Int. J, Immunopharmac., Vol. I, pp. 81-84
0192-0561/79/0401-0081
$02.00/0
(~? Pergamon Press Ltd. 1979. Printed in Great Britain.
REVIEW/COMMENTARY
IMMUNOLOGICAL ASPECTS OF HYPERTENSION ULRIK GERNER SVENDSEN
Medical Department C, Glostrup Hospital, Glostrup 2600, Denmark (Received in final form 2 October 1978)
in hypertensively damaged blood vessels demonstrated the importance of immune reactions in hypertensive disease. In rats with acute Angiotensin II hypertension, a pattern of mesenterial arterioles with dilated areas separated by intervening constricted segments was observed. This model had been previously described by Giese 0966), who found the arterial reaction pattern to be identical to that observed in the intestine and retina of rats with renal hypertension due to clamping of one renal artery plus contralateral nephrectomy, as reported in the classic work of Byrom (1954). It was shown by Giese and Olsen, using tracer colloidal carbon particles, that altered arterial permeability occurred predominantly in the dilated segments of the arterial tree and never in the constricted areas. In these dilated areas it was also found that plasma proteins had penetrated into the vessel walls, although the actual r61e of such protein deposits in vascular degeneration is not yet established. However, assuming that a marked deposition of plasma proteins in the vascular wall is followed by fibrin production, the consequent disturbance of the oxygen and nutrient supply could eventually lead to death of cells comprising the vessel walls. Thus, it may be hypothesized that such pathological changes reveal or develop antigenic substances in the walls. An indication of immunological involvement is provided by the observation that an inflammatory cellular reaction does indeed take place after the disposition of plasma protein in the vessel walls (Olsen, 1971). Initially the infiltrating cells are polymorphonuclear leucocytes but later mononuclear cells predominate (a " p r i m a r y " cellular reaction). If an additional Angiotensin II hypertensive phase is initiated in rats 8-10 days after termination of the initial hypertensive effects, a "secondary" cellular reaction is seen to occur around damaged arterioles. This secondary cellular reaction lasted 2-3 times longer and was dominated by mononuclear cells from the very beginning, the number of cells being 3-10 times greater than in the primary response. When thoracic duct cells--known to contain a high percentage of effector T-lymphocytes--from
Despite considerable therapeutic and surgical advances, hypertension remains one of the most serious diseases of modern man. Although the pathogenesis of human hypertension is still only poorly understood, a wealth of data has been obtained in animals with experimentally induced hypertension. Various techniques have been employed to induce experimental hypertension, including renal artery constriction (Goldblatt, 1948), injections of extracts of the kidney (Giese, 1966), partial infarction of the kidney (Loomis, 1946) and treatment with desoxycorticosterone acetate (DOCA) and 1°70 saline drinking water (Seley, 1942). Considering the species and etiological differences, the observed structural changes in both the arterial system and the organs supplied by the affected vessels are remarkably similar in all animal models. Thus, the vascular disease produced in "high renin hypertension" (due to renal artery constriction, for example) is very similar to that produced in "low renin hypertension" as caused by DOCA/salt treatment. However, caution is necessary in extrapolating from the experimental models to the human disease in view of apparent species differences. The development and history of hypertensive disease in rats and mice closely resembles that observed in man. However, the characteristic inflammatory cellular reaction commonly seen in hypertensively damaged arteries is less pronounced in man than in mice and rats; in the latter species it may even occur spontaneously with age. Interestingly, this cellular reaction bears a close resemblance to that found in periarteritis nodosa, a disease associated with immunological responsiveness to a wide range of antigens in both humans and animals (for references see Heptinstall, 1974). The close similarity between periarteritis nodosa and aspects of hypertensive disease suggests that one or more factors may be common to their pathogenesis. During the past decade a number of studies on the possible involvement of the immune response in the hypertensive disease of man and animals has been undertaken. Research by Olsen (1971) on the course and function of the inflammatory cellular infiltration 81
82
ULRIK GERNER SVENDSEN
hypertensive (Angiotensin II) rats were transferred to untreated syngeneic rats, an inflammatory cellular reaction around hypertensively damaged arterioles developed in the recipients. This reaction was up to 10 times greater than the cellular reaction seen in rats receiving thoracic duct lymphocytes from normotensive donors (Olsen, 1971). Olsen (1971) interpreted these results as evidence for the involvement of delayed type hypersensitivity in this experimental rat model of hypertensive vascular disease. Later, a similar experiment was performed by Svendsen (1973) using renal hypertensive donors, and again a difference in cellular reactivity against damaged arterioles could be demonstrated between recipients which had received lymphocytes from hypertensive donors and recipients of "normotensive lymphocytes". The similarity of the observed cellular infiltrations to those known to be caused by immune reactions and the apparent ability of thoracic duct cells to induce a secondary cellular reaction, seemed to justify the conclusion (Olsen, 1971) that a delayed type immune reaction really is involved in experimental hypertensive vascular disease. However, it should be remembered that thoracic duct cells are a mixed population of cells, which include B-lymphocytes and monocytes, and therefore the actual effector cell involved in the perivascular cellular reaction remains undefined. Patients with essential hypertension have raised serum concentrations of IgG and IgA compared with normotensive controls (Ebringer & Doyle, 1970; Olsen, Hilden & Ibsen, 1973; Kristensen, 1978). Individual IgG levels have been shown to be positively correlated with blood pressure in untreated patients and in poorly controlled patients, but not in patients receiving effective treatment (Kristensen, 1978). Immunofluorescence studies revealed that autoantibodies to nuclear antigens, smooth muscles and parietal cells were present more often and with higher titres in patients with essential hypertension than in normotensive controls. Treatment of the high blood pressure decreased the prevalence of autoantibodies. Moreover, hypertensive patients with raised IgG concentrations or with serum autoantibodies more often had a family history of hypertension compared with similar patients showing no immunological changes (Kristensen & Andersen, 1978). Comparative migration inhibition studies (with aortic tissue as antigen) using leucocytes from both patients suffering from essential hypertension and normotensive controls, suggested the involvement of thymus dependent immune reactions in the hypertensive disease (Olsen & Loft, 1973). The observed immunological changes may be either the result of secondary reactions caused by
tissue damage associated with hypertension, or a possible indication of a primary immunopathological disorder responsible for the vascular lesions seen in hypertension. Some experimental evidence in support of the last explanation has been provided. White & Grollmann (1964a) reported the development of hypertension in rats injected with isologous arterial tissue incorporated in Freund's complete adjuvant. In subsequent experiments injections of homogenates of homologous kidney tissue were followed by the development of hypertension similar to that which follows unilateral infarction of the kidney. These workers also found that cortisone or 6-mercaptopurine inhibited the development of such experimental autoimmune hypertension, (White & Grollmann, 1964b). Okuda & Grollmann (1967) reported that the hypertension induced in rats by means of partial infarction of one kidney and contralateral nephrectomy could be transferred by means of viable lymph node cells into normotensive recipient rats. Subsequently, Svendsen (1976, 1977) showed that the chronic phase of this form of hypertension, as well as the hypertension following repeated injections of desoxycorticosterone acetate (DOCA) combined with 1% saline as drinking water, is dependent in mice on the presence of the thymus. Mice with congenital aplasia of the thymus failed to maintain a high blood pressure into the chronic phase of the hypertension, in contrast to littermates with normal thymus functions. Thymus transplantation in the athymic mice prior to the experiment induced the ability to perform other thymus dependent immune reactions, such as skin allograft rejections, and also induced the ability to maintain a high blood pressure well into the chronic phase of both forms of the experimental disease. Treatment with an alkylating agent such as cyclophosphamide, which is known to be effective against diseases in which T-cells are implicated (Bach, 1976), lowered the blood pressure in the chronic phase of hypertension due to partial infarction of the kidney, although such drugs were ineffective in the initial phase of the disease (Svendsen, 1977). On the basis of these results it has been proposed that the chronic phase of the hypertension which follows either DOCA and saline treatment or infarction of the kidney is thymus dependent (Svendsen, 1978). The introduction of strains of rats (Okamoto & Aoki, 1963) and mice (Hicks, Giltinan & Pye, 1965) with a spontaneously high arterial blood pressure has provided new opportunities for research on the pathogenesis of hypertension. Rojo-Ortega, Yeghiayan & Genest (1973) reported that the thymus of spontaneously hypertensive rats with severe disease showed a marked hyperplasia, including hypertrophy
Immunological Aspects of Hypertension of the epithelial cells and numerous plasma cells, and suggested that an autoimmune mechanism was involved in the development of the vascular lesions observed in these animals. Studies in different strains of mice showed that increased mean arterial blood pressure values were foundin both the C3H/Tif and, more pronouncedly, in the NZB/Cr strain of mice. This spontaneous hypertension could be thymus dependent, since congenital athymic mice of the same strains failed to develop similarly increased blood pressure levels. In addition, treatment with cyclophosphamide in doses without a hypotensive effect on the blood pressure in normotensive mice of other strains, resulted in a significant blood pressure decrease in hypertensive NZB/Cr mice before renal lesions had been established (Svendsen, 1977b). However, the natural history and pathobiology of the athymic mice used in the above experiments are still only poorly understood. Further studies will be necessary in order to fully appreciate the significance of the observed results. What do these new findings suggest regarding a possible link between hypertension and immunological processes? The increased levels of immunoglobulins in hypertensive patients and the association of autoantibodies with a family history of hypertension could be secondary to the hypertensive vascular damage, although the possibility of primary pathogenic involvement of the immune system cannot be excluded. The actual immune mechanisms (cellular a n d / o r humoral) involved in hypertensive disease remain to be established. Are specific effector mechanisms with direct vasopressor activity involved as proposed by White & Grollmann (1964b), or should non-specific effector mechanisms including increased viscosity, increased peripheral resistance, release of vasoactive substances or ischaemia of pressor sensitive organs such as the kidney be considered? Further studies are definitely required before such questions can be answered properly. A new area of immunological research which may elucidate the importance of immune reactions in hypertensive disease is genetic studies concerning the linkage of genes coding for spontaneously high arterial blood pressure (or susceptibility of experimentally induced hypertension) with genes of the major histocompatibility complex (MCH, also termed the H L A complex or in mice, the H-2 complex for references, see Klein, 1975; Bodmer, 1978). The H L A system is the most complex genetic system known to exist in man. It consists of many closely linked genes which control a variety of characters. Besides its crucial importance in organ transplantation, it has been found that the MHC contains genes which control the immune response to a variety
83
of antigens and also some of the components of the complement cascade. Studies of the function of the MHC in animals have greatly extended our knowledge of the function of the immune system. Moreover, certain diseases occur with a greater frequency in individuals possessing certain HLA factors. For example, H L A typing can be used diagnostically in ankylosing spondylitis (see review by Sachs & Brewerton, 1978). At present it is generally stated that the finding of an association between H L A and a disease points to an infectious a n d / o r autoimmune etiology. However, other explanations are possible and should be kept in mind, (Svejgaard, Hauge, Jersild, Platz, Ryder, Staub Nielsen & Thomsen, 1973). Thus, a demonstration of linkage of genes coding for high blood pressure with the MHC could provide indirect support for the pathogenic importance of immune reactions in hypertensive disease. In hybridization studies with spontaneously hypertensive NZB/Cr mice, it was found that the high blood pressure in this strain was inherited as a dominant trait. The genes responsible for phenotypic high blood pressure were found to be located outside the H-2 complex. However, H-2 typing of backcross generations and F2 hybrids gave a weak indication that genes in, or closely linked to, the H-2 complex did influence the spontaneously high blood pressure in the NZB/Cr mouse strain. However, only a few backcross and F2 hybrid mice were investigated, so that even though there were significant differences in mean blood pressure between the groups repeated studies with larger groups of animals will be necessary to convince the geneticists (Svendsen, Koch & Rubin, to be published). Studies in humans with essential hypertension revealed a significant increase of HLA-Bw 15 in treated patients with a family history of the disease (Kristensen, Andersen, Lamm & Kissmeyer-Nielsen, 1977), while others have found increased frequencies of HLA-B8 and HLA-B12 in such patients (LOw, Schersten, Santor, Thulin & Mittelmann, 1975; Gelsthorpe, Doughty, Bing, O'Mally, Smith & Talbot, 1975). On the basis of available results, conclusions regarding the mooted connection between hypertension and immunological factors are extremely difficult to draw, due to the complexity of hypertensive disease. The theoretical and technical difficulties of testing the complex immunogenetic relationships are considerable. Nevertheless, it seems reasonable to put forward two tentative hypotheses, at least one of which might have validity with regard to the possible importance of immune reactions in hypertensive disease. Firstly, some cases of human hypertension may exist which do have an immunological pathogenesis due to either subclinical renal
84
ULRIK GERNERSVENDSEN
i n f a r c t i o n or a genetically d e t e r m i n e d impaired capacity to m a i n t a i n self-tolerance. Secondly, a linkage of genes coding for hypertension with the M H C should p e r h a p s be considered a risk factor in certain patients with severe a n d progressive deteri-
o r a t i o n o f the vascular system a n d the o r g a n s supplied by affected vessels. In view o f the frequency a n d severity o f hypertensive disease in m o d e r n m a n , c o n t i n u e d experimental a n d clinical research along various immunological lines is indeed w a r r a n t e d .
REFERENCES BACH, J. F. (1976). The pharmacological and immunological basis for the use of immunosuppressive drugs. Drugs, !!, 1-13. BOOMER, W. F. (1978). The HLA system: Introduction. Br. reed. Bull., 34, 213-216. BYROM, F. B. (1954). The pathogenesis of hypertensive encephalopathy and its relation to the malignant phase of hypertension. Experimental evidence from the hypertensive rat. Lancet, ii0 201-21 I. EBRINGER, A. & DOYLE, A. E. (1970). Raised serum IgG levels in hypertension. Br. reed. J., 2, 146--148. GELSTHORPE, K., DOUGHTY, R. W., BING, R. F., O'MALLEY, B. C., SMITH, A. J. & TALBOT, S. (1975). HLA-antigens in essential hypertension. Lancet, i, 1039-1040. GIESE, J. (1966). The Pathogenesis o f Hypertensive Vascular Disease. Munksgaard, Copenhagen. GOLDBLATT, H. (1948). The Renal Origin o f Hypertension (Monograph). Charles C. Thomas, Springfield. HEPTtNSTALL, R. H. (1974). Pathology o f the Kidney, 2nd. Edn. Little, Brown & Co, Boston. HIcKs, J. D., GILTINAN, P. & PYE, J. (1965). A new method of measuring blood pressure in mice. Lancet, ii, 930--932. KLEIN, .J. (1975). Biology o f the Mouse Histocompatibility--2 Complex. Springer, New York. KRISTENSEN, B. O. (1978). Increased serum levels of immunoglobulins in untreated and treated essential hypertension. I: Relation to blood pressure. Acta med. scand., 203, 49-54. KRISTENSEN, B. O. & ANDERSEN, P. L. (1978). Autoantibodies in untreated and treated essential hypertension. Acta med. scand., 203, 55--59. KRISTENSEN, B. O., ANDERSEN,P. L., LAMM, L. U. & KISSMEYER-NIELSEN,F. (1977). HLA antigens in essential hypertension. Relation to familiar disposition and serum immunoglobulins. Tissue Antigens. 10, 70-74. LOOMIS, D. (1946). Hypertension and necrotizing arteritis in the rat following renal infarction. Archs. Path. 41,231-268. LOW, B., SCHERSTEN,l . , SANTOR,G., THULIN, T. & MITTEIMANN, F. (1975). HLA-B8 and wl5 in diabetes and essential hypertension. Lancet, i, 695. OKAMOTO, T. & AOKI, K. (1963). DeveLopment of a strain of spontaneously hypertensive rats. Jap Circul. J., 27,282-293. OKUDA, Z. • GROLLMANN,A. (1967). Passive transfer of autoimmune-induced hypertension in the rat by lymph node cells. Tex Rep. Biol. Med., 25,257-264. OLSEN, F. (1971). Inflammatory Cellular Reaction in Hypertensive Vascular Disease. Munksgaard, Copenhagen. OLSEN, F. (~ LOFT, B. (1973). Delayed hypersensitivity and high blood pressure in man. Acta path. microbiol, scand. (A), 81, 145--147. OLSEN, F., H ILDEN,M. (~ I BSEN, H. (1973). Raised levels of immunoglobulins in serum of hypertensive patients. A cta path. microbiol, scand. (B), 81,775-778. ROJO-ORTEGA, YEGHIAYAN, E. & GENEST, J. (1973). The thymus of spontaneously hypertensive rats: light- and electronmicroscopic studies. Clin. Sci. Mol. Med., 45, 141--145. SACHS, J. A. & BREWERSTON, D. A. (1978). HLA, ankylosing spondylitis and rheumatoid arthritis. Br. reed. Bull., 34, 275-278. SELEY, H. (1942). Production of nephrosclerosis by overdosage with desoxycorticosterone acetate. Can. reed. Ass. J., 47, 515--519. SVEJGAARO,A., HAUGE, M., JERSILD,C., Pt.ATZ, P., RYDER,L. P., STAUBNIELSEN, L. & THOMSEN,M. (1975). The HLA System. An Introductory Survey. Karger, Basel. SVENDSEN, U. G. 0973). Increased cellular reaction to damage caused by angiotension in arterioles of normal recipient rats after transfer of lymphocytes from hypertensive rats. Acta path. microbiol, stand. (A), 81,241-246. SVENDSEN, U. G. (1976). Evidence for an initial, thymus independent and a chronic, thymus dependent phase of DOCA and salt hypertension in mice. Acta path. microbiol, scand. (A), 84, 523 528. SVENDSEN, U. G. (1977a). The importance of thymus in the pathogenesis of the chronic phase of hypertension in mice following partial infarction of the kidney. Acta path. microbiol, scand. (14). 85, 539-547. SVENDSEN, U. G. (1977b). Spontaneous hypertension and hypertensive vascular disease in the NZB strain of mice. Acta path. microbiol, scand. (A), 85, 548--554. SVENDSEN,U. G. (1978). The importance of thymus for hypertension and hypertensive vascular disease in rats and mice. Acta path. microbiol, scand. (A), Suppl. 267. WHITE, F. N. & GROI.LMANN, A. (1964a). Experimental periarteritis nodosa in the rat. Archs path., 78, 31 36. WHITE, F. N. & GROI.I.MANN, A. (1964b). Autoimmune factors associated with infarction of the kidney. Nephron., l, 93--102.
0192-0561/79/0401-0081
$02.00/0
(~? Pergamon Press Ltd. 1979. Printed in Great Britain.
REVIEW/COMMENTARY
IMMUNOLOGICAL ASPECTS OF HYPERTENSION ULRIK GERNER SVENDSEN
Medical Department C, Glostrup Hospital, Glostrup 2600, Denmark (Received in final form 2 October 1978)
in hypertensively damaged blood vessels demonstrated the importance of immune reactions in hypertensive disease. In rats with acute Angiotensin II hypertension, a pattern of mesenterial arterioles with dilated areas separated by intervening constricted segments was observed. This model had been previously described by Giese 0966), who found the arterial reaction pattern to be identical to that observed in the intestine and retina of rats with renal hypertension due to clamping of one renal artery plus contralateral nephrectomy, as reported in the classic work of Byrom (1954). It was shown by Giese and Olsen, using tracer colloidal carbon particles, that altered arterial permeability occurred predominantly in the dilated segments of the arterial tree and never in the constricted areas. In these dilated areas it was also found that plasma proteins had penetrated into the vessel walls, although the actual r61e of such protein deposits in vascular degeneration is not yet established. However, assuming that a marked deposition of plasma proteins in the vascular wall is followed by fibrin production, the consequent disturbance of the oxygen and nutrient supply could eventually lead to death of cells comprising the vessel walls. Thus, it may be hypothesized that such pathological changes reveal or develop antigenic substances in the walls. An indication of immunological involvement is provided by the observation that an inflammatory cellular reaction does indeed take place after the disposition of plasma protein in the vessel walls (Olsen, 1971). Initially the infiltrating cells are polymorphonuclear leucocytes but later mononuclear cells predominate (a " p r i m a r y " cellular reaction). If an additional Angiotensin II hypertensive phase is initiated in rats 8-10 days after termination of the initial hypertensive effects, a "secondary" cellular reaction is seen to occur around damaged arterioles. This secondary cellular reaction lasted 2-3 times longer and was dominated by mononuclear cells from the very beginning, the number of cells being 3-10 times greater than in the primary response. When thoracic duct cells--known to contain a high percentage of effector T-lymphocytes--from
Despite considerable therapeutic and surgical advances, hypertension remains one of the most serious diseases of modern man. Although the pathogenesis of human hypertension is still only poorly understood, a wealth of data has been obtained in animals with experimentally induced hypertension. Various techniques have been employed to induce experimental hypertension, including renal artery constriction (Goldblatt, 1948), injections of extracts of the kidney (Giese, 1966), partial infarction of the kidney (Loomis, 1946) and treatment with desoxycorticosterone acetate (DOCA) and 1°70 saline drinking water (Seley, 1942). Considering the species and etiological differences, the observed structural changes in both the arterial system and the organs supplied by the affected vessels are remarkably similar in all animal models. Thus, the vascular disease produced in "high renin hypertension" (due to renal artery constriction, for example) is very similar to that produced in "low renin hypertension" as caused by DOCA/salt treatment. However, caution is necessary in extrapolating from the experimental models to the human disease in view of apparent species differences. The development and history of hypertensive disease in rats and mice closely resembles that observed in man. However, the characteristic inflammatory cellular reaction commonly seen in hypertensively damaged arteries is less pronounced in man than in mice and rats; in the latter species it may even occur spontaneously with age. Interestingly, this cellular reaction bears a close resemblance to that found in periarteritis nodosa, a disease associated with immunological responsiveness to a wide range of antigens in both humans and animals (for references see Heptinstall, 1974). The close similarity between periarteritis nodosa and aspects of hypertensive disease suggests that one or more factors may be common to their pathogenesis. During the past decade a number of studies on the possible involvement of the immune response in the hypertensive disease of man and animals has been undertaken. Research by Olsen (1971) on the course and function of the inflammatory cellular infiltration 81
82
ULRIK GERNER SVENDSEN
hypertensive (Angiotensin II) rats were transferred to untreated syngeneic rats, an inflammatory cellular reaction around hypertensively damaged arterioles developed in the recipients. This reaction was up to 10 times greater than the cellular reaction seen in rats receiving thoracic duct lymphocytes from normotensive donors (Olsen, 1971). Olsen (1971) interpreted these results as evidence for the involvement of delayed type hypersensitivity in this experimental rat model of hypertensive vascular disease. Later, a similar experiment was performed by Svendsen (1973) using renal hypertensive donors, and again a difference in cellular reactivity against damaged arterioles could be demonstrated between recipients which had received lymphocytes from hypertensive donors and recipients of "normotensive lymphocytes". The similarity of the observed cellular infiltrations to those known to be caused by immune reactions and the apparent ability of thoracic duct cells to induce a secondary cellular reaction, seemed to justify the conclusion (Olsen, 1971) that a delayed type immune reaction really is involved in experimental hypertensive vascular disease. However, it should be remembered that thoracic duct cells are a mixed population of cells, which include B-lymphocytes and monocytes, and therefore the actual effector cell involved in the perivascular cellular reaction remains undefined. Patients with essential hypertension have raised serum concentrations of IgG and IgA compared with normotensive controls (Ebringer & Doyle, 1970; Olsen, Hilden & Ibsen, 1973; Kristensen, 1978). Individual IgG levels have been shown to be positively correlated with blood pressure in untreated patients and in poorly controlled patients, but not in patients receiving effective treatment (Kristensen, 1978). Immunofluorescence studies revealed that autoantibodies to nuclear antigens, smooth muscles and parietal cells were present more often and with higher titres in patients with essential hypertension than in normotensive controls. Treatment of the high blood pressure decreased the prevalence of autoantibodies. Moreover, hypertensive patients with raised IgG concentrations or with serum autoantibodies more often had a family history of hypertension compared with similar patients showing no immunological changes (Kristensen & Andersen, 1978). Comparative migration inhibition studies (with aortic tissue as antigen) using leucocytes from both patients suffering from essential hypertension and normotensive controls, suggested the involvement of thymus dependent immune reactions in the hypertensive disease (Olsen & Loft, 1973). The observed immunological changes may be either the result of secondary reactions caused by
tissue damage associated with hypertension, or a possible indication of a primary immunopathological disorder responsible for the vascular lesions seen in hypertension. Some experimental evidence in support of the last explanation has been provided. White & Grollmann (1964a) reported the development of hypertension in rats injected with isologous arterial tissue incorporated in Freund's complete adjuvant. In subsequent experiments injections of homogenates of homologous kidney tissue were followed by the development of hypertension similar to that which follows unilateral infarction of the kidney. These workers also found that cortisone or 6-mercaptopurine inhibited the development of such experimental autoimmune hypertension, (White & Grollmann, 1964b). Okuda & Grollmann (1967) reported that the hypertension induced in rats by means of partial infarction of one kidney and contralateral nephrectomy could be transferred by means of viable lymph node cells into normotensive recipient rats. Subsequently, Svendsen (1976, 1977) showed that the chronic phase of this form of hypertension, as well as the hypertension following repeated injections of desoxycorticosterone acetate (DOCA) combined with 1% saline as drinking water, is dependent in mice on the presence of the thymus. Mice with congenital aplasia of the thymus failed to maintain a high blood pressure into the chronic phase of the hypertension, in contrast to littermates with normal thymus functions. Thymus transplantation in the athymic mice prior to the experiment induced the ability to perform other thymus dependent immune reactions, such as skin allograft rejections, and also induced the ability to maintain a high blood pressure well into the chronic phase of both forms of the experimental disease. Treatment with an alkylating agent such as cyclophosphamide, which is known to be effective against diseases in which T-cells are implicated (Bach, 1976), lowered the blood pressure in the chronic phase of hypertension due to partial infarction of the kidney, although such drugs were ineffective in the initial phase of the disease (Svendsen, 1977). On the basis of these results it has been proposed that the chronic phase of the hypertension which follows either DOCA and saline treatment or infarction of the kidney is thymus dependent (Svendsen, 1978). The introduction of strains of rats (Okamoto & Aoki, 1963) and mice (Hicks, Giltinan & Pye, 1965) with a spontaneously high arterial blood pressure has provided new opportunities for research on the pathogenesis of hypertension. Rojo-Ortega, Yeghiayan & Genest (1973) reported that the thymus of spontaneously hypertensive rats with severe disease showed a marked hyperplasia, including hypertrophy
Immunological Aspects of Hypertension of the epithelial cells and numerous plasma cells, and suggested that an autoimmune mechanism was involved in the development of the vascular lesions observed in these animals. Studies in different strains of mice showed that increased mean arterial blood pressure values were foundin both the C3H/Tif and, more pronouncedly, in the NZB/Cr strain of mice. This spontaneous hypertension could be thymus dependent, since congenital athymic mice of the same strains failed to develop similarly increased blood pressure levels. In addition, treatment with cyclophosphamide in doses without a hypotensive effect on the blood pressure in normotensive mice of other strains, resulted in a significant blood pressure decrease in hypertensive NZB/Cr mice before renal lesions had been established (Svendsen, 1977b). However, the natural history and pathobiology of the athymic mice used in the above experiments are still only poorly understood. Further studies will be necessary in order to fully appreciate the significance of the observed results. What do these new findings suggest regarding a possible link between hypertension and immunological processes? The increased levels of immunoglobulins in hypertensive patients and the association of autoantibodies with a family history of hypertension could be secondary to the hypertensive vascular damage, although the possibility of primary pathogenic involvement of the immune system cannot be excluded. The actual immune mechanisms (cellular a n d / o r humoral) involved in hypertensive disease remain to be established. Are specific effector mechanisms with direct vasopressor activity involved as proposed by White & Grollmann (1964b), or should non-specific effector mechanisms including increased viscosity, increased peripheral resistance, release of vasoactive substances or ischaemia of pressor sensitive organs such as the kidney be considered? Further studies are definitely required before such questions can be answered properly. A new area of immunological research which may elucidate the importance of immune reactions in hypertensive disease is genetic studies concerning the linkage of genes coding for spontaneously high arterial blood pressure (or susceptibility of experimentally induced hypertension) with genes of the major histocompatibility complex (MCH, also termed the H L A complex or in mice, the H-2 complex for references, see Klein, 1975; Bodmer, 1978). The H L A system is the most complex genetic system known to exist in man. It consists of many closely linked genes which control a variety of characters. Besides its crucial importance in organ transplantation, it has been found that the MHC contains genes which control the immune response to a variety
83
of antigens and also some of the components of the complement cascade. Studies of the function of the MHC in animals have greatly extended our knowledge of the function of the immune system. Moreover, certain diseases occur with a greater frequency in individuals possessing certain HLA factors. For example, H L A typing can be used diagnostically in ankylosing spondylitis (see review by Sachs & Brewerton, 1978). At present it is generally stated that the finding of an association between H L A and a disease points to an infectious a n d / o r autoimmune etiology. However, other explanations are possible and should be kept in mind, (Svejgaard, Hauge, Jersild, Platz, Ryder, Staub Nielsen & Thomsen, 1973). Thus, a demonstration of linkage of genes coding for high blood pressure with the MHC could provide indirect support for the pathogenic importance of immune reactions in hypertensive disease. In hybridization studies with spontaneously hypertensive NZB/Cr mice, it was found that the high blood pressure in this strain was inherited as a dominant trait. The genes responsible for phenotypic high blood pressure were found to be located outside the H-2 complex. However, H-2 typing of backcross generations and F2 hybrids gave a weak indication that genes in, or closely linked to, the H-2 complex did influence the spontaneously high blood pressure in the NZB/Cr mouse strain. However, only a few backcross and F2 hybrid mice were investigated, so that even though there were significant differences in mean blood pressure between the groups repeated studies with larger groups of animals will be necessary to convince the geneticists (Svendsen, Koch & Rubin, to be published). Studies in humans with essential hypertension revealed a significant increase of HLA-Bw 15 in treated patients with a family history of the disease (Kristensen, Andersen, Lamm & Kissmeyer-Nielsen, 1977), while others have found increased frequencies of HLA-B8 and HLA-B12 in such patients (LOw, Schersten, Santor, Thulin & Mittelmann, 1975; Gelsthorpe, Doughty, Bing, O'Mally, Smith & Talbot, 1975). On the basis of available results, conclusions regarding the mooted connection between hypertension and immunological factors are extremely difficult to draw, due to the complexity of hypertensive disease. The theoretical and technical difficulties of testing the complex immunogenetic relationships are considerable. Nevertheless, it seems reasonable to put forward two tentative hypotheses, at least one of which might have validity with regard to the possible importance of immune reactions in hypertensive disease. Firstly, some cases of human hypertension may exist which do have an immunological pathogenesis due to either subclinical renal
84
ULRIK GERNERSVENDSEN
i n f a r c t i o n or a genetically d e t e r m i n e d impaired capacity to m a i n t a i n self-tolerance. Secondly, a linkage of genes coding for hypertension with the M H C should p e r h a p s be considered a risk factor in certain patients with severe a n d progressive deteri-
o r a t i o n o f the vascular system a n d the o r g a n s supplied by affected vessels. In view o f the frequency a n d severity o f hypertensive disease in m o d e r n m a n , c o n t i n u e d experimental a n d clinical research along various immunological lines is indeed w a r r a n t e d .
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