The Review article by She on the relative con-tributions of HLA-DR and -DQ to type 1 dia-betes (Ref. 1), suffers in my opinion from thepaucity of in-depth studies in the field.Whenever there have been sufficient data,HLA-DQ alleles have always shown a muchstronger association with susceptibility or re-sistance to type 1 diabetes than DR alleles.Furthermore, except in one case (see below),DR alleles do not have an independent contribution either to susceptibility or resist-ance in this disease. Two very large studiesare relevant in this regard: (1) part of the 11thInternational HLA Workshop, with 981 unre-lated patients and 2228 healthy controlsworldwide (reviewed in Ref. 2); and (2) theSwedish childhood diabetes study, of 425children consecutively diagnosed with type 1diabetes (ascertainment rate .95%), and 367unrelated controls3. Both studies show HLA-DQ as the true susceptibility locus, while anyassociation with DR alleles arises from link-age disequilibrium of such alleles with theDQ alleles. The Swedish study went even fur-ther, in testing for the association with diseaseof the nine HLA-DR4 alleles found in the gen-

eral Swedish population. Of these DR4 al-leles, DRB1*0401 is most often linked to type1 diabetes (62% of patients and 25% of con-trols with an odds ratio of 4.95). The oddsratio for the high risk DQ allele A1*0301/B1*0302 (DQ8) is 7.47, higher than that of DRB1*0401. Furthermore, the DRB1*0401allele is linked to susceptibility when in link-age with the susceptible DQ8 allele (oddsratio of 7.69), and linked to resistance, whenin linkage with the resistant alleleDQA1*0301/B1*0301 (DQ7) (odds ratio 0.52).Other DR4 alleles fare even worse by this comparison. In addition, a test ofstrongest association as developed by Svejgaard and Ryder4 was performed in thisstudy, showing that indeed DQ is by far thestrongest linkage locus and all linkages to DRare secondary and due to linkage dis-equilibrium alone. By contrast, a recent studyhas shown that whereas HLA-DQ is the pri-mary susceptibility locus, the alleleDRB1*0403 significantly protected from type1 diabetes, even in the presence of the highest risk heterozygous genotype(A1*0301/B1*0302–A1*0501/B1*0201), bybeing present in 5/49 control subjects and0/171 type 1 diabetics5. This difference be-tween the two studies is certainly worthy offurther investigation. Furthermore, the fact

that certain DQ alleles susceptible or resistantto type 1 diabetes, are obtained by trans-com-plementation and correlate with susceptibil-ity to type 1 diabetes better than DR alleles6,can only mean one of two things: eitherDQAB is the true susceptibility gene for thedisease; or two genes, one closely linked toDQA and another to DQB, constitute such agene – a rather unlikely possibility.

The many studies that She analyses, in-variably have far fewer patients and controlsthan the two quoted above, and all of themlack the test of strongest association criterion,hence no testing of an independent effect ofany HLA-DR alleles. In particular the studiesof the Chinese population suffer, as type 1 di-abetes is very rare there, and this populationis extremely heterogeneous regarding HLA,with any two studies showing substantiallydifferent percentages of certain HLA-DR or -DQ allelic frequencies within the controlpopulation7. Thus it is necessary for popu-lation studies (of any ethnicity) to have a suf-ficiently large number of patients and con-trols, along with an analysis as perfomed inthe studies above, in order to provide an an-swer to the possible contribution of DR tosusceptibility or resistance to type 1 diabetes.

Last, susceptible and resistant HLA-DQmolecules can be grouped, respectively,

I much enjoyed the Trends article by Welling-hausen et al.1 entitled ‘The immunobiology ofzinc’ since it soundly emphasized the criticalrole of zinc in the orchestration of the immuneresponse both at the basic and clinical level.However, I think that it may be salient to addsome data that should stimulate further re-search into this important, but as yet poorlyunderstood area of immune regulation.

The authors postulated that ‘the exact sig-nalling pathway underlying zinc-inducedcell stimulation is unknown’. Therefore, itmay be fruitful to note that I had previously

reported the finding of putative zinc-bindingdomains in immunoglobulin (Ig) constant re-gions2,3. These sequences, encompassing dis-tinctly spaced cysteines and histidines, wereproposed to achieve conformations con-ducive to an interaction with nucleic acids inthe context of a reducing intracellular envi-ronment and in the presence of zinc ions2,3.As such, these Ig-derived fragments could in-fluence the expression of genes involved inthe regulation of the immune response,amounting to an autoregulation of Ig produc-tion2,3. The evolutionary implication of thisstudy was then that antibodies and transcrip-tion factors might intriguingly share a com-mon ancestor molecule2,3. Interestingly, myanalysis2,3 accorded with earlier experimentsthat had shown both binding of zinc by Ig(Ref. 4) and (self)regulation of Ig mRNAtranslation by Ig proteins5,6.

Following up on these molecular hints maynot only advance basic aspects, but also yield

clinically useful applications such as immuni-zation protocols involving zinc and small zinc-binding peptides that mimic antibodies.

Razvan T. RadulescuMolecular Concepts Research,Guardinistraße 47,D-81375 München, Germany.

References1 Wellinghausen, N., Kirchner, H. and Rink, L.

(1997) Immunol. Today 18, 519–521

2 Radulescu, R.T. (1994) in Proc. AACR Special

Conference: Transcriptional Control of Cell Growth and

Differentiation Abstr. C46

3 Radulescu, R.T. (1995) Med. Hypotheses 44,

137–145

4 Prasad, A.S. and Oberleas, D. (1970) J. Lab. Clin.

Med. 76, 416–425

5 Stevens, R.H. and Williamson, A.R. (1973)

J. Mol. Biol. 78, 505–516

6 Stevens, R.H. and Williamson, A.R. (1973)

J. Mol. Biol. 78, 517–525

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J U N E 1 9 9 8Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0167-5699/98/$19.00

l e t t e r sImmune modulation by zinc: clues from immunoglobulin

structure and function

Genetics of type 1 diabetes