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The nutritional regulation of T lymphocyte function
Medical
Hypotheses
THE NUTRITIONAL
5:
969-985,
REGULATION
1979
OF T LYMPHOCYTE FUNCTION.
D.F. Horrobin, M.S. Manku, M. Oka, R.O. Morgan, S.C. Cunnane, T. Ghayur, M. Schweitzer and R.A. Karmali. Clinical Research of Montreal, 110 Pine Avenue West, Montreal H2W lR7, Canada.
A.I. Ally, Institute
SUMMARY Prostaglandin (PG) El plays a major role in the regulation of thymus development and T lymphocyte function and the evidence for this is reviewed. The production of PGEl is dependent on nutritional factors with linoleic acid, gamma-linolenic acid, pyridoxine, zinc and vitamin C playing key Inadequate intake of any one of these will lead to inadequate PGEl roles. formation and defective T lymphocyte function. Megadoses of any one are likely to be only minimally effective in the absence of adequate intakes By careful attention to diet it should be possible to of the others. in the large number of diseases including activate. T lymphocyte function rheumatoid arthritis, various auto-immune diseases, multiple sclerosis, and cancer in which such function is defective. It is possible that T lymphocytes may require both endogenous and exogenous PGEl in order to function adequately. It is therefore of particular interest that many cancer cells and virally infected cells are unable to make PGEI because they cannot convert linoleic acid to gamma-linolenic acid. The direct provision of gamma-linolenic or dihomo-gammalinolenic acids in these situations is worthy of full investigation. INTRODUCTION The central role of T lymphocytes in the resistance of the body to disease T lymphocytes play is one of the great themes of modern medical research. a critical role in cellular immunity. The sub-group of the helper T lymphocytes is required to enable B lymphocytes.to respond to specific antigens. The suppressor T lymphocytes are essential to control abnormally overactive B cells and to prevent the latter producing antibodies to a wide variety of both self antigens and commonly encountered exogenous antigens. T lymphocyte abnormalities have been described in almost every disease which we do not yet understand. Abnormal susceptibility to infections, cancer, autoimmune disorders of various types, “collagen” diseases, rheumatoid arthritis, multiple sclerosis, primary biliary cirrhosis, Crohn’s disease,
969
diabetes
me1 1 i tus are just some of the situations in which T lymphocyte uncertain as to whether It is, of course, defects have been described. the T lymphocyte defects are causal or are merely associated with the This will be decided only after we can normalise T cell function disease. There is enormous interest specificqlly and then follow the consequences.
in this possibility on the part of the pharmaceutical industry and there is some evidence that both levamisole and penicillamine may exert some of One attractive concept their favourabie effects by activating T cells. is that a fundamental T cell failure could produce a wide variety of different diseases depending on the genetic characteristics and environmental Correction of the T cell failure would therefore history of the individual. be effective in many different clinical situations. One factor that has largely been ignored is the possibility of regulating Recent evidence strongly suggests T cell function by nutritional means. that prostaglandin (PG) El may be of central importance in normal T cell The formation of PGEl is very susceptible to manipulation defunction. pending on the nutritional intake of essential fatty acids, other fats, carbohydrates, pyridoxine, zinc, ascorbic acid and alcohol. There are therefore many opportunities for regulating T lymphocyte function using nutritional techniques. The purpose of this paper is to present all the evidence which suggests that PGEl does regulate T lymphocytes and that PGEl levels may be manipulated by diet. PROSTAGLAND I N E 1 and
THYMUS DEVELOPMENT
There are two series of prostaglandins derived from the linoleic acid series of essential fatty acids (EFAs). The 1 series are derived from dihomogammalinolenic acid (DGLA) and the 2 series from arachidonic acid Both precursors are stored as esterified lipids in most and probably (AA). all cells of the body. However in most tissues the amounts of AA greatly exceed DGLA, and there has been a tendency, on this basis, to ignore 1 series PGs. It is therefore of particular interest that one of the tissues in which rather large amounts of PGEl have been identified is the thymus In the calf and the human PGEl was the only PG identified and (1 ,293). in most species there seems to be more PGEl in the thymus than in any other tissue, raising the possibility that it may be playing a functional role. That this distinct
possibility lines of
is probably evidence.
correct.
is
strongly
suggested
by
several
1.
PGEl in vitro has an effect very similar to that of thymic hormone in causing maturation oi T lymphocytes (4). PGEl had a biphasic effect with the stimulating action being reversed at high concentrations, a form of dose response which is very common with PGEl.
2.
Prolactin is able to enhance the formation of PGEl in rat vascular tissue (5). Its action on PGEl in the thymus has not been investigated but it is possible that it has a similar effect. In prolactin-deficient dwarf mice, the thymus atrophies on weaning when the animals are deprived of prolactin in the milk. Prolactin injections prevent this The thymus also atrophies on weaning in Bar Harbor 129 atrophy (6). dystrophic mice (7,8,9) and this atrophy can be in part prevented by exogenous prolactin injections (10). 970
3.
In Bar Harbor 129 with gamma-linolenic GLA is the (10) -
4.
Glucocorticoids tion (5,ll).
5.
Lithium, at concentrations found in plasma depression, inhibits formation of PGEl (5). thymus atrophy in rats (12).
6.
Zinc seems to be necessary for the mobilisation of DGLA from DGLA esters and hence for the formation of PGEl (5,13). Zinc deficiency leads to severe thymus atrophy in animals (14,15) and in humans. The most dramatic example of this is acrodermatitis enteropathica which appears to be a disease in which the zinc absorption mechanism in the intestine is defective (16,17,18,19). All the features of the disease can be reversed by high doses of oral zinc which overcome the block. These patients are hairless and have a general failure of the immune It seems not to have system: both defects respond completely to zinc. been generally realised by immunologists that this is a human model of the nude mouse (20) ! Less dramatically but perhaps in the long run malnourished children, who have small thymuses and more importantly, defective ccl 1 mediated immunity, respond to zinc supplementation with an increase in thymus size and restoration of normal immune responses
mice thymus atrophy can be prevented by treatment acid (GLA) in the form of evening primrose oil immediate precursor of DGLA and hence of PGEl.
at physiological Glucocorticoids
concentrations cause dramatic
inhibit PGEl thymus atrophy. in
humans treated Li thi urn causes
forma-
for manic severe
(21).
7.
Ascorbic acid at physiological concentrations is important for the conversion of DGLA to PGEl (22). Ascorbic acid seems to be important in the production of a thymic humoral factor (23,24).
Although each single item is open to criticism and to alternative the overall impression must be that PGEl is important in tions, opment and functioning of the thymus and hence of T lymphocytes. PGEl
and
explanathe devel-
MATURE T LYMPHOCYTE FUNCTION
The NZB/W mouse is widely used as an animal model of a state of defective T The most compelling evidence for a cell and overactive B cell function. Treatment of role of PGEl in T cell function has come from this model. these animals with exogenous PGEl substantially prolongs survival, maintains normal T cell function and inhibits the overactive B cells, preventing the deposition of immune complexes in the kidneys (25,26,27). Treatment with Since this mouse GLA, a precursor of PGEl, has similar effects (28). model is remarkably similar to human systemic lupus erythematosus, the possibi 1 i ty of treating the human disease with PGEl or its precursors is an attractive one. Adjuvant arthritis in rats also seems to be a disease in which defective T cell function plays a part since the syndrome is exaggerated by T cell Exogenous PGEl treatment in this situation also prevents the depletion. onset of the disease and retards inflammation (29).
971
Other evidence cells is largely pretations but 1.
for
the role indirect. the overall
of PGEl in Again each impression
regulation item is is
of function of open to alternative
mature inter-
~_
persuasive.
In adults made vitamin C deficient there is qreatly enhanced susceptibility to infection suggesting immune system failure. In a major study under carefully controlled conditions all five adults expcsed to selective vitamin C deficiency developed features of Sjogren’s syndrome, a classic situation in which defective cell mediated immunity is coupled In vitamin C del’i;it:nwith evidence of overactive B lymphocytes (30). guinea pigs transplants are not rejected whereas vitamin C inject ii-!*>c enable rejection to occur normally (31). Penicillamine and levamisole are both widely used as immunostimuTants and there is evidence that they may work in part by activating T suppressor cells and inhibiting overactive B cells, for example in primarv Both agents have act ions which are consiscert bi 1 iary cirrhosis (32). with enhancement of PGEl synthesis (33,34). Of course they also have ; ‘j c L /:: many other effects and the use of penicillamine, in particular, plicated by its zinc-chelating property which will tend to inhibir PGEI synthesis if body zinc stores become depleted. In adults to fluctuate a possible
with
acrodermatitis with the zinc cause.
enteropathica intake. Variations
the
immune in PGEl
status seems formation a!!(~
Coichicine seems remarkably effective in control 1 ing the inf1ammaic~r.y episodes and immune complex deposition in familial Mediterranean fever (35,36) and there is preliminary evidence that it may be of value Tr! multiple sclerosis (37) another disease in which T cell defects rm;. play a role. In unpublished studies we have been able to show that very low concentrations of colchicine seem able to enhance the effects of agents like zinc which stimulate PGEl formation. The mechanism inhibition of 6.
In of
of steroid-induced PGEl synthesis
vitro PGEl at T lymphocytes
immunosuppression be a candidate.
must
low concentrations to measles infected
was able to cells (38).
is
double
unknown,
the
but
adhere::<.@
Again the overall impression is that PGEl and agents which stimulate PGEI synthesis may be able to enhance the activity of at least some types of T It is important to note, however, that here as with many of the cells. other biological effects of PGEl there is evidence of a biphasic bellHigh levels of PGEl fail to cause maturation shaped dose response curve. of T lymphocytes (4)) reduce lymphocyte mediated cytotoxicity (39) and depress various types of immune responses (40,41). Prolactin, which inhibits phytohaemagglutinin responsiveness of enhances PGEl synthesis, High levels of intake of essential fatty acids may human lymphocytes (42). inhibit the development of experimental allergic encephalomyel i tis in anima 1s and the rejection of renal transplants in humans (43,44,45). There ii,
972
therefore a possibility that overproduction of PGEl may reduce the efficiency of the immune system either because at high concentrations its stimulating effect on T lymphocytes is last or reversed or because such high concentrations oversuppress B lymphocyte function. Clearly much work remains to be done in sorting out precisely the effects of PGEl (and of other PGs) on the individual components of the immune system, Such biphasic effects may help to extraordinarily dosage.
explain why difficult
penicillamine drugs to
and manage,
levamisole particularly
have in
proved relation
such to
INFLAt+IATION There is now an overwhelming amount of evidence to indicate that in most inflammatory situations there is an overproduction of 2 series PGs from arachidonic acid and that the aspirin-like anti-inflammatory drugs work largely by inhibiting this overproduction. It is therefore surprising to find that there are consistent reports that PGs, and 3n particular PGEl, may also be anti-inflammatory (46,47,25,26,27,25). What may be the explanation? as already discussed, PGEl may be anti-inflammatory because it In part, reduces B cell activity, but that is not the whole story. PGEl itself may be a regulator of the arachidonic acid cascade and in platelets has been shown to block the mobilisation of free arachidonic acid (48). This mechanism is potentially important because of the great discrepancy between stores of AA and DGLA in most tissues. The amount of AA exceeds that of DGLA by 10 to 40 fold, except in the human liver where the AA:DGLA ratio is only 4:l (49). This means that in a situation where supplies of EFAs are inadequate, DGLA stores will be depleted at a time when AA stores have Reduction of PGEl formation in this situation will hard1 y been touched. therefore lead to Jver-production of 2 series PGs because of loss of control of mobilisation of AA from the large tissue stores. Two recently described situations in humans indicate that this is a practical and not merely a theoretical concept. Children with cystic fibrosis have reduced levels of linoleic acid either because of a primary defect or as a consequence of Circulating to inadequateEFA absorption. pancreatic failure leading elevated (50). It might therefore levels of 2 series PGs are strikingly of extra linoleic acid which can be conhave been expected that pr 0 vision In contrast, raise concentrations of 2 series PGs. verted to AA would further 1 inoleic acid supplementat on led to a fall of 2 series PG levels to normal. Our interpretation of this is that the 2 series overproduction was due to inadequate PGEl formation. Restoration of the DGLA stores by EFA supplementation al lowed restoration of normal PGEl synthesis and of normal control in humans with excessive over the 2 series pathway ( 51 952). Similarly menstrual bleeding circulating levels of 2 series PGs are up and the bleeding can in part be controlled by inhibitors of PG synthesis (53). Again one would have expected EFAs to aggravate the situation but in four women with excessive menstrual flow (3 with intra-uterine contraceptives) we have shown over a period of a year that bleeding can be successfully controlled It is possible that the antiby EFA repletion using evening primrose oil. fami 1 i al Mediterranean fever and inflammatory effects of colchicine in gout, Behr;et!s syndrome (54) may be related to enhanced PGEl formation.
973
CANCER AND VIRAL INFECTIONS There is no doubt that cell mediated immunity is to viral Infections. Much of the current research predicated on the somewhat less certain assumption to malignant disease is dependent upon cell-mediated
important in resistance effort in cancer is that resistance immunity.
The preceding discussion provides very strong reasons for believing that PGEl may be of major importance in the regulation of T lymphocytes and of ccl 1 mediated immune mechanisms. It is not clear whether PGEl must be produced by the lymphocytes themselves or must be provided exogenously. Both may be important but the series of studies by Zurier on the NZB/W mouse leave no doubt that exogenous PGEl can be effective. Since this is the case, it is possible that PGEl production by target tissues may be a critical factor in determining the effectiveness of the immune response. It is therefore of extraordinary interest that the great majority of malignant and virally-transformed ccl 1s are unable to produce PGEl. This is because, coincident with transformation or malignant change, the ability to convert linoleic acid to GLA is lost (55,56). Since cell stores of GLA and DGLA are extremely limited, such cells are effectively unable to produce PGEl . The importance of this loss of delta-6-desaturase activity is as yet uncertain. It has been suggested that it is merely an accidental and unimportant consequence of the massive cell disruption which Imust inevitably be associated with malignant change or viral infection. if 52 it is very surprising that the loss is so consistent and that it never seems to be associated with the loss of the closely related delta-s-desaturase which converts DGLA to AA. If production of PGEl within a tissue cytes to mount a response against that the importance of this loss of the it, emphasizing. NUTRITIONAL
REGULATION
is important in tissue or against delta-6-desaturase
OF PGEl
enabling T lymphosome component of hardly needs
SYNTHESIS
If PGEl is important in T lymphocyte function then it is possible that the immune system could be modulated by nutritional changes which determine PGEl formation. The nutritional and other factors which can modify the pathway have recently been much more clearly understood. Essential fatty acids, pyridoxine (vi tamin B6), zinc and vitamin C are all important. There is evidence that in some members of Western societies intake of all four of these agents may be marginal and therefore that a nutritional failure of PGEl synthesis may be common. If so it is surely desirable to try to correct this by nutritional measures which are unlikely to over-ride the endogenous control mechanisms. Drugs may over-ride these control mechanisms. Not only that but if, as is the case with penicillamine and levamisole, part of their effect may be dependent on PGEl synthesis, that effectiveness wi 11 be severely 1 imited if PGEl precursors are not available. Part of the variation in responsiveness to these two agents may relate to differences between patients in nutritionalstatus.
974
DlEiARY LA
LA STORE
FREE LA DIETARY
GlA NVSULIN
GLA
FREE
DGLA STORE
LACK
I
FREE DGLA OPIATES WHEAT
0
I PGE 1
An outline of the biosynthesis of prostaglandin El. LA, Fig. 1. DGLA, dihomogann-nalinolenic linoleic acid; GLA, gamma-linolenic acid; Vitamin C and ethanol both activate the last acid; 66, pyridoxine. Peptides derived from milk step, the conversion of DGLA to PGEl. proteins may also inhibit this last step. The precise site of it could be at the GLA to DGLA step. pyridoxine action is uncertain:
975
The pathway of PGEl biosynthesis is outlined in Fig. 1. The main EFA in There are moderate amounts of food in most populations is linoleic acid. in a variety of foods, including meat, dairy products arachidonic acid and seaweed, but there are only very small amounts of GLA and DGLA in most Effectively, diets. therefore PGEl must be derived from dietary linoleic acid. Vegetable oils are the main sources of linoleic acid. After absorption linoleic acid may be incorporated into stores (mainly membrane phosphomay be oxidised to provide energy or may be converted to GLA. 1 ipids), Only the conversion to GLA has any relevance as far as EFA activity is This has been convincingly shown in cats which lack the concerned. In cats on an EFA desaturase enzyme which converts linole’rc acid to GLA. deficient diet, even very large amounts of linoleic acid are completely ineffective while GLA has clear cut favourable effects (57). It seems that because of this enzyme lack cats have developed highly efficient mechanisms for utilization of the very small amounts of GLA and DGLA in food. There is a major sex difference between the amount of linoleic goes down the EFA pathway and the amount which is metabolised Females seem to utilize the EFA route two to three routes. effectively than males and in consequence male requirements acid are two to three times greater than female requirements
acid which via other times more for 1 inoleic
(58).
Much of the linoleic acid is incorporated into membrane stores and the ability to utilise this stored material may be important between meals and during temporary periods of reduced EFA intake. A high blood glucose level seems to block very efficiently the conversion of esterified to free linoleic acid, possibly in part by an insulin-dependent mechanism. As a consequence if elevated blood glucose levels are maintained, signs of essential fatty acid deficiency can appear very rapidly in humans following the exclusion of EFAs from the diet (59). These signs appear in spite of apparently adequate body stores of EFAs. Only linoleic acid in the cis form (cLA) can be converted to GLA and act as a precursor of 1 series PGs. A failure to understand this point clearly lies at the root of much of the confusion surrounding the possible value of polyunsaturated oi 1 rich diets. Only cLA makes any contribution to the value of such diets and their usefulness can be very seriously 1 imited by a variety of factors: 1.
Hydrogenation of vegetable oils converts up to 40% of the linoleic acid (tLA) which cannot serve as a substrate for desaturase. Estimates of EFA intake rarely make allowances so much of our apparent intake is of no value.
2.
The tLA is actually of cLA to GLA and
3.
Saturated ase and
fats reduce
worse increases
and cholesterol GLA formation
than useless since EFA requirements are
effective
(62,63,64). 976
it
inhibits
cLA to trans the delta-6for this and
the
conversion
(60,61). inhibitors
of
the
desatur-
4.
Many sources related fatty
of cLA acids
contain which
large amounts also interfere
of with
oleic cLA
acid and conversion
other to GLA
(62,63,64). 5.
6.
7.
Insulin
deficiency
inhibits
for
desaturase
(62,63,64,65).
the
In animals not appear importance
GLA formation
since
insulin
aging leads to loss of desaturase activity to have been studied in humans as yet but given the age structure of our population.
seems
is
(63). of
required
This potential
does
Pyridoxine deficiency has many features in common with EFA deficiency. It seems that pyridoxine is able to enhance the conversion of cLA to The precise polnt at which it operates has not the active EFAs (66). been identified but the most likely sites are the conversion of cLA to
GLA and
of
GLA to
DGLA.
Thus in estimating the EFA value of a diet, the ability to lead to GLA formation is the factor of critical importance. This has never been seriously considered for example in the design of cholesterol-lowering diets, and it is obvious that many such diets because of their content of tLA and of factors which will reduce GLA formation may actually be worse than Foods which can supply GLA directly, such as plants of the borage useless. family and the seeds of the evening primrose are therefore of exceptional interest. The conversion of GLA to DGLA seems to be efficient and tightly coupled (67) and the next reactions of interest are those governing the conversion of Unti 1 recently it was assumed stored DGLA to free DGLA and of DGLA to PGEl. that the reactions governing conversion of AA and DGLA from their stored form to the PGs were regulated in very similar ways. Recent evidence suggests that although there are indeed common features, such as the blockade of mobilisation of both DGLA and AA esters by glucocorticoids and the inhibition of conversion of both DGLA and AA to PGs by aspirin-like drugs, there are also many differences (5,68,69,70,71 ,72) and it is in these differences that the keys to understanding the PG system may lie. For almost fifty years it has been known that the consequences of zinc deficiency and EFA deficiency are virtually identical. Skin defects, poor wound healing, inadequate immune responses and reproductive failure are We have recently demonstrated that remarkably similar in both syndromes. zinc seems able to enhance the formation of PGEl by mobilising DGLA from If this is a major effect of zinc, then many of the its stored form (5 ). effects of zinc deficiency should be prevented or reversed by provision of adequate amounts of free GLA or DGLA, and we have recently been able to show Others have also reported that zinc may work that this is true (13,73). by increasing conversion of EFAs to PGs although they have not specified the particular PG involved (15,74). Prolactin also enhances PGEl formation and many prolactin target organs are exceptionally rich in zinc, raising in the mechanism of action of the possibility that zinc may be important other agents which activate PGEl formation (5,34). Investigation of the conversion of DGLA to PGEl by human platelets yielded some major surprises.
977
Over precisely the range of concentrations found in human tissues, yitamin C caused a concentration dependent enhancement of the formation of PGEi Over the range of concentrations from 30 to 300 mg% ethyl alcohol (22). There were minor differences between al so enhanced PGEl formation (70). the alcohol and vitamin C effects Indicatrng that coupled with their different distributions in the body the effects of these agents in the Finally opiate drugs and natural intact individual would not be Identical. opioids could cause either enhancement or inhibition of PGEl formation. The precise action depended on Both effects were naloxone reversible. concentration and compound type suggesting These act ions were specific receptors (71). not demonstrable with AA.
the to
possibility DGLA and
of two opiate similar ones were
The possibilities that these actions of vitamin C and alcohol may account for many of the known physiological effects of these agents have been With regard to the immune system discussed in companion papers C 75,76). it is possible that a deficiency of PGEl could contribute to the immune PGEl stimulation due to vitamin C could contribute failure seen in scurvy. PGEl stimulation by alcoto the reported anti-viral effects of this agent. hol could be important in the traditional remedy for colds and flu of going The potential relevance of the opiate to bed with a hot alcoholic drink! Digestion of a variety of food effects is only just being explored. protiens, includinggliadin and a-casein, leads to the production of fragments with opiate-like activity which may be absorbed (77). Cholecystokinin, likely to be released in large amounts by fat-rich meals also has The possibility that foods may be able to reopiate-like activity (78). gulate PGEl synthesis and hence the activity of T lymphocytes lends substantial support to those who advocate that diet is of major importance in regulating immune function. Milk and wheat products are both rich in the opioid precursors and it is possible that many allergies, including eczema, rhinitis and asthma which can be related to grain or dairy product consumption are consequences of opioid inhibition of PGEl formation and hence of T lymphocyte function. PRACT I CAL CONSEQUENCES At least four essential dietary constituents, EFAs, pyridoxine, zinc and vitamin C are thus necessary for the effective formation of PGEl. It is particularly important to note that all four must be present together and that a deficiency of any one of them may nullify the value of large intakes For example, there is likely to be little point in taking of the others. large doses of vitamin C unless supplies of free DGLA are adequate. There is excellent evidence that members of our society intakes of all four of these agents. There is a relatively that an individual will be deficient in at least one of 1.
may
have high
marginal probability
them.
It has been the traditional view that 1% of the daily calorie EFAs. intake should be in the form of EFAs. A recent authoritative report from the FAO (89) suggested that this was inadequate and that a minimum intake of 3% of total calories rising to 4-5% in pregnant and lactating mothers and children was desirable. When all the factors which govern the formation of GLA from cLA are taken into consideration it is evident
978
that relatively Since a rise in pressure (79) it ation may reflect particular risk able to replace
few EFA is a since them
individuals are likely to have an adequate intake. intake can lawer both blood cholesterol and arterial possible that the high levels of both in our populcommon EFA deficiency state. Alcholics may be at they are likely to use up DGLA stores and be unbecause of poor diet.
2.
Pyridoxine. Daily requirements of this vitamin in humans have been inadequately studied but there is suggestive evidence that a marginal deficiency state is common. Many women who become depressed wh i le taking oral contraceptives (80) and many women with the premenstrual syndrome (81) may have theftsymptoms relieved by pyridoxine, suggesting that prior to taking the vitamin their intake of it was inadequate.
3.
Zinc. There as a result the population
4.
it
has recently has become is at risk
been a surge of clearly evident of zinc deficiency
interest in that a high (81).
this metal proportion
and of
Vitamin C. The required daily intake of vitamin C is a hotly debated topic. There seems little doubt that in otherwise well nourished individuals the amount of vitamin C required to prevent scurvy is small. On the other hand this amount is almost certainly not optimum, particularly since animals which do not suffer from the human metabolic error make such enormous amounts of it. There is therefore a strong case for a substantially higher intake (83) and careful studies are beginning to justify this (84) even in populations not suffering from cancer, trauma, infections or other forms of stress which substantially In healthy individuals a minimum increase the vitamin C requirement. dose of 170 mg four times a day is required to maintain maximal blood concentrations of the vi tamin (85).
Again it must be stressed that the absence of any one of these four factors will largely nullify the value of the others. At present the daily intakes required to provide optimal PGEl levels for T lymphocyte function must regrettably be a matter of speculation in the absence of adequate human studies. Reasonable intakes would appear to be 25-50 mg pyridoxine, 5-15 and 250-500 mg vitamin C three or four times a day. The requ i red mg zinc, daily intake of EFAs is much more difficult to estimate because of the critical effects of the rest of the diet on the conversion of cLA to GLA. A cLA intake which is adequate in one dietary context may be totally inadequate in another. In view of this uncertainty there is considerable potential in the development of the few foods which contain GLA and which allow this vulnerable step to be by-passed. The only one currently readily available is the seed oil of the evening prlmrose which contains about 10% There is preliminary evidence of its of GLA as well as about 70% of cLA. value in a number of situations (37,52,86,87,88). The direct provision of C) may be of particular cancer since the affected It is possible that the may have been substantially in conjunction with zinc
GLA (of course in comblination with zinc and vitamin value in patients with viral infections and with tissues cannot make their own GLA or PGEl. reported value of vitamin C In these situations underestimated because it has never been given and GLA or DGLA.
979
CONCLUS I ON There is a large amount of evidence pointing to the importance of PGEl in There is the regulation of T lymphocyte function and in cellular immunity. also much evidence to indicate that nutritional factors may limit the formation of PGEl in those on a Western-style diet. Since defects in T lymphocyte function and cell-mediated immunity are very commonly associated with the majority of diseases which we do not yet understand, it is at the very least worth ensuring that PGEl formation in these individuals Nutritional regulation of is not inadequate for nutritional reasons. PGEl production and immunity may play a major part in disease prevention. REFERENCES Biochem
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THE NUTRITIONAL
5:
969-985,
REGULATION
1979
OF T LYMPHOCYTE FUNCTION.
D.F. Horrobin, M.S. Manku, M. Oka, R.O. Morgan, S.C. Cunnane, T. Ghayur, M. Schweitzer and R.A. Karmali. Clinical Research of Montreal, 110 Pine Avenue West, Montreal H2W lR7, Canada.
A.I. Ally, Institute
SUMMARY Prostaglandin (PG) El plays a major role in the regulation of thymus development and T lymphocyte function and the evidence for this is reviewed. The production of PGEl is dependent on nutritional factors with linoleic acid, gamma-linolenic acid, pyridoxine, zinc and vitamin C playing key Inadequate intake of any one of these will lead to inadequate PGEl roles. formation and defective T lymphocyte function. Megadoses of any one are likely to be only minimally effective in the absence of adequate intakes By careful attention to diet it should be possible to of the others. in the large number of diseases including activate. T lymphocyte function rheumatoid arthritis, various auto-immune diseases, multiple sclerosis, and cancer in which such function is defective. It is possible that T lymphocytes may require both endogenous and exogenous PGEl in order to function adequately. It is therefore of particular interest that many cancer cells and virally infected cells are unable to make PGEI because they cannot convert linoleic acid to gamma-linolenic acid. The direct provision of gamma-linolenic or dihomo-gammalinolenic acids in these situations is worthy of full investigation. INTRODUCTION The central role of T lymphocytes in the resistance of the body to disease T lymphocytes play is one of the great themes of modern medical research. a critical role in cellular immunity. The sub-group of the helper T lymphocytes is required to enable B lymphocytes.to respond to specific antigens. The suppressor T lymphocytes are essential to control abnormally overactive B cells and to prevent the latter producing antibodies to a wide variety of both self antigens and commonly encountered exogenous antigens. T lymphocyte abnormalities have been described in almost every disease which we do not yet understand. Abnormal susceptibility to infections, cancer, autoimmune disorders of various types, “collagen” diseases, rheumatoid arthritis, multiple sclerosis, primary biliary cirrhosis, Crohn’s disease,
969
diabetes
me1 1 i tus are just some of the situations in which T lymphocyte uncertain as to whether It is, of course, defects have been described. the T lymphocyte defects are causal or are merely associated with the This will be decided only after we can normalise T cell function disease. There is enormous interest specificqlly and then follow the consequences.
in this possibility on the part of the pharmaceutical industry and there is some evidence that both levamisole and penicillamine may exert some of One attractive concept their favourabie effects by activating T cells. is that a fundamental T cell failure could produce a wide variety of different diseases depending on the genetic characteristics and environmental Correction of the T cell failure would therefore history of the individual. be effective in many different clinical situations. One factor that has largely been ignored is the possibility of regulating Recent evidence strongly suggests T cell function by nutritional means. that prostaglandin (PG) El may be of central importance in normal T cell The formation of PGEl is very susceptible to manipulation defunction. pending on the nutritional intake of essential fatty acids, other fats, carbohydrates, pyridoxine, zinc, ascorbic acid and alcohol. There are therefore many opportunities for regulating T lymphocyte function using nutritional techniques. The purpose of this paper is to present all the evidence which suggests that PGEl does regulate T lymphocytes and that PGEl levels may be manipulated by diet. PROSTAGLAND I N E 1 and
THYMUS DEVELOPMENT
There are two series of prostaglandins derived from the linoleic acid series of essential fatty acids (EFAs). The 1 series are derived from dihomogammalinolenic acid (DGLA) and the 2 series from arachidonic acid Both precursors are stored as esterified lipids in most and probably (AA). all cells of the body. However in most tissues the amounts of AA greatly exceed DGLA, and there has been a tendency, on this basis, to ignore 1 series PGs. It is therefore of particular interest that one of the tissues in which rather large amounts of PGEl have been identified is the thymus In the calf and the human PGEl was the only PG identified and (1 ,293). in most species there seems to be more PGEl in the thymus than in any other tissue, raising the possibility that it may be playing a functional role. That this distinct
possibility lines of
is probably evidence.
correct.
is
strongly
suggested
by
several
1.
PGEl in vitro has an effect very similar to that of thymic hormone in causing maturation oi T lymphocytes (4). PGEl had a biphasic effect with the stimulating action being reversed at high concentrations, a form of dose response which is very common with PGEl.
2.
Prolactin is able to enhance the formation of PGEl in rat vascular tissue (5). Its action on PGEl in the thymus has not been investigated but it is possible that it has a similar effect. In prolactin-deficient dwarf mice, the thymus atrophies on weaning when the animals are deprived of prolactin in the milk. Prolactin injections prevent this The thymus also atrophies on weaning in Bar Harbor 129 atrophy (6). dystrophic mice (7,8,9) and this atrophy can be in part prevented by exogenous prolactin injections (10). 970
3.
In Bar Harbor 129 with gamma-linolenic GLA is the (10) -
4.
Glucocorticoids tion (5,ll).
5.
Lithium, at concentrations found in plasma depression, inhibits formation of PGEl (5). thymus atrophy in rats (12).
6.
Zinc seems to be necessary for the mobilisation of DGLA from DGLA esters and hence for the formation of PGEl (5,13). Zinc deficiency leads to severe thymus atrophy in animals (14,15) and in humans. The most dramatic example of this is acrodermatitis enteropathica which appears to be a disease in which the zinc absorption mechanism in the intestine is defective (16,17,18,19). All the features of the disease can be reversed by high doses of oral zinc which overcome the block. These patients are hairless and have a general failure of the immune It seems not to have system: both defects respond completely to zinc. been generally realised by immunologists that this is a human model of the nude mouse (20) ! Less dramatically but perhaps in the long run malnourished children, who have small thymuses and more importantly, defective ccl 1 mediated immunity, respond to zinc supplementation with an increase in thymus size and restoration of normal immune responses
mice thymus atrophy can be prevented by treatment acid (GLA) in the form of evening primrose oil immediate precursor of DGLA and hence of PGEl.
at physiological Glucocorticoids
concentrations cause dramatic
inhibit PGEl thymus atrophy. in
humans treated Li thi urn causes
forma-
for manic severe
(21).
7.
Ascorbic acid at physiological concentrations is important for the conversion of DGLA to PGEl (22). Ascorbic acid seems to be important in the production of a thymic humoral factor (23,24).
Although each single item is open to criticism and to alternative the overall impression must be that PGEl is important in tions, opment and functioning of the thymus and hence of T lymphocytes. PGEl
and
explanathe devel-
MATURE T LYMPHOCYTE FUNCTION
The NZB/W mouse is widely used as an animal model of a state of defective T The most compelling evidence for a cell and overactive B cell function. Treatment of role of PGEl in T cell function has come from this model. these animals with exogenous PGEl substantially prolongs survival, maintains normal T cell function and inhibits the overactive B cells, preventing the deposition of immune complexes in the kidneys (25,26,27). Treatment with Since this mouse GLA, a precursor of PGEl, has similar effects (28). model is remarkably similar to human systemic lupus erythematosus, the possibi 1 i ty of treating the human disease with PGEl or its precursors is an attractive one. Adjuvant arthritis in rats also seems to be a disease in which defective T cell function plays a part since the syndrome is exaggerated by T cell Exogenous PGEl treatment in this situation also prevents the depletion. onset of the disease and retards inflammation (29).
971
Other evidence cells is largely pretations but 1.
for
the role indirect. the overall
of PGEl in Again each impression
regulation item is is
of function of open to alternative
mature inter-
~_
persuasive.
In adults made vitamin C deficient there is qreatly enhanced susceptibility to infection suggesting immune system failure. In a major study under carefully controlled conditions all five adults expcsed to selective vitamin C deficiency developed features of Sjogren’s syndrome, a classic situation in which defective cell mediated immunity is coupled In vitamin C del’i;it:nwith evidence of overactive B lymphocytes (30). guinea pigs transplants are not rejected whereas vitamin C inject ii-!*>c enable rejection to occur normally (31). Penicillamine and levamisole are both widely used as immunostimuTants and there is evidence that they may work in part by activating T suppressor cells and inhibiting overactive B cells, for example in primarv Both agents have act ions which are consiscert bi 1 iary cirrhosis (32). with enhancement of PGEl synthesis (33,34). Of course they also have ; ‘j c L /:: many other effects and the use of penicillamine, in particular, plicated by its zinc-chelating property which will tend to inhibir PGEI synthesis if body zinc stores become depleted. In adults to fluctuate a possible
with
acrodermatitis with the zinc cause.
enteropathica intake. Variations
the
immune in PGEl
status seems formation a!!(~
Coichicine seems remarkably effective in control 1 ing the inf1ammaic~r.y episodes and immune complex deposition in familial Mediterranean fever (35,36) and there is preliminary evidence that it may be of value Tr! multiple sclerosis (37) another disease in which T cell defects rm;. play a role. In unpublished studies we have been able to show that very low concentrations of colchicine seem able to enhance the effects of agents like zinc which stimulate PGEl formation. The mechanism inhibition of 6.
In of
of steroid-induced PGEl synthesis
vitro PGEl at T lymphocytes
immunosuppression be a candidate.
must
low concentrations to measles infected
was able to cells (38).
is
double
unknown,
the
but
adhere::<.@
Again the overall impression is that PGEl and agents which stimulate PGEI synthesis may be able to enhance the activity of at least some types of T It is important to note, however, that here as with many of the cells. other biological effects of PGEl there is evidence of a biphasic bellHigh levels of PGEl fail to cause maturation shaped dose response curve. of T lymphocytes (4)) reduce lymphocyte mediated cytotoxicity (39) and depress various types of immune responses (40,41). Prolactin, which inhibits phytohaemagglutinin responsiveness of enhances PGEl synthesis, High levels of intake of essential fatty acids may human lymphocytes (42). inhibit the development of experimental allergic encephalomyel i tis in anima 1s and the rejection of renal transplants in humans (43,44,45). There ii,
972
therefore a possibility that overproduction of PGEl may reduce the efficiency of the immune system either because at high concentrations its stimulating effect on T lymphocytes is last or reversed or because such high concentrations oversuppress B lymphocyte function. Clearly much work remains to be done in sorting out precisely the effects of PGEl (and of other PGs) on the individual components of the immune system, Such biphasic effects may help to extraordinarily dosage.
explain why difficult
penicillamine drugs to
and manage,
levamisole particularly
have in
proved relation
such to
INFLAt+IATION There is now an overwhelming amount of evidence to indicate that in most inflammatory situations there is an overproduction of 2 series PGs from arachidonic acid and that the aspirin-like anti-inflammatory drugs work largely by inhibiting this overproduction. It is therefore surprising to find that there are consistent reports that PGs, and 3n particular PGEl, may also be anti-inflammatory (46,47,25,26,27,25). What may be the explanation? as already discussed, PGEl may be anti-inflammatory because it In part, reduces B cell activity, but that is not the whole story. PGEl itself may be a regulator of the arachidonic acid cascade and in platelets has been shown to block the mobilisation of free arachidonic acid (48). This mechanism is potentially important because of the great discrepancy between stores of AA and DGLA in most tissues. The amount of AA exceeds that of DGLA by 10 to 40 fold, except in the human liver where the AA:DGLA ratio is only 4:l (49). This means that in a situation where supplies of EFAs are inadequate, DGLA stores will be depleted at a time when AA stores have Reduction of PGEl formation in this situation will hard1 y been touched. therefore lead to Jver-production of 2 series PGs because of loss of control of mobilisation of AA from the large tissue stores. Two recently described situations in humans indicate that this is a practical and not merely a theoretical concept. Children with cystic fibrosis have reduced levels of linoleic acid either because of a primary defect or as a consequence of Circulating to inadequateEFA absorption. pancreatic failure leading elevated (50). It might therefore levels of 2 series PGs are strikingly of extra linoleic acid which can be conhave been expected that pr 0 vision In contrast, raise concentrations of 2 series PGs. verted to AA would further 1 inoleic acid supplementat on led to a fall of 2 series PG levels to normal. Our interpretation of this is that the 2 series overproduction was due to inadequate PGEl formation. Restoration of the DGLA stores by EFA supplementation al lowed restoration of normal PGEl synthesis and of normal control in humans with excessive over the 2 series pathway ( 51 952). Similarly menstrual bleeding circulating levels of 2 series PGs are up and the bleeding can in part be controlled by inhibitors of PG synthesis (53). Again one would have expected EFAs to aggravate the situation but in four women with excessive menstrual flow (3 with intra-uterine contraceptives) we have shown over a period of a year that bleeding can be successfully controlled It is possible that the antiby EFA repletion using evening primrose oil. fami 1 i al Mediterranean fever and inflammatory effects of colchicine in gout, Behr;et!s syndrome (54) may be related to enhanced PGEl formation.
973
CANCER AND VIRAL INFECTIONS There is no doubt that cell mediated immunity is to viral Infections. Much of the current research predicated on the somewhat less certain assumption to malignant disease is dependent upon cell-mediated
important in resistance effort in cancer is that resistance immunity.
The preceding discussion provides very strong reasons for believing that PGEl may be of major importance in the regulation of T lymphocytes and of ccl 1 mediated immune mechanisms. It is not clear whether PGEl must be produced by the lymphocytes themselves or must be provided exogenously. Both may be important but the series of studies by Zurier on the NZB/W mouse leave no doubt that exogenous PGEl can be effective. Since this is the case, it is possible that PGEl production by target tissues may be a critical factor in determining the effectiveness of the immune response. It is therefore of extraordinary interest that the great majority of malignant and virally-transformed ccl 1s are unable to produce PGEl. This is because, coincident with transformation or malignant change, the ability to convert linoleic acid to GLA is lost (55,56). Since cell stores of GLA and DGLA are extremely limited, such cells are effectively unable to produce PGEl . The importance of this loss of delta-6-desaturase activity is as yet uncertain. It has been suggested that it is merely an accidental and unimportant consequence of the massive cell disruption which Imust inevitably be associated with malignant change or viral infection. if 52 it is very surprising that the loss is so consistent and that it never seems to be associated with the loss of the closely related delta-s-desaturase which converts DGLA to AA. If production of PGEl within a tissue cytes to mount a response against that the importance of this loss of the it, emphasizing. NUTRITIONAL
REGULATION
is important in tissue or against delta-6-desaturase
OF PGEl
enabling T lymphosome component of hardly needs
SYNTHESIS
If PGEl is important in T lymphocyte function then it is possible that the immune system could be modulated by nutritional changes which determine PGEl formation. The nutritional and other factors which can modify the pathway have recently been much more clearly understood. Essential fatty acids, pyridoxine (vi tamin B6), zinc and vitamin C are all important. There is evidence that in some members of Western societies intake of all four of these agents may be marginal and therefore that a nutritional failure of PGEl synthesis may be common. If so it is surely desirable to try to correct this by nutritional measures which are unlikely to over-ride the endogenous control mechanisms. Drugs may over-ride these control mechanisms. Not only that but if, as is the case with penicillamine and levamisole, part of their effect may be dependent on PGEl synthesis, that effectiveness wi 11 be severely 1 imited if PGEl precursors are not available. Part of the variation in responsiveness to these two agents may relate to differences between patients in nutritionalstatus.
974
DlEiARY LA
LA STORE
FREE LA DIETARY
GlA NVSULIN
GLA
FREE
DGLA STORE
LACK
I
FREE DGLA OPIATES WHEAT
0
I PGE 1
An outline of the biosynthesis of prostaglandin El. LA, Fig. 1. DGLA, dihomogann-nalinolenic linoleic acid; GLA, gamma-linolenic acid; Vitamin C and ethanol both activate the last acid; 66, pyridoxine. Peptides derived from milk step, the conversion of DGLA to PGEl. proteins may also inhibit this last step. The precise site of it could be at the GLA to DGLA step. pyridoxine action is uncertain:
975
The pathway of PGEl biosynthesis is outlined in Fig. 1. The main EFA in There are moderate amounts of food in most populations is linoleic acid. in a variety of foods, including meat, dairy products arachidonic acid and seaweed, but there are only very small amounts of GLA and DGLA in most Effectively, diets. therefore PGEl must be derived from dietary linoleic acid. Vegetable oils are the main sources of linoleic acid. After absorption linoleic acid may be incorporated into stores (mainly membrane phosphomay be oxidised to provide energy or may be converted to GLA. 1 ipids), Only the conversion to GLA has any relevance as far as EFA activity is This has been convincingly shown in cats which lack the concerned. In cats on an EFA desaturase enzyme which converts linole’rc acid to GLA. deficient diet, even very large amounts of linoleic acid are completely ineffective while GLA has clear cut favourable effects (57). It seems that because of this enzyme lack cats have developed highly efficient mechanisms for utilization of the very small amounts of GLA and DGLA in food. There is a major sex difference between the amount of linoleic goes down the EFA pathway and the amount which is metabolised Females seem to utilize the EFA route two to three routes. effectively than males and in consequence male requirements acid are two to three times greater than female requirements
acid which via other times more for 1 inoleic
(58).
Much of the linoleic acid is incorporated into membrane stores and the ability to utilise this stored material may be important between meals and during temporary periods of reduced EFA intake. A high blood glucose level seems to block very efficiently the conversion of esterified to free linoleic acid, possibly in part by an insulin-dependent mechanism. As a consequence if elevated blood glucose levels are maintained, signs of essential fatty acid deficiency can appear very rapidly in humans following the exclusion of EFAs from the diet (59). These signs appear in spite of apparently adequate body stores of EFAs. Only linoleic acid in the cis form (cLA) can be converted to GLA and act as a precursor of 1 series PGs. A failure to understand this point clearly lies at the root of much of the confusion surrounding the possible value of polyunsaturated oi 1 rich diets. Only cLA makes any contribution to the value of such diets and their usefulness can be very seriously 1 imited by a variety of factors: 1.
Hydrogenation of vegetable oils converts up to 40% of the linoleic acid (tLA) which cannot serve as a substrate for desaturase. Estimates of EFA intake rarely make allowances so much of our apparent intake is of no value.
2.
The tLA is actually of cLA to GLA and
3.
Saturated ase and
fats reduce
worse increases
and cholesterol GLA formation
than useless since EFA requirements are
effective
(62,63,64). 976
it
inhibits
cLA to trans the delta-6for this and
the
conversion
(60,61). inhibitors
of
the
desatur-
4.
Many sources related fatty
of cLA acids
contain which
large amounts also interfere
of with
oleic cLA
acid and conversion
other to GLA
(62,63,64). 5.
6.
7.
Insulin
deficiency
inhibits
for
desaturase
(62,63,64,65).
the
In animals not appear importance
GLA formation
since
insulin
aging leads to loss of desaturase activity to have been studied in humans as yet but given the age structure of our population.
seems
is
(63). of
required
This potential
does
Pyridoxine deficiency has many features in common with EFA deficiency. It seems that pyridoxine is able to enhance the conversion of cLA to The precise polnt at which it operates has not the active EFAs (66). been identified but the most likely sites are the conversion of cLA to
GLA and
of
GLA to
DGLA.
Thus in estimating the EFA value of a diet, the ability to lead to GLA formation is the factor of critical importance. This has never been seriously considered for example in the design of cholesterol-lowering diets, and it is obvious that many such diets because of their content of tLA and of factors which will reduce GLA formation may actually be worse than Foods which can supply GLA directly, such as plants of the borage useless. family and the seeds of the evening primrose are therefore of exceptional interest. The conversion of GLA to DGLA seems to be efficient and tightly coupled (67) and the next reactions of interest are those governing the conversion of Unti 1 recently it was assumed stored DGLA to free DGLA and of DGLA to PGEl. that the reactions governing conversion of AA and DGLA from their stored form to the PGs were regulated in very similar ways. Recent evidence suggests that although there are indeed common features, such as the blockade of mobilisation of both DGLA and AA esters by glucocorticoids and the inhibition of conversion of both DGLA and AA to PGs by aspirin-like drugs, there are also many differences (5,68,69,70,71 ,72) and it is in these differences that the keys to understanding the PG system may lie. For almost fifty years it has been known that the consequences of zinc deficiency and EFA deficiency are virtually identical. Skin defects, poor wound healing, inadequate immune responses and reproductive failure are We have recently demonstrated that remarkably similar in both syndromes. zinc seems able to enhance the formation of PGEl by mobilising DGLA from If this is a major effect of zinc, then many of the its stored form (5 ). effects of zinc deficiency should be prevented or reversed by provision of adequate amounts of free GLA or DGLA, and we have recently been able to show Others have also reported that zinc may work that this is true (13,73). by increasing conversion of EFAs to PGs although they have not specified the particular PG involved (15,74). Prolactin also enhances PGEl formation and many prolactin target organs are exceptionally rich in zinc, raising in the mechanism of action of the possibility that zinc may be important other agents which activate PGEl formation (5,34). Investigation of the conversion of DGLA to PGEl by human platelets yielded some major surprises.
977
Over precisely the range of concentrations found in human tissues, yitamin C caused a concentration dependent enhancement of the formation of PGEi Over the range of concentrations from 30 to 300 mg% ethyl alcohol (22). There were minor differences between al so enhanced PGEl formation (70). the alcohol and vitamin C effects Indicatrng that coupled with their different distributions in the body the effects of these agents in the Finally opiate drugs and natural intact individual would not be Identical. opioids could cause either enhancement or inhibition of PGEl formation. The precise action depended on Both effects were naloxone reversible. concentration and compound type suggesting These act ions were specific receptors (71). not demonstrable with AA.
the to
possibility DGLA and
of two opiate similar ones were
The possibilities that these actions of vitamin C and alcohol may account for many of the known physiological effects of these agents have been With regard to the immune system discussed in companion papers C 75,76). it is possible that a deficiency of PGEl could contribute to the immune PGEl stimulation due to vitamin C could contribute failure seen in scurvy. PGEl stimulation by alcoto the reported anti-viral effects of this agent. hol could be important in the traditional remedy for colds and flu of going The potential relevance of the opiate to bed with a hot alcoholic drink! Digestion of a variety of food effects is only just being explored. protiens, includinggliadin and a-casein, leads to the production of fragments with opiate-like activity which may be absorbed (77). Cholecystokinin, likely to be released in large amounts by fat-rich meals also has The possibility that foods may be able to reopiate-like activity (78). gulate PGEl synthesis and hence the activity of T lymphocytes lends substantial support to those who advocate that diet is of major importance in regulating immune function. Milk and wheat products are both rich in the opioid precursors and it is possible that many allergies, including eczema, rhinitis and asthma which can be related to grain or dairy product consumption are consequences of opioid inhibition of PGEl formation and hence of T lymphocyte function. PRACT I CAL CONSEQUENCES At least four essential dietary constituents, EFAs, pyridoxine, zinc and vitamin C are thus necessary for the effective formation of PGEl. It is particularly important to note that all four must be present together and that a deficiency of any one of them may nullify the value of large intakes For example, there is likely to be little point in taking of the others. large doses of vitamin C unless supplies of free DGLA are adequate. There is excellent evidence that members of our society intakes of all four of these agents. There is a relatively that an individual will be deficient in at least one of 1.
may
have high
marginal probability
them.
It has been the traditional view that 1% of the daily calorie EFAs. intake should be in the form of EFAs. A recent authoritative report from the FAO (89) suggested that this was inadequate and that a minimum intake of 3% of total calories rising to 4-5% in pregnant and lactating mothers and children was desirable. When all the factors which govern the formation of GLA from cLA are taken into consideration it is evident
978
that relatively Since a rise in pressure (79) it ation may reflect particular risk able to replace
few EFA is a since them
individuals are likely to have an adequate intake. intake can lawer both blood cholesterol and arterial possible that the high levels of both in our populcommon EFA deficiency state. Alcholics may be at they are likely to use up DGLA stores and be unbecause of poor diet.
2.
Pyridoxine. Daily requirements of this vitamin in humans have been inadequately studied but there is suggestive evidence that a marginal deficiency state is common. Many women who become depressed wh i le taking oral contraceptives (80) and many women with the premenstrual syndrome (81) may have theftsymptoms relieved by pyridoxine, suggesting that prior to taking the vitamin their intake of it was inadequate.
3.
Zinc. There as a result the population
4.
it
has recently has become is at risk
been a surge of clearly evident of zinc deficiency
interest in that a high (81).
this metal proportion
and of
Vitamin C. The required daily intake of vitamin C is a hotly debated topic. There seems little doubt that in otherwise well nourished individuals the amount of vitamin C required to prevent scurvy is small. On the other hand this amount is almost certainly not optimum, particularly since animals which do not suffer from the human metabolic error make such enormous amounts of it. There is therefore a strong case for a substantially higher intake (83) and careful studies are beginning to justify this (84) even in populations not suffering from cancer, trauma, infections or other forms of stress which substantially In healthy individuals a minimum increase the vitamin C requirement. dose of 170 mg four times a day is required to maintain maximal blood concentrations of the vi tamin (85).
Again it must be stressed that the absence of any one of these four factors will largely nullify the value of the others. At present the daily intakes required to provide optimal PGEl levels for T lymphocyte function must regrettably be a matter of speculation in the absence of adequate human studies. Reasonable intakes would appear to be 25-50 mg pyridoxine, 5-15 and 250-500 mg vitamin C three or four times a day. The requ i red mg zinc, daily intake of EFAs is much more difficult to estimate because of the critical effects of the rest of the diet on the conversion of cLA to GLA. A cLA intake which is adequate in one dietary context may be totally inadequate in another. In view of this uncertainty there is considerable potential in the development of the few foods which contain GLA and which allow this vulnerable step to be by-passed. The only one currently readily available is the seed oil of the evening prlmrose which contains about 10% There is preliminary evidence of its of GLA as well as about 70% of cLA. value in a number of situations (37,52,86,87,88). The direct provision of C) may be of particular cancer since the affected It is possible that the may have been substantially in conjunction with zinc
GLA (of course in comblination with zinc and vitamin value in patients with viral infections and with tissues cannot make their own GLA or PGEl. reported value of vitamin C In these situations underestimated because it has never been given and GLA or DGLA.
979
CONCLUS I ON There is a large amount of evidence pointing to the importance of PGEl in There is the regulation of T lymphocyte function and in cellular immunity. also much evidence to indicate that nutritional factors may limit the formation of PGEl in those on a Western-style diet. Since defects in T lymphocyte function and cell-mediated immunity are very commonly associated with the majority of diseases which we do not yet understand, it is at the very least worth ensuring that PGEl formation in these individuals Nutritional regulation of is not inadequate for nutritional reasons. PGEl production and immunity may play a major part in disease prevention. REFERENCES Biochem
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