The Helicobacter genus: now we are nine

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expressing T-cell receptors that use particular Vpgenes. Since the total spectrum of Vp families is

genetically determined, individuals will vary in theirsusceptibility to diseases associated with this type ofresponse (autoimmune disorders). Such variation haslong been associated with inheritance of certain majorhistocompatibility complex (MHC) alleles and,although the functional link between that locus andTCR is obscure, it is undoubtedly real. 7

Dalgleish et al sought to test the validity of theautoimmune concept of AIDS by searching forevidence of selective involvement of T cells expressingparticular TCR Vp genes. Within the limitations ofthe technology available, they obtained a positiveresult in that patients in the early stages of HIV-1infection seem to have expanded the population oflymphocytes bearing T-cell receptors of the Vp5’3subfamily. It will be considerably more difficult, inview of the general lymphocyte depletion of advanceddisease, to show subsequent accelerated elimination ofthe same population, but the findings accord withthe growing body of data pointing to

immunopathogenic mechanisms as the key to HIV-induced disease. Although we do not know for certainwhich components of the virus may behave as

alloantigen or superantigen, resolution of the three-dimensional structure of the envelope glycoproteinreveals a conserved region with striking homology tothe alloactivating determinant of human MHC.8 8

Dalgleish et al believe their model suggests that thegp 120/41 envelope glycoprotein mimics a conserveddomain of MHC class II and class I.

Proponents of the autoimmune hypothesis ofAIDS still have important questions to answer. Inother settings, superantigen or alloantigen responsesare blocked rather easily by antibodies directed againstthe foreign determinant or against TCR or MHC/ Sowhy is the process not aborted in most individuals byone or more of the many antibodies generated in thecourse of HIV infection? Furthermore, while

participation of particular V (3 gene families and MHCalleles in pathogenesis may explain the extremespecies specificity of HIV-associated disease, whydoes the involvement of these polymorphicdeterminants in man show only relative specificity inthe sense that ultimately all CD4 lymphocytes aredestroyed irrespective of their TCR characteristics?Similarly, while most autoimmune disorders affectonly the susceptible minority, it appears that the greatmajority of human beings infected with HIV willeventually get AIDS. Those rare individuals whoremain well and immunologically intact for ten yearsor more after HIV seroconversion represent an

especially important group for future studies.

1. Duesberg PH. Human immunodeficiency virus and acquiredimmunodeficiency syndrome: correlation but not causation. Proc NatlAcad Sci USA 1989; 86: 755-64.

2. Weiss RA, Jaffe HW. Duesberg, HIV and AIDS. Nature 1990; 345:659-60.

3. Webb S, Morris C, Sprent J. Extrathymic tolerance of mature T cells:clonal elimination as a consequence of immunity. Cell 1990; 63:1249-56.

4. Kawake Y, Ochi A. Programmed cell death and extrathymic reduction ofV&bgr;6-CD4-T cells in mice tolerant to staphylococcal enterotoxin B.Nature 1991; 349: 245-48.

5. Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal eliminationin the thymus. Cell 1987; 49: 273-80.

6. Watson JD, Hopkins NH, Roberts JW, Steitz JA, Weiner AM.Molecular biology of the gene. 4th ed. Menlo Park: Benjamin/Cummings, 1987: 882-86.

7. Miller A, Hafler DA, Weiner HL. Tolerance and suppressor mechanismsin experimental autoimmune encephalomyelitis: implications for

immunotherapy of human autoimmune diseases. FASEB J 1991; 5:2560-66.

8. Hounsell L, Renouf D, Liney D, Dalgleish AG, Habeshaw JA. Aproposed molecular model of the carboxyterminus of gp120 showingstructural features of a T cell alloepitope. Mol Aspects Med (in press).

The Helicobacter genus: nowwe are nine

The new genus name, Helicobacter, first publishedin October, 1989, now seems to have justified itscreation, encompassing a respectable number ofdistinct species. H pylori was the first clinicallysignificant organism in the genus, and was culturedinitially in Western Australia ten years ago.2-4 Thename Campylobacter pyloridis was suggested in 1983,5but grammatical rules required the change to

C pylori.6 It was Marshall,4 recalling Armstrong’sobservation that the flagella were sheathed, whosuggested that the organism was not a Campylobacter;sheathed flagella are now regarded as the characteristicfeature of all members of the Helicobacter genus. H

pylori was also shown to have a unique cellular fattyacid profile. By 1988, the Perth microbiology teamhad sufficient evidence to justify a new genus name,and H pylori was the type species; simultaneously, theferret gastric spiral organism, H mustelae, was

included in the genus.1Probably the first member of the genus to be

cultured was a spiral organism in the lower gut of ratsand mice,8 now named H muridarum.9 FiveHelicobacter species have been isolated from the

stomach, three from the lower gut, and one from bothsites. The three other gastric organisms are H felisfound in the cat and dog, H nemestrinae in a pigtailedmacaque," and "H acim.myx" in cheetahs with

gastritis.12 Two human pathogens associated withgastroenteritis were originally put in the

Campylobacter genus but are now known as H cinaediand H fennelliae.l3 "Flexispira rappini"14 was firstisolated from aborted lambs15 but has recently beenfound in human beings with gastroenteritis16 and inthe stomachs of beagle dogs. 17 Although this organismshows some phenotypic differences from H pylori, itpossesses urease and genotypically should be in theHelicobacter genus as "H rappini".9°13Most reports of spiral organisms in the stomachs of

human beings and animals have not distinguished theshorter, loosely spiralled H pylori from the longer,tightly spiralled "(Mon7/MM AewK’MM", whichtightly been cultured and characterised and thereforehas not been cultured and characterised and therefore

841

not officially named. The report of beagle dogst7showed three electron micrographs-the first was"H rappini", the second H felis, and the third "Ghominis". By means of a specific DNA probe for theHelicobacter genus, three more distinct, unnamedspecies of Helicobacter have been discovered in thefaeces of terns, gulls, house sparrows, and pigsl9 andanother ferret Helicobacter species distinct fromH mustelae has been found in ferret feces.The urease enzymes of gastric helicobacters-

H pylori, H mustelae, and H felis-have two pHoptima, including one at acid pH,2O,21 but the latter ismissing from the ureases of helicobacters that colonisethe lower gut, such as H muridarum.21 It has been

suggested that possession of such a urease is a

prerequisite for gastric colonisation.Why should we take an interest in these animal

helicobacters? H felis can be inoculated into mice toproduce an intense colonisation and inflammation ofthe stomach.22 Such a model could be used to studythe antibacterial effect of single drugs andcombinations. Unfortunately, H pylori administeredto ferrets that were free of H mustelae did not colonise.

However, sparse colonisation followed oralinoculation of H felis into these animals. 23 Manyworkers have erroneously concluded that minimuminhibitory concentrations of antibiotics determined atneutral pH against H pylori are a reliable guide totherapy. Numerous drugs are much less active at acidpH,24 and single drugs effective in vitro--eg,erythromycin-fail totally in vivo.25Animal helicobacters and animal models will be

required to test any H pylori vaccine; a successfulvaccine could prevent H pylori gastritis and its

sequelae. Duodenitis due to H pylori is an essentialprerequisite for nearly all duodenal ulcers,26 and a highproportion of gastric ulcers are H pylori-associated. Inpopulations at high risk of gastric cancer, H pylori ismuch more common in children than in low-risk

populations, and leads to lifelong infection. 27Excessive salt intake and a diet low in antioxidantsfrom fresh fruit and vegetables are important factorsin the development of gastric cancer, but H pyloriinfection is a strong candidate for the previouslyunknown epidemiological factor that characteriseshigh-risk populations.27

1. Goodwin CS, Armstrong JA, Chilvers T, et al. Transfer of

Campylobacter pylori and Campylobacter mustelae to Helicobacter gen.nov. as Helicobacter pylori comb. nov. and Helicobacter mustelae comb.nov., respectively. Int J Syst Bacteriol 1989; 39: 397-405.

2. Marshall BJ, Royce H, Annear DI, et al. Original isolation of

Campylobacter pyloris from human gastric mucosa. Microbios Lett1984; 25: 83-88.

3. Warren JR. Unidentified curved bacilli on gastric epithelium in activechronic gastritis. Lancet 1983; i: 1273.

4. Marshall B. Unidentified curved bacilli on gastric epithelium in activechronic gastritis. Lancet 1983; i: 1273-74.

5. Skirrow MB. Taxonomy and biotyping. In: Pearson AD, Skirrow MB,Rowe B, Davies JR, Jones DM, eds. Campylobacter II. Proceedings ofthe 2nd International Workshop on Campylobacter Infections.London: Public Health Laboratory Service, 1983. 33-38.

6. Marshall BJ, Goodwin CS. Revised nomenclature of Campylobacterpyloridis. Int J Syst Bacteriol 1987; 37: 68.

7. Goodwin CS, McCulloch RK, Armstrong JA, Wee SH. Unusual cellularfatty acids and distinctive ultrastructure in a new spiral bacterium(Campylobacter pyloridis) from the human gastric mucosa. J MedMicrobiol 1985; 19: 257-67.

8. Phillips MW, Lee A. Isolation and characterisation of a spiral bacteriumfrom the crypts of rodent gastrointestinal tracts. Appl Environ Microbiol1983; 45: 675-83.

9. Lee A, Phillips MW, O’Rourke JL, et al. Helicobacter muridarum sp. nov.,a microaerophilic helical bacterium with a novel ultrastructure isolatedfrom the intestinal mucosa of rodents. Int J Syst Bacteriol 1992; 42:27-36.

10. Paster BJ, Lee A, Dewhirst FE, et al. The phylogeny of Helicobacter felisnov., a spiral-shaped bacterium isolated from the gastric mucosa of thecat, Helicobacter mustelae, and related bacteria. Int J Syst Bacteriol1991; 41: 31-38.

11. Bronsdon MA, Goodwin CS, Sly LI, et al. Helicobacter nemestrinae sp.nov., a spiral bacterium found in the stomach of a pigtailed macaque(Macaca nemestrina). Int J Syst Bacteriol 1991; 41: 148-53.

12. Eaton KA, Radin MJ, Fox JG, et al. Helicobacter acinonyx, a new speciesof Helicobacter isolated from cheetahs with gastritis. Microb Ecol HlthDis 1991; 4 (spec suppl): 104.

13. Vandamme P, Falsen E, Rossau R, et al. Revision of Campylobacter,Helicobacter, and Wolinella taxonomy: emendation of genericdescriptions and proposal of Arcobacter gen. nov. Int J Syst Bacteriol1991; 41: 88-103.

14. Bryner JH. "Flexispira rappini", gen nov sp nov: a motile, urease-producing rod similar to Campylobacter pyloridis. In: Kaijser B, FalsenE, eds. Campylobacter IV, Proceedings of the 4th InternationalWorkshop on Campylobacter Infection. Sweden: University of

Gotëborg, 1987: 440-42.15. Kirkbride CA, Gates CE, Collins JE, Ritchie AE. Ovine abortion

associated with an anaerobic bacterium. J Am Vet Med Assoc 1986; 186:789-91.

16. Archer JR, Romero S, Ritchie AE, et al. Characterization of anunclassified microaerophilic bacterium associated with gastroenteritis.J Clin Microbiol 1988; 26: 101-05.

17. Henry GA, Long PH, Burns JL, Charbonneau DL. Gastric spirillosis inbeagles. Am J Vet Res 1987; 48: 831-36.

18. McNulty CAM, Dent JC, Curry A, et al. New spiral bacterium in gastricmucosa. J Clin Pathol 1989; 42: 585-91.

19. Paster BJ, Dewhirst FE, Seymour C, Fraser GJ, Fox JG. Helicobacterspecies isolated from bird and swine feces. Microbial Ecol Health Dis1991; 4 (spec suppl) S107.

20. Taylor MB, Goodwin CS, Karim QN. Two urease activities withdifferent pH optima in Campylobacter pylori and similar organisms.FEMS Microbiol Letters 1988; 55: 259-62.

21. Ferrero RL, Lee A. The importance of urease in acid protection for thegastric-colonising bacteria, Helicobacter pylori and Helicobacter felis sp.nov. Microbiol Ecol Health Dis 1991; 4: 121-34.

22. Lee AL, Fox JG, Otto G, Murphy J. A small animal model of humanHelicobacter pylori active chronic gastritis. Gastroenterology 1990; 99:1315-23.

23. Fox JG, Otto G. Murphy JC, et al. Gastric colonization of the ferret withHelicobacter species: natural and experimental infections. Rev Infect Dis1991; 13 (suppl 8): S671-80.

24. McNulty CAM, Dent JC, Ford GA, Wilkinson SP. Inhibitoryantimicrobial concentrations against Campylobacter pylori in gastricmucosa. J Antimicrob Chemother 1988; 22: 729-38.

25. McNulty CAM, Gearty JC, Crump B, et al. Campylobacter pyloridis andassociated gastritis: investigator blind, placebo controlled trial ofbismuth salicylate and erythromycin ethylsuccinate. Br Med J 1986;293: 645-49.

26. Goodwin CS. Duodenal ulcer, Campylobacter pylori, and the "leakingroof" concept. Lancet 1988; ii: 1467-69.

27. Correa P. Is gastric carcinoma an infectious disease? N Engl J Med 1991;325: 1170-71.

Warm heart surgery

Lancet readers who come across papers advocating"warm heart surgery"12 may well be puzzled by thisapparent wave of enthusiasm emanating from Canadaand the USA for normothermic cardiopulmonarybypass.The techniques that made cardiac surgery possible

were developed in the 1950s. Moderate hypothermiato about 30°C was described by a Canadian group3 andperfected at the Middlesex Hospital in London by