Immunology Today, vol. 4, No. 8, 1983

Oncogenes and B-lymphocyte neoplasia- contd, from page 206

20 kd of the c-abl polypeptide is missing. The v-abl gene has also undergone point mutations, one of which converts a Cys (in c-abl) to a Tyr (in v-abl) within the transforming region. A minimal trans- forming region has been localized, and it contains 40 kd of c-abl sequences plus 3 kd of the viral gag sequences; it contains the tyrosine kinase domain.

An unusual series of early B-cell turnouts produced by M. Potter (NIH) by injection of Abelson leukemia virus plus pristane into BALB/c mice have been found to contain a rearranged c-myb gene which is actively transcribed (F. Mushinski, NIH). The fascinating but unresolved issue is whether or not the

Abelson virus figured in the origin of these tumours and cause d the c-myb gene alteration in a hit-and-run event.

The complete transcript of this meet- ing will be published soon as a mono- graph by Editiones (Roche), Basel, Switzerland.

Suzanne Co~y is a Senior Research Fellow at The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria 3050, Australia.

References 1 Hayward, W. S., Ned, B. G. and Astrin, S.

M. (1981)Nature (London)290, 475-480 2 Colby, W. W., Chen, E. Y., Smith, D. H.

and Levinson, A. D. (1983) Nature (London) 301, 722-725

T h e i m m u n o l o g y o__f 0-ce l l f a i l u r e

A case for immune response genes? from Gordon Reeves

Diabetes is not a single disease. Some patients develop insulin deficiency fairly rapidly and these are usually young, have lymphocytic infiltration of their pancreatic islets, possess circulating islet-cell antibody, and show a strong association with certain HLA phenotypes. This form of the disease is designated type I (juvenile onset or insulin-dependent diabetes mellltus, IDDM). The key factors involved in its pathogenesis were recently reviewed at the fourth of a series of international meetings on the immunology of diabetes*. This meeting was held in memory of Andrew Cudworth whose standing was pre-eminent in the

immunogenetics of diabetes and whose untimely death is keenly felt 1.

Reviewing the genetics of this disorder, Jorn Nerup (Copenhagen) emphasized that the data do not fit any simple Men- delian model - a fact which professional geneticists should now accept 2. As with a number of immunologically mediated disorders, the HLA association is strong- est at the D/DR locus where two different alleles, DR3 and DR4, are involved. This and the marked increase in DR3/DR4 heterozygosity suggests the presence of two closely linked susceptibility genes 3. Walter Bodmer (London) contrasted the detailed mapping of the I region in the mouse with the fragmentary data which exist concerning possible immune res- ponse (Ir) genes in man, although data were presented from the Nottingham Prospective Study indicating that low and high antibody responsiveness to in- jected insulin associates with DR3 and DR7, respectively. Michael Crumpton (London) and Per Peterson (Sweden) reviewed the progress that has been made in unravelling the finer detail of the

* The IV International Workshop on 'Immun- ology of Insulin-Dependent Diabetes Mellitus' took place at St Bartholomew's Hospital, London, on 5-6 April 1983.

H L A - D R region using monoclonai anti- bodies, two-dimensional immunopreci- pition gels and DNA cloning. There does now seem to be general agreement that human class-II M H C antigens consist of at least three distinct a- and/J-chain vari- eties, and the multiplicity of HLA-D- related specificities are best explained by the existence of three adjacent loci desig- nated SB, DC (or MT) and DR. The degree of homology with the murine I-A and I -E/C regions is impressive at both DNA and protein levels.

1974 was marked not only by the dis- covery of the HLA association with type- I diabetes but also by the detection of islet-cell antibody in such patients. The collaborative study set up by Andrew Cudworth at St Bartholomew's Hospital wi thJohn Lister in Windsor, and known as the Barts/Windsor study, has proved singularly productive in weaving to- gether the significance of these two phen- omena. Kate Spencer (London) report- ed that seven first-degree relatives of pro- bands with type-I diabetes had devel- oped the same condition during the five years of this prospective study and that all were haplo-identical or identical for H L A - D R and all had islet-cell antibody

207

present well before the diagnosis was made. The considerable length of time during which islet-cell antibody can be present before the acute onset of clinical symptoms of diabetes suggests that the pathogenesis of this disorder has a slow tempo ~. The fact that many of these patients also show antibodies to cells in the anterior pituitary adds a further di- mension, in keeping with the finding that the peak age of onset is around puberty and is often associated with a growth spurt and advanced bone age. Evidence from animal studies (see below) indicates that diabetogenic virus can induce im- munological reactions in the pituitary as well as the pancreas.

Franco Bottazzo (London) reported immunofluorescence studies on pan- creatic tissue obtained 24 hours after type-I diabetes was diagnosed in a young girl. Her serum contained islet-cell anti- body of conventional, complement- fixing and surface-hinding varieties. The islets had marked lymphocytic infdtra- tion with, in addition, many cells synthe- sizing IgG and plentiful extracellular IgG throughout. The infiltrating cells were mostly T cells of suppressor/killer phenotype and cells bearing markers for activated T cells; Ia-bearing cells were also present. No viral particles were identified in the islets.

Although the epidemiological evi- dence of virus infection - be it with Cox- sackie or other viruses - has never been as strong as many would like, the fulfil- ment of Koch's postulates in a case of acute Coxsackie-virus infection s has revived interest in the role of viruses as initiating agents in this disease. Abner Notkins (Bethesda) reviewed the evi- dence from various animal models con- cerning the potential for fl-ceU destruc- tion during virus infection. The en- cephalomyocarditis (EMC)-virus model seems, perhaps, the most fussy in that the virus pool contains both diabetogenic and non-diabetogenic variants which can only be distinguished by RNA finger-printing, the genes controlling susceptibility to the diabetogenic strain segregating in mice as an autosomal re- cessive. Mengo virus, on the other hand, causes acute encephalitis and diabetes in most strains of mice and it appears that there are separate receptors for these two viruses. In the reovirus model an auto- immune response develops to both pitui- tary and pancreatic cells, and autoanti- bodies reactive with growth hormone and insulin are induced if the virus is ino- culated before 30 days of life 6. Antibodies reactive with the free hormones are, ap- parently, not found in EMC virus- infected mice and are only found in the reovirus model when a strain of virus

© Elsevier Biomedical Press 1983 0167-491918310000-0000/$1.00

208 Immunology Today, vol. 4, No. 8, 1983

IMMUNE RESPONSE ]

[ anti-viral I oR ' /

[interferon ] , , ' " /

' VIRUS receptors I "1 replication I =1 lysis ] .-*1

] ~ I * , , ~ variable [ [

CHEMICALS r " / I metabolism J [ e.g. alloxan

streptozotocin nitrosamines

Fig. 1. Factors determining ~-ceU destruction. • Points at which genetic factors may have an important influence.

auloimmune I*(e'g" DR3)

ICA/CF-ICAfTcelIs \

4"

[B CELL ] DESTRUCTION

l-- regeneration

of ~ cells

Reproduced with permission from Holborow, E. J . and Reeves, W. G. (eds) (1983) Immunology and Medicine, 2nd Edn (p. 366), Orune and Stratton

containing the haemagglutinin gene is used. This virus associates intimately with cytoplasmic membranes and its fusion with membranes involved in hor- mone secretion may induce autoanti- body production via a carrier effect. The fact that reovirus is only slowly lytic may enhance this effect. Although the carrier effect may explain the induction of auto- reactive insulin antibody following treat- ment with bovine insulin preparations 7, insulin antibodies are not readily de- tected in patients with untreated acute type-I diabetes.

The role of chemical insults in in- ducing 0-ceil damage has gained mom- entum since the report from Iceland s suggesting a role for the ingestion of cured mutton containing nitrosamines. John Stowers (Aberdeen) reviewed re- cent experiments indicating that dia- betes can be induced by feeding mice with the same exotic material but with the surprising finding that diabetes can be induced in offspring when cured mutton was fed to either parent- suggesting a mutagenic effect. Nitro- samines show chemical similarities with streptozotocin and alloxan and are pre- sent in many preserved foodstuffs. Other work indicates that chemical insults of this kind may augment the effect of virus infection in susceptible individuals 9.

The complexit), of the interaction between 'seed' and 'soil' prompted the question byJ. C. Woodrow (Liverpool): 'How will we know we have found the

diabetes-susceptibility gene?'. This did not receive a clear answer although it provided much food for thought. A pathogenetic framework (see Fig. 1) should include viral, chemical and im- munological factors which may lead to fl- cell destruction. Susceptibility genes may operate at various points within each of these compartments and future work needs to identify their major sites of action before 'tailor-made' therapeutic measures can be envisaged.

The prognosis of type-I diabetes has not improved significantly since insulin therapy began more than 50 years ago and major advances will only be possible at the preventative level before acute+ symptoms are manifest and the patho- genetic horse has bolted. This is why the BB rat is of such interest. E. B. Marliss (Canada) drew attention to the similarity between the diabetic disorder which appears in around 50 % of these animals and type-I diabetes in man. In BB rats acute insulin-deficient diabetes develops in association with lymphocytic infiltra- tion of the islets and the presence of islet- cell antibody. There is also a marked lymphopenia which mostly affects T-helper cells. Various immunological maneouvres, for example thymectomy and treatment with anti-lymphocyte serum, can reduce its severity and recent studies indicate that cyclosporine can prevent the development of diabetes in most animals ~°. If non-toxic means of prevention do become available in man,

then the identification of the susceptible phenotype will become even more im- portant. However, the prospect of keeping such individuals on potentially life-long 'prophylactic' therapy with powerful drugs is not an attractive one and the possibility that either or both of the susceptibility genes is of the Ir-gene type suggests that other forms of immu- nological manipulation are important likelihoods for the future u .

W . G. Reeves is in the Department o/Immunology University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK.

References 1 Bottazzo, G. F. (1983) Diabetologia 24, 73 2 Rotter, J. I., Anderson, C. E., Rubin, R. et

aL (1983) lh'abetes 32, 169-174 3 Wolf, E., Spencer, K. M. and Cudworth,

A. G. (1983) Diabetologia 24, 224-230 4 Gorsuch, A. N., Spencer, K. M., Lister, J. et

aL (1981) Lancet ii, 1363-1365 5 Yoon. J.-W., Austin, M., Onodera, T. and

Notkins, A. L. (1979)/~ Engl. J. Med. 300, 1173-1179

60nodera, T., Toniolo, A., Ray, U. R. et aL (1981)J. Exp. Med. 153, 1457-1473

7 Reeves, W. G. and Kelly, U. (1982) Clin. Exp. lmmunol. 50, 163-170

8 Helgason, T. and Jonasson, M. R. (1981) Lancet ii, 716 720

90nodera, T., Suzuki, M., Toniolo, A. and Notkins, A. L. (1983)Diabetologia 24, 218-219

10 Laupacis, A., Garden, C., Dupre, J. et al. (1983) Lancet i, 10-11

11 Steinman, L., Rosenbaum, J. T., Sriram, S. and McDevitt, H. O. (1981) Proc. NatlAcad. Sci. USA 78, 7111-7114