Immunology Today, voL 7, No. 5, 1986

-reviews The binding of HTLV-III to T4 becomes even more interesting in the light of a recent finding by R.J. Benjamin and H. Waldmann (Nature 320,449-451), that the immune system of mice can be manipulated to become tolerant to certain protein antigens by administration of the antigens during a brief period of treatment with a monoclonal antibody directed to the L3T4 molecule on helper T lymphocytes (the mouse equivalent of the T4 molecule). This finding may form the basis of a novel generalized means of tolerance induction in which, if the same process happens in humans, anti-idiotype antibodies against HTLV-III may be expected to have an anti-T4 function which might therefore induce tolerance against HTLV-III itself! The availability of both the sequences to HTLV-III envelope glycoprotein 2 8 and T4 2 4 , taken together with the ability to overproduce these proteins in a new cellular environment will hopefully lead to a more detailed analysis of not only the specific recognition event between T4 and HTLV-tll but also the role of MHC class II antigens in T4 recognition events. Furthermore a detailed analysis of the pathogenicity of HTLV-III on T4 + cells may help reveal new information on how these lymphocytes regulate the immune system. It is becoming increasingly clear that the highly specific immunological aberrations seen in HTLV-III infected patients cannot be due to the few cells which are infected (and then presumably die) as even the uninfected cells are functionally abnormal. It is interesting to consider that the 'AIDS virus' may yet be the key to unlocking the hitherto secrets of the T4 molecule and the major histocompatibility antigens not to mention the function of the human immune system.

References

1 Reinherz, E.L. and Schlossman,S.F. (1980) Cell 19,821-827 2 Reinherz, E.L., Meuer, S.C. and Schlossman,S.F. (1983) Irnmunol. Today4, 5-8 3 Reinherz, E.L., Kung, P.C., Goldstein, G. etal. (1979) Proc, Natl Acad. Sci. USA 76, 4061~4065 4 Reinherz, E.L., Morimoto, C., Penta,A.C. etaL (1980) Eur. J. Irnrnunol. 1O, 570

5 Thomas, Y., Sosman,J., Iregoyen, S. etaL (1980) J. Immunol. 125, 2402 6 Morimoto, C., Reinherz,E.L., Bond, Y. etaL (1981)J. Clin. Invest. 67, 753 7 Morimoto, C., Distaso,J., Borel, Y. etaL (1982) J. ImmunoL 128, 1645 8 Gatenby, P.A., Kotzin, B.L., Kansas, G.S. etaL (1982)1 Exp. Med. 156, 55 9 Meuer, S.C., Hussey, R.E., Hodgdow, J.C. etal. (1985) Science 218, 471473 10 Reinherz, E.L., Morimoto, C., Penta, A.C. etal. (1981) J. Immunol. 126, 67 11 Morimoto, C., Reinhertz, E.L., Borel, Y. etaL (1983) J. ImmunoL 130, 157 12 Thomas, Y., Rogozinski, L., Irigoyen, O.H. etaL (1982) J. IrnmunoL 128, I386 13 Morimoto, C., Letvin, N.L., Distaso, J.K. etaL (1985) J. Immunol. 134, 1508 14 Morimoto, C., Letvin, N.L., Boyd, A.W. etaL (1985) J. ImmunoL 134, 3762 15 Royozinski,L., Bass,A., Glickman, E. etal. (1984) J. ImmunoL 132, 735 16 Stohl, W. and Kunkel, H.G. (1984) Scand. J, Immunol. 20, 273-277 17 Jefferies, W.A., Green, J.R. and Williams, A.F. (1985) J. Exp. Med, 162, 117-127 18 Dalgleish, A.G., Beverley,P.C.L., Clapham, P. etaL (1984) Nature (London) 312, 763-767 19 Wood, G.S., Warner, N.L. and Warnke, R.A. (1983) J. ImrnunoL 131,212-215 20 Biddison, W.E., Rao, P.E.,Talle, M.A. etaL (1983) J. Immunol. 131,152 21 Biddison, W.E., Rao, P.E.,Talle, M.A. etal. (1984) J. Exp. Med. 159, 783 22 Bank, [. and Chess, L. (1985) J. Exp. Med. 162, 1294-1303 23 Pernis,B. and Axel, R. (1985) Ce1141, 13 16 24 Maddon, P.J., Littmann, D.R., Godfrey, M. etal. (1985) Cell 42, 93-104 25 Littman, D.R., Thomas, Y., Maddow, P.J.etal. (1985) Cell 40, 237-246 26 Blue, M.L., Daley, J.F., Levine, H. etaL (1985) Proc Natl Acad. Sci. USA 82, 8178-8182 27 McDougal, J.S., Kennedy, M.S., Sligh, J.M. etal. (1986) Science 231,382 385 28 Ratner, U., Haseltine, W., Patarca, R. etal. (1985) Nature (London) 313, 277-284

Is spondylitiscaused by Klebsiella? The aetiology of ankylosing spondylitis involves some genetic predisposition: the disease occurs mainly in males, and many spondylitics have the HLA-B27 antigen. However, the correlation with known genetic factors is not absolute. For example, not all identical twin siblings of spondylitics develop the disease. In this review Andrew Keat discusses the genetic and environmental factors which may contribute to the development of spondylitis.

Ankylosing spondylitis is a common disorder affecting up to 1% of the Caucasian male population. It is an inflammatory disease of synovial joints of the spine which is also characterized by inflammatory lesions at entheses-junctional zones between tendon or ligament 144

Department of Rheumatology,CharingCrossand WestminsterMedical School, London SW1P 2AP, UK. O 1986, Elsevier Science Publishers B.V., Amsterdam

0167

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AndrewKeat and bone both within and at a distance from the spine. Spondylitis is a chronic but fluctuating inflammatory disorder with exacerbations and periods of symptomatic and objective quiescence: bony ankylosis and deformity are the end-results in only a small proportion of severely affected individuals. Other lesions including peripheral joint arthritis, acute inflammatory eye disease (anterior uveitis), aortic valve disease, bursitis and tendonitis occur in association with spondylitis in a minority of individuals. These lesions occur asynchronously with spinal disease and frequently occur without any other associated disease. They also appear to segregate distinct from spondylitis within families. It is likely therefore that, although linked with spondylitis, these lesions have

Immunology Today, voL 7, No. 5, 1986

reviews-

different aetiologies from the spinal disease itself. long been regarded as a likely cause of this condition. Spondylitis frequently occurs in isolation but individuals This view has been strengthened by the recognition of with,psoriasis or inflammatory bowel disease are espeimmune response genes in the major histocompatibility cially pre-disposed to it. complex determining the immune responses to foreign Family and twin studies have shown that heritable antigens and infectious agents 14-16. Although spondylifactors are involved in the development of spondylitis. tics do not report exacerbations of their disease during or Early studies concluded that spondylitis is caused by a after transient episodes of diarrhoea, the development of single autosomal dominant gene. However, the strong sacroiliitis and less commonly of typical ankylosing sponassociation between ankylosing spondylitis and the dylitis in individuals with acute reactive arthritis associated histocompatibility antigen HLA-B27, 96% of Caucasian with certain forms of bacterial diarrhoea is firmly spondylitics possessing the antigen compared with 7% established. In this condition of acute remitting polyof healthy controls 1'2, has led to a reappraisal of the arthritis, infections by Shigella flexneri, Salmonella enterigenetics of this condition. Although the strength of the tidis, Campylobacterjejuni and Yersinia enterocolitica are association with B27 is very striking, it is important that strongly implicated 17. Some evidence linking spondylitis the association is not absolute. Apart from the 4% of with chronic prostatic infection also emerged in the Caucasian spondytitics who are B27 negative, there is 1950s 18 2o but this evidence is controversial. The assoconsiderable variation from one population to another; ciation between spondylitis and non-infective inflamma8 0 % of Mexicans 3 and Japanese4 with spond~/litis and tory bowel disease has also led to speculation that only 50% of North American black spondytitics possess inflammation of the colo-rectal mucosa might allow the antigen. The presence of other diseases - or normal gut commensals or microbial pathogens to have susceptibility to them - also appears to contribute to abnormal access to the immune system and thus, in susceptibility to spondylitis; when spondylitis occurs in some unspecified way, to trigger the spondylitic process. conjunction with psoriasis or inflammatory bowel disease Some investigators have suggested that colo-rectal the association with HLA-B27 becomes weaker with only . mucosal abnormalities are extremely common in patients about 50% of patients possessing HLA-B27. This inwith spondylitis 21 though these data are also controverfluence appears to be genetic rather than related to the sial. In this context it is of interest that Stodell and presence of disease: HLA-B27-negative spondylitis segrecolleagues 22 reported an abnormal increase in the gates separately from inflammatory bowel disease in absolute numbers of IgG plasma cells in rectal lamina families in which both diseases occur 6. propria of individuals with spondylitis and clinically Several recent studies 7'8 indicate that B27-positive normal bowel; this could imply that there is a local relatives of probands with spondylitis are significantly immune response to microbial antigens within the gut more likely to have spondylitis than B27-positive relatives lumen. of normal B27-positive individuals. This latter group of It has, therefore, been a logical step for investigators B27-positive relatives are however more likely to have to seek an infectious cause for spondylitis and to look for spondylitis than B27-negative individuals. These studies it in the gastrointestinal tract. imply that either the B27 antigen in individuals with spondylitis is different from that in disease-free indiHypotheses viduals or that an additional factor(s) is also present in Current hypotheses attempting to explain the involvethe spondylitic families. The possible existence of more ment of HLA-B27 in the pathogenesis of spondylitis fall 'than one epitope of the B27 antigen has been explored into two major groups. The first postulates that other by several groups and Grumet in 19819 reported the genes within the major histocompatibility complex, genserological definition of two B27 determinants desigetically linked with HLA-B27 but distinct from it, are nated M1 and M2. Preliminary studies have not shown a primarily important in determining susceptibility to sponclear-cut association between either variant and dylitis. Thus inherited defects in the handling of certain spondylitislO,11. microorganisms or classes of microorganisms might Another factor which requires consideration is the account for the development of the disease precipitated strong predilection of the disease for men. Most workers by infection in genetically susceptible individuals. An now recognize that inheritance of spondylitis is likely to alternative hypothesis proposes that the HLA-B27 antibe multi-factorial, with genes outside the major histogen itself is directly involved in the tissue damaging compatibility complex, perhaps including sex-related process, tn this event, either the cell surface determinant genes, exerting an influence on the development and functions as a specific receptor for important mediators phenotypic expression of the disease 12. in the inflammatory process or antigenic similarity exists Other conditions associated with spondylitis, especially between the B27 determinant and antigens of particular acute uveitis and reactive arthritis, are also independently infecting microorganisms leading to an inappropriate linked with HLA-B27. These acute disorders may share immune response. This could lead to either tolerance some important pathogenic mechanisms with ankylosing with persistence of the microorganism leading to disease spondylitis but, in contrast to its insidious onset and or autoimmunity. Though substantially different from chronic course, they are of acute onset and relatively each other, recent studies from A. Ebringer et aL and A. brief course and are distinct from spondylitis so that Geczy et al. have focused attention on hypotheses concepts of one do not necessarily apply to the other. favouring direct interaction between a bacterium and the HLA-B27 cell surface determinant in the aetiology of Environmental factors spondylitis. In addition to genetic predisposing factors, discordance of identical twins for spondylitis, with regard to Molecular mimicry hypothesis both presence and severity of symptoms, argues strongly The concept that disease might result from a chance in favour of an environmental factors(s) 13. Infection has similarity between naturally occurring cell surface anti-

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-reviews gens of the host and those expressed on infectious microorganisms has been referred to as the molecular mimicry hypothesis 23. Support for this concept as a crucial mechanism in the development of spondylitis has been vigorously advanced by the Ebringer brothers and their colleagues 24. In 1976 they reported studies with a rabbit antiserum raised to human B27-positive lymphocytes 2s. When tested in a gel diffusion assay against 27 different strains of bacteria a precipitin line formed against Klebsiella aerogenes. An antiserum raised against this microorganism was also shown to specifically lyse B27-positive lymphocytes from patients with spondylitis in a complement dependent assay.

Faecalcarriageof Klebsiella

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These workers postulated that the presence of Klebsiella microorganisms in the bowel might be the stimulus for activating spinal inflammation. Subsequently they reported the isolation of Klebsiella pneumoniae from the stools of 13 out of 14 patients with active spondylitis but in only 4 out of 24 with inactive disease and 47 out of 124 healthy controls 26. Such studies are fraught with dangers as, on the one hand, Klebsiella carriage is seasonal27 and increased by eating fresh uncooked foods such as salads and, on the other, there is no consensus amongst clinicians as to how 'active' spondylitis might be defined. These findings were also criticized 28 on the grounds that if all the spondylitic patients were taken together the overall isolation rate was almost identical with that amongst healthy controls so that the interpretation of these findings depends entirely upon the division between active, probably active and inactive disease. In addition, patients with active disease were cultured more frequently than the healthy controls; since Klebsiella may persist in the bowel for some months repeated sampling of one group but not of the other may also introduce bias. A similar association with active spondylitis was reported by Kuberski and colleagues 29 but several other groups 3 0 3 2 have failed to find any association between Klebsiella carriage and the presence or activity of spondylitis. Further studies from the Middlesex group indicating that patients with inactive spondylitis who acquire Klebsiella in the bowel subsequently had an increase in activity of their spinal disease33 also met with equivocal34 or conflicting3°'35 results from other workers. An attempt to reduce Klebsiella carriage by dietary manipulation36failed to eliminate the microorganism or to influence spondylitic symptoms. In advocating a crucial role of the B27 gene itself, Ebringer and colleagues have proposed the crosstolerance hypothesis 37. The critical component of the hypothesis is the generation of an antibody response to Klebsiella antigen which is qualitatively or quantitatively inadequate for elimination of the organism. Persistence of the organism or recurrent infections by it lead to the continued production of the antibody which partially cross-reacts with the host tissue. In doing so it binds complement and so brings about complement-mediated tissue damage. The hypothesis further postulates that much of the antibody is generated in the lymphoid tissue draining the large bowel which is situated near the sacroiliac joints and spine which, being near to the lymph node activity, become inflamed. No bacterium or bacterial antigen travels to the site of inflammation, only antibody. The primary site of infection may be asymptomatic.

Receptor hypothesis The lack of credibility of clinical studies threw some doubt upon the observation of serological crossreactivity between Klebsiella antigens and the HLA-B27 antigen. However in 1979 Seager and colleagues 3~ reported their independent findings that an antiserum raised to a Klebsiella (designated 427) lysed the lymphocytes of B27-positive patients with spondylitis but not those of B27-negative spondylitics nor those from B27positive and negative healthy controls. Only this strain of Klebsiella and the cells of B27-positive spondylitics appeared to possess these cross-reactive antigens. Other workers have so far been unable to reproduce these results but it has been possible for cells from the UK39'4° and The Netherlands 41 to be tested in Sydney using the Klebsiella antiserum and correctly identified as spondylitic or non-spondylitic. The Sydney group proposed that this system demonstrated the presence of a specific cell surface marker for spondylitis and that this is either the B27 determinant or associated with it. With the work of Arnason and colleagues 42 as a basis, they postulated that the cross-reactive cellular determinant might be part of the B27 molecule modified by the addition of some bacterial component and that this might allow the initiation of a genetically restricted immune reaction which could be damaging to host tissue. This notion was greatly strengthened by further observations of the Sydney group. They demonstrated that it was possible to modify the antigenic appearance of B27-positive cells from non-spondylitic individuals by incubation with Klebsiella culture filtrates 43. After such incubation the cells then resembled those from B27-positive spondylitic patients and were lysed by the anti-Klebsiella serum. By inference the culture filtrate contained a critical modifying factor(s) and only cells which bore the B27 antigen were susceptible to it, suggesting that the B27 determinant itself acted as a receptor for the modifying factor.

Properties of 'modifying factor' The Klebsiella-specific B27-associated determinant has been shown to be distributed on T and B lymphocytes, EBV transformed lymphoblastoid celt lines, platelets and skin fibroblasts 44. Further studies have demonstrated that cells from some individuals with isolated B27positive uveitis, in the absence of joint disease45 and with Reiter's syndrome 46, are also susceptible to lysis by the anti-Klebsiella serum. Limited family studies indicate that susceptibility to lysis by the Klebsiella antiserum is acquired rather than inherited. In two families, each with two affected individuals, only the cells of spondylitic patients were susceptible to lysis whilst haplotype identical, first degree relatives were not 44. However, just as with the clinical studies of Klebsiella carriage, so abnormal cellular responses to Klebsiella and the production and actions of modifying factor have not to date been confirmed by other investigators 47~9. Studies from the Sydney group indicate that Klebsiellaproduced modifying factor originates from the outer membrane of the bacterium and has a molecular weight of 26-30kDa (Ref. 50), although higher figures had been suggested by earlier studies. The factor is destroyed by heating at 56°C for 30 min and by treating with neuraminidase although it is stable to treatment by water-soluble trypsin or chymotrypsin. Only about 8% of Klebsiella isolates appear capable of producing mod-

ImmunologyToday, voL ~No. ~ 1986

ifying factor sl but studies have shown that the factor is not associated with the biotype or phage type of the microorganism. The finding that cells from B27-positive spondylitics remained susceptible to lysis by Klebsiella antiserum even after culture for 20 generations 52 suggested that the target for the antiserum is genetically determined and constantly synthesized. By contrast, cells from B27positive normal subjects, rendered susceptible to lysis by Klebsiella anti-serum through exposure to modifying factor, rapidly lose their susceptibility to lysis, suggesting that the Klebsiella culture filtrate contains a molecule(s) which temporarily adheres to the cell surface and which is subsequently shed. There is no one biotype or phage type of Klebsiella which possesses the capacity to produce 'modifying factor'; this capacity is shared by individual isolates, apparently at random. In this respect the capacity to produce modifying factor is similar to antibiotic resistance which is transmitted between microorganisms by plasmids. One interpretation of this work is that bacteria are able to pass between themselves plasmids coding f o r a surface determinant. This determinant may then appear on the cells of a suitable human host - namely a B27-positive individual - and is associated with the development "of spondylitis. Exploring this possibility, Cameron and colleagues s3 reported finding such a plasmid. They also demonstrated that curing of Klebsiella by acridine orange removed the plasmid and rendered the microorganisms incapable of synthesizing modifying factor whilst transfer of ptasmid DNA to Escherischia coil resulted in the elaboration of modifying factor by the recipient microorganism. Recently, A. Geczy et aL have reported absorption of antibody to K43 by a variety of gram-negative and -positive faecal bacteria isolated from individuals with spondylitis 41. These data are consistent with the ptasmid theory and could account for the failure to identify consistently any one causal microorganism. Mechanisms

Any comprehensive hypothesis seeking to explain the pathogenesis of spondylitis in the light of this phenomenon of cross-reactivity between B27-bearing cells and Klebsiella pneurnoniae must explain the biological consequence of such cross-reactivity and define the mediators of the specific tissue damage. Such an hypothesis must also take into account four important factors in the disease: the predominance of spondylitis amongst men in the third decade of life; the high prevalence of other disease features independently linked to HLA-B27. amongst individuals with spondylitis; not all spondylitics possess the HLA-B27 antigen; and the presence of HLA-B27 on all nucleated cells, although most tissues appear to be unaffected by the spondytitic process. The concept that HLA-B27 itself is directly involved in the pathogenesis of spondylitis is immediately contentious. In all studies, around 4% of patients, or more, do not possess HLA-B27. When spondylitis which is in other respects typical of the idiopathic disease occurs in individuals with inflammatory bowel disease or psoriasis the prevalence of the B27 antigen is considerably lower. Either B27-negative individuals have a different disease which merely clinically resembles B27-positive disease or other genes are capable of predisposing to the disease without HLA-B27. Several studies s4-s6 have failed to

reviewsdocument any differences between B27-positive and negative spondylitis although, of necessity, small numbers of B27-negative spondylitics were included. One possibility invoked to explain this discrepancy is the presence in B27-negative patients of a group of HLA antigens which serologically cross-react with it (CREG antigens), namely B7, Bw22, B40 and Bw42 (Ref. 57). It is certainly true that most B27-negative patients with spondylitis do possess one of the other antigens within the B7-CREG; but it should be borne in mind that one of these, HLA-B7, is present in approximately 27% of normal Caucasians and none of these antigens has been shown to be present with increased frequency in patients with spondylitis. There are some patients who have typical spondylitis but possess none of these antigens. The postulated cross-reactive antibody of the crosstolerance hypothesis remains elusive. Studies of cellmediated immunity to certain gram-negative bacteria in spondylitis have produced conflicting results. Reduced 38,s8, normal s9,6° and increased 61 mononuclear cell responses have all been demonstrated. Data concerning specific antibody titres are scanty. Total IgA levels are known to be raised in patients with a.nkylosing spondylitis 62 but there are similar changes in both serum and saliva in rheumatoid disease and psoriatic arthritis 63. Raised levels of IgA antibody to Klebsiella have been found in spondylitic sera 64, but there was no correlation with disease activity. These findings appear compatible with raised titres of IgA anti-Yersinia antibody in Yersinia arthritis 6s'66 and raised titres of chlamydial antibody in sexually acquired reactive arthritis 67-7°. However, this study is open to several criticisms and other workers have found normal 71 or low 72 levels of antibody to a variety of gram-negative bacteria, including Klebsiella. Nor have pathological studies of the lesions of spondylitis yet been carried out to provide evidence of an antibody- and complement-mediated disease. This crucial piece of work will remain difficult to perform as, perhaps fortunately, appropriate tissue for study rarely becomes available in this non-fatal disease. In the model proposed by Svejgaard and Ryder 73 the cell surface HLA determinant functions as a receptor for some circulating ligand. A possible extension of the receptor hypothesis has been provided by Geczy, Edmonds and colleagues from Sydney. In contrast to the molecular mimicry hypothesis in which it is host antibody which is thought to produce tissue damage, in a receptor theory microbe-derived antigens present on the surface of certain host cells initiate the disease process. This could result from incorporation of prokaryotic plasmid DNA into the host genome - which is apparently not quite unprecedented in biology TM - or through adherence of a constantly produced bacterial product, or through derepression of normally unexpressed genes, induced by the presence of a bacterial product such as 'modifying factor'. Conclusion

Gut infection is highly likely to be important in the aetiology of ankylosing spondylitis. Serological crossreactivity between a determinant on HLA-B27 positive spondylitic cells and certain gut bacteria is a fact. These significant studies have begun the detailed exploration of the possible mechanisms by which mircoorganisms may precipitate disease in genetically susceptible individuals. But it is important that concepts arising out of ex-

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-reviews. perimental viral infections in animals are not without proper justifications applied to bacterial infections in man. It is also important that antigenic cross-reactivity between gut bacteria and human cell surface antigens may be a commonplace phenomenon, exemplified by the sharing of ABO blood group antigens between human erythrocytes and Escherichia coil So far no naturally pathogenic consequences of such crossreactivity have been demonstrated and the possibility remains that cross-reactivity between HLA-B27 and bacterial antigens may be a genuine phenomenon but of no pathogenic significance. It must also be emphasized that the concept of ankylosing spondylitis as a form of reactive arthritis is, while attractive, largely unsupported by facts, and hypotheses have to comply with the clinical facts of the disease. The possibility that bacterial DNA might induce disease through incorporation into the human genome is an extraordinary and exciting concept. To keep this idea alive, the protagonists will have to produce a gene probe and identify plasmid-DNA sequences within the human genome. Indeed, it is high time that genetic engineering techniques are brought to bear on this classic disease model. Meanwhile, the divide between unique MHCrelated determinants at the cell surface and the characteristic lesions of ankylosing spondylitis remains unbridged. References

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1 Brewerton, D.A., Hart, F.D., Nicholls, A. etal. (1973) Lanceti, 904-907 2 Schlosstein, L., Terasaki, P. I., Bluestone, R. etal. (1973)N. EngL J. Meal. 238, 704-706 3 Arellano, J., Vallejo, M., Jimenez,J. etaL (1984) Tissue Antigens 23, 112-116 4 Ryder, L.P., Anderson, E. and Svejgaard, A. (Eds)(1979) HLA and Disease Registry: Third Report, Munksgaard, Copenhagen 5 Kahn, M.A., Braun, W.E., Kushner, I. etal.(1977)l Rheumatol. 4 (suppl. 3) 39-43 6 Enlow, R.W., Bias,W.B. and Arnett, F.C. (1980) Arthritis Rheum. 23, 1359 1366 7 Calin, A., Marder, A., Becks, E. etal. (1983)Arthritis Rheum. 26, 1460-1464 8 Van Der Linden, S.M., Valkenburg, H.A. and Cats, A. (1985) in Advances in Inflammation Research Vol. 9, The Spondyloarthropathies (Ziff, M. and Cohen, S. eds) pp. 83-89, Raven Press, New York 9 Grumet, F.C., Fendly, B.M. and Engleman, E.G. (1981) Lancet ii, 174-176 10 Breuning, M.H., Lucas, C.J., Breur, B.S. etal. (1982)Hum. ImrnunoL 5, 259-268 11 Van Bohemen, C.G., Grumet, F.C. and Zanen, H.C. (1985) in Advances in Inflammation Research Vol. 9, The Spondyloarthropathies (Ziff, M. and Cohen, S.B. eds) pp. 157-164, Raven Press,New York 12 Brewerton, D.A. (1984) Lancet ii, 799-802 13 Eastmond, C.J. and Woodrow, J.C. (1977)Ann. Rheum. Dis. 36, 360-364 14 Zinkernagel, R.M. and Doherty, P.C. (1977) Contemporary Topics in Immunobiology 7, pp. 179-201, Plenum Press,New York 15 McMichael, A., Ting, A., Zweerink, H.J. etaL (1977) Nature (London) 270, 524-526 16 Keat, A. (1982)J. Infect. 5, 227-239 17 Keat, A. (1983) N. Engl. J. Med. 309, 1606-1615 18 Romanus, R. (1953)A(ta Med. Scand. (suppl.~280, 172178 19 Mason, R.M., M urray, R.S., Oates, J.K. eta/. (1958) Br. Med. J. 1,748-751

20 Domeij, B., Giertz, E., Olhagen, B. etaL (1958)Acta Chir.

Scand. 115, 1-10

21 Jayson, M.I.V., Salmon~ P.R.and Harrison, W.J. (1970) Gut 11,506-511 22 Stodell, M.A., Butler, R.C., Zemelman, V.A. etaL (1984) Ann. Rheum. Dis. 43, 172-176 23 Benacerraf, B. and McDevitt, H.O. (1972) Science 175, 273-279 24 Ebringer, A. (1979) Lanceti, 1186 25 Ebringer, A., Cowling, P., Ngwa-Suh, N. etal. (1980)in HLA andDisease (Dausset, J. and Svejgaard, A. eds) p. 27, INSERM 58, 27 26 Ebringer, R., Cooke, D., Cawdell, D.R. etaL (1977)Rheum. Rehab. 16, 190-196 27 Cooke, E.M., Sazegar, E.,,Edmondson,A.S. etaL (1980) J. Hyg. 84, 97-101 28 Brewerton, D.A. and Warren, R.E.(1978)Ann. Rheum. Dis. 37,298 29 Kuberski, T.T., Morse, H.G., Rate, R.G. etaL (1983)Br, J. Rheumatol. 22 (Suppl. 2) 85-90 30 Warren, R.E.and Brewerton, D.A. (1980) Ann. Rheum. Dis, 38, 37-44 31 Eastmond, C.J., Willshaw, H.E., Burgess, S.E.D. etaL (1980) Ann. Rheum. Dis. 39, 118-123 32 Hunter, T., Harding, G.K.M., Kaprove, R.E.etal. (1981) Arthritis Rheum. 24, 106-108 33 Ebringer, R.W., Cawdell, D.R., Cowling, P. etal. (1978)Ann Rheum. Dis. 37, 146-151 34 Wright, V., Neumann, V., Shinebaum, R. etaL (1983)Br. J. RheumatoL 22 (Suppl. 2) 29-32 35 Eastmond, C.J., Calguneri, M., Shinebaum, R. etaL (1982) Ann. Rheum. Dis. 41, 15-20 36 Wright, V., Neumann, V.C., Shinebaum, R. etal. (1985)in Advances in Inflammation Research Vol. 9, The Spondyloarthropathies (Ziff, M. and Cohen, S. eds) pp. 249259, RavenPress,New York 37 Ebringer, A. (1983) Br. J. RheumatoL 22 (Suppl. 2) 53-66 38 Seager, K., Bashir, H.V., Geczy, A.F. et aL (1979)Nature (London) 277, 68-70 39 Archer, J.R., Stubbs, M.M., Currey, H.L.F. etaL (1985) Lancet i, 344-345 40 Struthers, G. (1985) Lancet i, 764 41 Prendergast,J.K., McGuigan, L.E., Geczy, A.F. etaL (1984) Infect. Immun. 46, 686-689 42 Arnason, A., Thorsteinsson,J. and Sigurbergsson, K. (1978) Lancet i, 339-340 43 Geczy,A.F., Alexander, K. and Bashir, H.V. (1980) Nature (London) 283,782-784 44 Geczy, A.F., Alexander, K., Bashir, H.V. etal. (1983) ImmunoL Rev. 70, 23-50 45 Edmonds, J., Portek, I., Wakefield, D. etaL (1981)Rev. Rhum. Abstr. 239 46 Edmonds, J., Macauley, D., Tyndall, A. etal. (1981)Arthritis Rheum. 24, 1-7 47 Trapani, J. and McKenzie, I.F.C. (1985)Ann. Rheum. Dis. 44, 169 175 48 Kinsella,T.D, Lanteigne, C., Fritzler, M.J. etaL (1984)Ann. Rheum. Dis. 43, 590-593 49 Feltcamp, T.E.W. (1985) in Advances in Inflammatory Research Vol 9, The Spondyloarthropathies (Ziff, M and Cohen, S.B. eds) pp. 211-216, RavenPress,New York 50 Druery, C., Bashir, H., Geczy, A.F. etaL (1980) Hum. ImmunoL 1, 151-160 51 Geczy, A.F. and Yap, J. (1982) J. Rheumatol. 9, 97-100 52 Orban, P., Sullivan,J.S., Geczy, A.F. etal. (1983) Clin. Exp. ImmunoL 53, 10-16 53 Cameron, F.H., Russell,P.J., Sullivan, J. etaL (1983) Mol. ImmunoL 20, 563-566 54 Van der Linden, J.M.J.P., De Ceulaer, K., Van Romunde, L.K.J. etal. (1977)1 RheumatoL 4 (Suppl. 3) 54-56 55 Khan, M., Kushner, I. and Braun, W.F. (1977)Arthritis Rheum. 20, 909-912

Immunology Today, voL 7, No. 5, 1986

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59 Mawle, A.C., Hobbs, J.R., Warren, R.E.etal. (1979)Ann. Rheum. Dis. 38, 197-198 60 Kinsella,T.D., Laneigne,C., Fritzler, M.J. etaL (1984)Ann. Rheum. Dis. 43,590-593 61 Gross,W.L., Ludemann, G., Ulmann, U. etal. (1983) Br. J. Rheumatol. 22 (Suppl. 2) 50-52 62 Kinsella,T.D., Espinoza,L. and Vasey, B. (1975) J. Rheumatol. 2, 308-313 63 Neumann, V.C., Hickling, P., Turnbull, L. etaL (1984) Br. J. Rheumatol. 23 (Abstr.) 147-149 64 Trull, A., Ebringer, A., Panayi,G. etal. (1984) Clin. Exp. ImmunoL 55, 74-80 65 Aho, K., Ahvonen, P., Juvakoski, T. etaL (1979)Ann. Rheum. Dis. 38 (Suppl.) 123-126

This month two more software packages designed to manage bibliographic reference databases are reviewed. DG Systems' REF-11 is designed spedfically for reprint files but has some limitations and a very poor manual Eagle's CITATION is an aft purpose professional database program designed for many applications with a very good manual but with some major limitations. REF-1 1 is a database management system for references which, advertisements claim, has 'many advanced features normally found in highly priced software . . . to make the system as user friendly as possible'. REF-1 l's main menu allows the user to: add, change, delete or output references, select a reference volume, change defaults or exit the program. Default parameters may be set to define automatically the terminal type, volume (reprint) file and printing commands. There is no easy way to learn to use REF-11; a new user must read the manual or rely upon an experienced user. Help is not provided in REF-11 itself. Once instructed, however, the user will find that adding references is easy, as is editing existing references with a full screen editor which 'paints' an entire reference on the screen. The user moves from one area of the screen to another with cursors to enter or edit data (in any order) for each reference. The user enters up to 8 authors, article name, year, volume, pages, Department of Internal Medicine, Universityof Iowa, Iowa Ci/y,IA 52242, USA. (~) 1986, Elsevier Science Publishers B.V, Amsterdam

0167

t ce-q

66 Granfors, K., Viljanen, M., Tiilikainen, A. etaL (1980) 1 Infect. Dis. 141,424~429 67 Kousa, MJ., Saikku, P., Richmond, S. etal. (1978) Sex. Trans. Dis. 5, 57-61 68 Keat, A.C., Thomas, B.J.,Taylor-Robinson, D. etal. (1980) Ann. Rheum. Dis. 39, 431437 69 Vilppula, A.H., Yli-Kerttula, U.I., Ahlroos, A.K. etal. (1981) 5cand. J. Rheumatol. 10, 181-185 70 Martin, D.H., Pollock, S., Kuo, C.-C. etaL (1984)Ann. Intern. Med. 100, 207-213 71 Pease,C.T., Fordham, J., Stubbs, M. et al, (i[~ press) 72 Van Bohemen, C.G., Nabbe, A.J.J.GM., Decker-Saeys,A.J. eta/. (1985) in Advances in Inflammation Research Vol 9, The Spondyloarthropathies (Ziff, M. and Cohen, S.B. eds) pp. 165-171, Raven Press, New York 73 Svejgaard,A. and Ryder, L.P. (1976)Lancet ii, 547 549 74 Gelvin, S.B., Gordon, M.P., Nester, E.W. etaL (1981) Plasmid 6, 17-29

The computer and the reprint file (3) fromJohnM. Weiler journal name, up to 8 topics and up to 20 lines of 80 characters/line of comments per reference. References may range from 4 to 2500 characters (bytes); a small reference would be contained in 100 bytes of storage space allowing 3600 references per double-sided double-density diskette. The user should enter the data in a consistent manner (e.g. always Lastname, FM, Sr); however, if he uses some other format, REF-11 will try to convert it to a standard format. Thus, FM Lastname, F.M. Lastname, F. M. Lastname, F M Lastname, Lastname, F.M. and seven other forms will all be converted to Lastname, FM. This requires that the user capitalize the first letter of the lastname and the initials; full first and middle names are not acceptable. When it is possible to enter more than 1 line (comments, title, etc.), the words wrap around to the next line automatically. However, the user can only edit single lines making it difficult to insert a sentence or word. There are three formats for entering data; journal (article), book chapter and book, each tailored to the specific entry. If the program ends abruptly due to error it is said that data will not be lost. Searching is also easy. The user selects the item he wishes to search and may even truncate the item (e.g., lymphoc* rather than lymphocyte, lymphocytic or lymphocytes). Any number of items may be used in the search (authors• title, journal). REF-11 looks for an exact match of

4919186/$02.00

the characters anywhere in the specified field(s) (e.g., title, authors, comments). The delete reference function in REF-11 actually deletes the space in which the reference was held whereas many other programs require the user to run a compress program later to do so. The output function allows the user to copy references to another volume, to a variety of peripheral devices (mostly printers) or to the screen, tt outputs a one line summary, a two line summary, a summary with no comments, a summary with comments or a formatted output for a particular journal. The output function works well; however, only five journal formats are provided. The user may enter additional formats but must 'use his favorite text editor'. An example of what the user must enter is: //Journal of Comparative Neurology /LITERATURE CITED L. F.M. • and F.M. L ,F.M. L

(y)

J? T. A. _V_: P. (There are six more lines to this format not reproduced here.) This is not an ideal way to enter journal formats. The instructions on how to enter these formats require about 18 pages (almost 1/4 of the manual). Users must remember to enter LPT1 as the output device if it is not already the default output device. For a programmer, this is not a prob-

149