774

involved in the synthesis of RNAs encoded by EBVand adenovirus. Thus some autoantibodies peculiar tothe rheumatic diseases may be stimulated by an earlierphase of transient or persistent virus infections. It isalso possible that some virus infections activate B cellspolyclonally, as in many conventional microbial

infections, thereby accelerating the natural history ofrheumatic diseases in genetically predisposedindividuals. In a controlled prospective study De-VereTyndall et a12’ identified a significant associationbetween intercurrent virus infections andexacerbations of juvenile chronic arthritis.

Intriguing observations of this kind sustain the beliefthat rheumatoid arthritis could have an infectious

aetiology. The Lyme arthritis story has shown thatspirochaetal infection in exposed communities induceserosive arthritis and immune complex disease in

genetically susceptible individuals.28 Nothing so

striking has yet been attributed to virus infections, butthe features of virus infections that might provokechronic arthritis might prove hard to unravel bystandard techniques. Thus in a detailed study of avianreoviruses Gouvea and Schnitzer9 have shown thatarthritogenic strains of virus are subtly different fromthose which lack this characteristic. It would be

premature for believers to abandon their faith.

OPIATES, OPIOID PEPTIDES, AND IMMUNITY

VIRAL hepatitis, pulmonary infections, endocarditis,bacteraemia, cellulitis, injection-site abscesses, and otherinfections are common among opiate addictsl-6 and arefrequently attributed to injection of contaminated materialsor unsterilised needles. Some workers, however, havesuggested that morphine addicts are abnormally susceptibleto infections.3,s Despite reports of immunologicaldisturbances such as lymphocytosis7 or

hypergammaglobulinaemia in opiate addicts,3,8 and evensystematic in-vitro studies of cellular immunity,9 littleattention has been paid to this suggestion. Now Tubaro and

27. De-Vere Tyndall A, Bacon T, Parry R, Tyrrell DAJ, Denman AM, Ansell BM.Infection and interferon production in systemic juvenile chronic arthritis: a

prospective study. Ann Rheumat Dis 1984; 43: 1-7.28. Steere AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal aetiology of Lyme

disease. N Engl J Med 1983; 308: 733-40.29. Gouves V, Schnitzer TJ. Pathogenicity of avian reoviruses: Examination of six isolates

and a vaccine strain. Infect Immun 1982; 38: 731-38.1. Luttgens WF. Endocarditis in "main line" opium addicts. Arch Intern Med 1949; 83:

653-64.2. Hussey HH, Katz S. Infections resulting from narcotic addiction: report of 102 cases.

Am J Med 1950; 9: 186-93.3. Louria DB, Hensle T, Rose J. The major medical complications of heroin addiction.

Ann Intern Med 1967; 67: 1-22.4. Briggs JH, McKerron CG, Souhami RL, Taylor DJE, Andrews H. Severe systemic

infections complicating "mainline" heroin addiction. Lancet 1967; ii: 1227-31.5. Cherubin CE, Brown J. Systemic infections in heroin addicts. Lancet 1968; i: 298-99.6. Louria DB. Medical complications of pleasure-giving drugs. Arch Intern Med 1969;

123: 82-87.7. Sapira JD. The narcotic addict as a medical patient. Am J Med 1968; 45: 555-88.8. Cherubin CE, Millian SJ. Serologic investigations in narcotic addicts; I. Syphilis,

lymphogranuloma venereum, herpes simplex and Q fever. Ann Intern Med 1968; 69:739-42.

9. Brown SM, Stimmel B, Taub RN, Kochwa S, Rosenfield RE. Immunologicdysfunction in heroin addicts. Arch Intern Med 1974; 134: 1001-06.

colleagues have provided welcome data on the effects ofmorphine on resistance to infection. Their investigations,though open to some methodological criticisms, indicate thatperitoneal neutrophils and macrophages from morphine-treated mice were not only less numerous but also lessefficient at phagocytosis and killing of Candida albicans thanthose from controls. These abnormalities were not site or

species restricted: murine bone-marrow neutrophils andrabbit alveolar macrophages from morphine-treated animalslikewise showed functional phagocytic and candicidal

impairment. In addition, morphine-treated mice succumbedmore readily to peritoneal infections with Klebsiella

pneumoniae (LDso 3-3xlO’ organisms vs 9.55 x 106 forcontrol animals). These data suggest that morphineadministration, at least to mice and rabbits, hampersphagocyte function. In man, direct data on phagocytes arelacking, but lymphocyte subtypes and function have beenstudied.9,11 Brown et al9 examined peripheral blood cellsfrom 38 unselected heroin addicts and observed strikinglylow lymphoproliferative responses to stimulation with

phytohaemagglutinin, pokeweed mitogen, or concanavalin-A. However, these effects could have been mediated bymonocyte (ie, phagocyte) suppression of the

lymphoproliferative response. 12Resistance to tumours is another arm of host immunity that

may be altered by opiates. Aylsworth and colleagues13reported that opiate antagonists could inhibit growth ofinduced mammary tumours in rats, and Lewis et al14 havelately shown that a high dose of morphine reduces survival ofrats injected with the mammary ascites tumour MAT13762 B. -Zagon and McLaughlin,l5 however, report thatheroin inhibits tumour growth in mice with transplantedneuroblastoma; and the same workers have shownl6 that theopiate antagonist naltrexone has dose-dependent stimulatoryor inhibitory effects on neuroblastoma growth in mice.Interpretation of these data is difficult. Many experimentalmammary tumours grow faster in response to a rise in plasmaprolactin,17 and morphine can increase prolactin secretion bythe pituitary.18 Murine neuroblastoma cells may possessopiate receptors.19 Thus, indirect or direct effects of opiates,in these animal models, may have influenced tumour growthwithout affecting the immune responses. However,alterations in natural killer (NK) cell activity could provide analternative mechanism of action. NK cells cause lysis ofvarious malignant cells and seem to contribute to immunesurveillance against tumours.20 Reporting that morphine

10. Tubaro E, Borelli G, Croce C, Cavallo G, Santiangeli C. Effect of morphine onresistance to infection. J Infect Dis 1983; 148: 656-66.

11. McDonough RJ, Madden JJ, Falek A, et al. Alteration of T and null lymphocytefrequencies in the peripheral blood of human opiate addicts; in vivo evidence foropiate receptor sites on T lymphocytes. J Immunol 1980; 125: 2539-43.

12. Rice L, Laughter AH, Twomey JJ. Three suppressor systems in human blood thatmodulate lymphoproliferation J Immunol 1979; 122: 991-96.

13. Aylsworth CF, Hodson CA, Meites J Opiate antagonists can inhibit mammary tumorgrowth in rats. Proc Soc Exp Biol Med 1979; 161; 18-20.

14. Lewis JW, Shavit Y, Terman GW, Gale RP, Liebeskind JC. Stress and morphine affectsurvival of rats challenged with a mammary ascites tumor (MAT 13762 B). NatImmun Cell Growth Reg (in press).

15. Zagon IS, McLaughlin PJ Heroin prolongs survival time and retards tumor growth inmice with neuroblastoma. Brain Res Bull 1981; 7: 25-32

16. Zagon IS, McLaughlin PJ. Naltrexone modulates tumor response m mice withneuroblastoma Science 1983; 221: 671-73

17. Welsch CW, Nagasawa H. Prolactin and murine mammary tumorigenesis: a review.Cancer Res 1977, 37: 951-63.

18. deWeid D, Van Ree JR, de Jong W. In: Zimmerman E, George R, eds. Narcotics and thehypothalamus. New York: Raven Press 1974; 251.

19. Klee WA, Nirenberg M. A neurobiastoma x glioma hybrid cell line with morphinereceptors Proc Natl Acad Sci USA 1974; 71: 3474-77.

20. Herberman RB, Ortaldo JR. Natural killer cells: their role in defenses against disease.Science 1981; 214: 24-30.

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causes a dose-related suppression of NK activity in rats,Shavit and co-workers2l speculate whether these opiateeffects are direct or indirect (eg, via glucocorticoids, whichmay suppress NK activity22).

If opiates can influence host immunity against infectionsand tumours, what of their endogenous counterparts, theopioid peptides? The evidence, although intriguing, remainsindirect. Stress can affect immune competence and tumour

growth.23 In rats, footshock stress may result in endogenousopioid activity (judged by the effects of naltrexone) or not,according to the mode of application.24 Using this system,Liebeskind and his colleagues have shown that stress

enhances mammary ascites tumour growth in rats25 andsuppresses splenic NK cell activity,2’ and that both effectscan be blocked by opiate antagonists. The implication is thatopioid peptides are responsible somehow for the effects onNK cell activity and tumour growth. Data in man are few.Mathews et al,26 working on peripheral blood cells fromnormal volunteers, have shown that (3-endorphin and Met-enkephalin enhance NK cell activity, but Leu-enkephalin,a-endorphin, and morphine do not. Met-enkephalin has alsobeen reported to alter the activity of T lymphocytes fromlymphoma patients, in vitro.27Whether opiates and opioid peptides act directly or

indirectly upon immune function remains to be determined.Certainly there is evidence for opioid receptors on

monocytes,28 neutrophils,28 lymphocytes,11,29,30 and mastcells.31 Nevertheless, indirect action via the pituitary-adrenalaxis cannot be excluded. Finally, mention should be made ofthe structural similarities between human leucocyteinterferon (a-IFN), corticotropin, and endorphins.32 a-IFN,but not fibroblast or immune (y)IFN, binds to opiatereceptors in vitro33 and intracerebral injection of a-IFN, inmice, causes potent endorphin-like effects that are preventedby naloxone.33 Therefore there seems to be a very closerelation between these components of the immune and opioidpeptide systems. These exciting areas of research may soon beyielding information relevant not only to drug addiction, butalso to infection and oncology.

21 Shavit Y, Lewis JW, Terman GW, Gale RP, Liebeskind JC. Opioid peptides mediatethe suppressive effect of stress on natural killer cell cytotoxicity. Science 1984; 223:188-90.

22. Cox WI, Holbrook NJ, Grasso RJ, Specter S, Friedman H. Suppression of the naturalkiller cell activity of murine spleen cell cultures by dexamethasone. Proc Soc ExpBiol Med 1982; 171: 146-50.

23. Riley V. Psychoneuroendocrine influences on immunocompetence and neoplasia.Science 1981, 212: 1100-09.

24. Lewis JW, Cannon JT, Liebeskind JC. Opioid and nonopioid mechanisms of stressanalgesia. Science 1980; 208: 623-25.

25. Lewis JW, Shavit Y, Terman GW, Nelson LR, Gale RP, Liebeskind JC. Apparentinvolvement of opioid peptides in stress-induced enhancement of tumor growth.Peptides 1983; 4: 635-38.

26. Mathews PM, Froelich CJ, Sibbitt WL, Bankhurst AD. Enhancement of naturalcytotoxicity by &bgr;-endorphin. J Immunol 1983; 130: 1658-62.

27 Miller GC, Murgo AJ, Plotnikoff NP. Enkephalins-enhancement of active T-cellrosettes from lymphoma patients. Clin Immunol Immunopathol 1983; 26: 446-51.

28. Lopker A, Abood LG, Hoss W, Lionetti FJ. Stereospecific muscarinic acetylcholineand opiate receptors in human phagocytic leukocytes. Biochem Pharmacol 1980; 29:1361-65.

29. Wybran J, Appelboom T, Famaey J-P, Govaerts A. Suggestive evidence for receptorsfor morphine and methionine-enkephalin on normal human blood T lymphocytes. JImmunol 1979; 123: 1068-70.

30 Hazum E, Chang K-J, Cuatrecasas P. Specific nonopiate receptors for &bgr;-endorphin.Science 1979; 205: 1033-35.

31 Yamasaki Y, Shimamura O, Kizu A, Nakagawa M, Ijichi H. Interactions of morphinewith PGE1, isoproterenol, dopamine and aminophylline in rat mast cells; theireffect on IgE-mediated 14C-serotinin release. Agents Actions 1983; 13: 21-28.

32 Blalock JE, Smith EM. Human leukocyte interferon: structural and biologicalrelatedness to adrenocorticotropic hormone and endorphins. Proc Natl Acad SciUSA 1980; 77: 5972-74.

33 Blalock JE, Smith EM. Human leukocyte interferon: potent endorphin-like opioidactivity. Biochem Biophys Res Commun 1981; 101: 471-78.

COELIAC DISEASE IN THE ELDERLY

THAT coeliac disease affects adults as well as children isnow common knowledge. As a disease of the elderly it is

perhaps less well recognised. The standard teachingconcerning clinical features of adult coeliac disease (ACD)has derived largely from reports published in the 1950s and1960s. The disease was relatively unfamiliar then, wasusually detected because of obvious malabsorption, andtended to cluster in a few specialist centres. These earlyreports thus do not give a wholly accurate picture either ofdisease prevalence or of the subtler ways in which thecondition may be manifest. In later accounts adult coeliacdisease seems more prevalent,4,s symptoms of malabsorptionare less prominent,6,7 and the population affected is ratherolder than before.6-8 In the large Birmingham series, forinstance, described in 1953 and since updated, only 7% ofpatients presented over the age of 60. The figure from theMayo Clinic in 19603 was comparable at 4%. By contrast, inthe 1970s and 1980s around a quarter of the Northwick Park

6

and St Bartholomew’s8 cases were diagnosed in or after theseventh decade. This skew to the right in terms of age,observed also in the USA,9 Sweden,4 Scotlands and

Ireland, probably reflects clinicians’ greater willingness toconsider the diagnosis in the elderly rather than a true changein the nature of the disease. Many of these older patients arediagnosed on the basis of rather vague symptoms in thepresence of mild haematological abnormalities or a familyhistory of coeliac disease. Unexplained macrocytosis, lowfolate reserves, or a blood film showing splenic atrophy(Howell Jolly bodies, target cells, thrombocythaemia) shouldalways suggest possible adult coeliac disease, even in theabsence of gastrointestinal symptoms. A Swedish studyll hasshown that 30% of those prospectively investigated becauseof unexplained low folate levels had coeliac disease while in aScottish 12 survey haematological features of splenic atrophyinvariably indicated coeliac disease if the spleen had not beenremoved. Despite this, some still present in the classicmanner with steatorrhoea-in fact, adult coeliac disease is thecommonest cause of fatty diarrhoea in the elderly,13 withpancreatic insufficiency and blind-loop syndrome takingsecond and third places.There is still an apparent regional discrepancy in the

prevalence of adult coeliac disease in England and Wales andsome have suggested that this reflects variations in diagnosticenthusiasm at hospital level. Certainly coeliac disease seems

1. Cooke WT, Holmes GKT. Coeliac disease. London: 1984. Churchill Livingstone.2. Bossak ET, Wang CI, Adlersberg D. Clinical aspects of the malabsorption syndrome

(idiopathic sprue). J Mount Sinai Hosp 1957; 286-3033. Green PA, Wollaeger EE. The clinical behaviour of sprue in the United States.

Gastroenterology 1960; 38: 399-418.4. Hallert C, Gotthard K, Norrby K, Walan A On the prevalence of adult coeliac disease

in Sweden. Scand J Gastroenterol 1981; 16: 257-61.5. Rifkind EA, Logan RFA, Busuttil A, Gilmour H, Ferguson A. Coeliac disease in

Edinburgh and the Lothians 1900-80. Scott Med J 1982; 27: 256.6. Swinson CM, Levi AJ. Is coeliac disease underdiagnosed? Brit Med J 1980; 281:

1258-60.7. Campbell CB, Roberts RK, Cowen AE. The changing clinical presentation of coeliac

disease in adults. Med J Aust 1977; i: 89-93.8. Clark ML Coeliac disease. In: Bouchier IAD, Allan RN, Hodgson HJF, Keighley

MRB, eds. Textbook of gastroenterology. London: W. B. Saunders (in press)9. Mann JG, Brown WR, Kern F. The subtle and variable clinical expressions of gluten-

induced enteropathy (adult celiac disease, nontropical sprue). Am J Med 1970; 48:357-66

10. Kirby J, Fielding JF. Very adult coeliac disease! The need for jejunal biopsy in themiddle aged and elderly. Irish Med J 1984; 77: 35-36.

11. Hallert C, Tobiasson P, Walan A. Serum folate determinations in tracing adult coeliacScand J Gastroenterol 1981; 16: 263-67.

12. Ferguson A, Hutton MM, Maxwell ID, Murray D. Adult coeliac disease in

hyposplenic patients. Lancet 1970, i: 163-64.13. Price HL, Gazzard BG, Dawson AM. Steatorrhoea in the elderly. Br Med J 1977; i:

1582-84.