrane well before the viral replication cycle is complete 3 These antigens render the infected cell susceptible to recognition and destruction by the host immunological response. Such cells can be destroyed in four waysby antibody and complement mediated cell lysis,’ by the interaction of antibody, complement, and leucocytes,3 by specific cell-mediated Iysis,5 or by the synergistic effect of antibody and non-immune effector cells (antibody-dependent cell-mediated toxicity).6,7 It on

Brunner, H. R., Sealey, J. E., Laragh, J. H. Hypertension Manual (edited by J. H. Laragh); p. 71. New York, 1974. 20. Mroczek, W. J., Finnerty, F. A., Catt, K. J. Lancet, 1973, ii, 464. 21. Papper, S., Vaamonde, C. A. in Diseases of the Kidney (edited by M. B. Strauss and L. G. Welt).; p. 735. Boston, 1971. 22. Bell, E. T., Clawson, B. J. Archs Path. 1928, 5, 939. 23. Tracy, R. E., Toca, V. T. Lab. Invest. 1974, 30, 30. 24. Smith, J. P. J. Path. Bact. 1955, 69, 147. 25. Bell, E. T. Renal Diseases. Philadelphia, 1946. 26. Sambhi, M. P., Crane, M. G., Genest, J. Ann. intern. Med. 1973, 79, 411. 27. Crane, M. G., Harris, J. J., Johns, V. J. Am. J. Med. 1972, 52, 457. 28. Spark, R. F., O’Hare, C. M., Regan, R. M. Archs intern. Med. 1974, 133, 205. 29. Angell-James, J. E. Circulation Res. 1973, 32, 149. 30. Angell-James, J. E. J. Physiol., Lond. 1971, 217, 30P. 31. Angell-James, J. E. Circulation Res. 1974, 34, 27. 32. Haber, E., Sancho, J. Re. R., Barger, A. C. Third meeting of International Society of Hypertension, Milan, 1974. Clin. Sci. mol. med. (in the press). 33. Gavras, H., Brunner, H. R., Vaughan, E. D., Laragh, J. H. Science, 1973, 180, 1369. 19.