ASSOCIATION BETWEEN IMMUNOGLOBULIN ALLOTYPES AND IMMUNE RESPONSES TO HÆMOPHILUS INFLUENZÆ AND MENINGOCOCCUS POLYSACCHARIDES

190

ASSOCIATION BETWEEN IMMUNOGLOBULIN ALLOTYPES AND IMMUNE RESPONSES TO HÆMOPHILUS INFLUENZÆ AND MENINGOCOCCUS POLYSACCHARIDES

on the heavy chain linkage group in mice.2-4 In man, there is limited evidence for HLAlinked control of immune responses 5- 10 and for associations between Gm allotypes of IgG and immune re-

determinants

Evidence has also been presented for an association between an uncommon Gm phenotype and neuroblastoma 14 which may be due to Ir genes in linkage disequilibrium with Gm loci which regulate the synthesis of blocking antibodies. We have studied the association between Km and Gm allotypes and antibody responses after immunisation in White and Black children. sponses to certain

J. P. PANDEY G. VIRELLA C. B. LOADHOLT

H. H. FUDENBERG C. U. KYONG R. M. GALBRAITH

Departments of Basic and Clinical Immunology and Microbiology, Pediatrics, and Biometry, Medical University of South

Carolina, Charleston, South Carolina 29403, U.S.A.

antigens.l1-13

E. C. GOTSCHLICH

Rockefeller University, New York, New

York 10021

J. C. PARKE, JR Department of Pediatrics, Charlotte Memorial Hospital and Medical Center, Charlotte, North Carolina 28234 were collected from 20 White and 33 Black infants healthy before and after immunisation with three doses of diphtheria-pertussis-tetanus vaccine and with one dose of Hœmophilus influenzœ type b polyribose phosphate vaccine and meningococcal group A and group C polysaccharide vaccines. Antibodies to these immunogens were measured and sera were allotyped for several Gm, A2m, and Km antigens. A highly significant association was found between the Km(1) allotype and the immune responses (difference between post-immunisation and pre-

Summary

Serum

samples

immunisation antibody levels) to H. influenzœ and ingococcus C polysaccharides in the White children.

men-

INTRODUCTION

IMMUNE responsiveness is now known to be under genetic control and a large number of specific immune response (Ir) genes have been described in laboratory animals. These fall into two main categories. Genes linked to the major histocompatibility complex (M.H.C.) have been described in several species, and especially in inbred strains of mice and guineapigs.Others are linked to the genes controlling immunoglobulin (Ig) allotype

PATIENTS AND METHODS

Serum samples were collected from 20 healthy White and 33 Black infants with a mean age of 19.7 months. All the children were immunised with three doses of diphtheria-pertussistetanus vaccine and with one dose of Hcemophilus influenza type b polyribose phosphate vaccine (lot no. BVHF-1) and meningococcal group A and group C polysaccharide vaccines (lot no. 2495T). Blood was collected immediately before immunisation and 4 weeks after all the vaccines had been administered. Antibodies to diphtheria and tetanus toxoids were measured by reversed rocket immunoelectrophoresis,15 and antibodies to the polysaccharide antigens were measured by radioimmunoassay.16 The values for the immune response to H. influenza in Km(l)+ children and for meningococcus C in Km(1)children are negative (table I) because in some infants antibody titres were higher before immunisation than afterwards (although the difference was within the limit of error for the technique used). Thus, negative values simply indicate no antibody response. Our standard hmmagglutination inhibition technique" was used to detect Gm antigens 1, 2, 3, 5, 6, 13, 14, 17, and 21, as well as A2m(l), A2m(2), and Km(l). The nonparametric (Mann-Whitney) test was used to determine the significance of the associations between the Ig allotypes and immune responses. RESULTS

In White children there was a striking association between the Km(l) allotype and the strength of certain immune responses (table I). Family and population studies have shown that the Km antigens are inherited via three alleles-Kml, Kml 2, and Km3.18 Since we typed

TABLE I-ALLOTYPES AND IMMUNE RESPONSES IN WHITE CHILDREN

Median immune response is difference between post-immunisatiop and antibody per ml serum (H. influenza, meningococcus).

pre-immunisation antibody levels

in units

(diphtheria, tetanus)

or

in ,ig

191 TABLE II-ALLOTYPES AND IMMUNE RESPONSES IN BLACK CHILDREN

i

only for Km(l), our Km(1)- subjects were probably homozygous for Km3, with all other possible genotypic combinations of the three alleles being Km(l)+. Children positive for Km(l) failed to respond to H. influenz6e and children without this allotype did respond (n=0008); the opposite was true when the immunogen was meningococcus C polysaccharide (P=0.005) (table i). The mean ages of Km(l)+ and Km(l)- children were 20.5 and 19 2 months, respectively. Five Gm phenotypes, all common, were present in the population with the expected frequencies (table I). The most frequent was Gm(3; 5, 13, 14). The only significant association with Gm phenotypes (table I) was between Gm(l, 2, 3, 17; 5, 13, 14, 21) and the response to H. influenze polysaccharide (p=0.022). Most of the children were homozygous for A2m(l); none were homozygous for A2m(2). (The frequency of the A2m(2) allele in Whites is only 0-013.) A few were heterozygous for these markers. No significant associations were found for the A2m phenotypes. Almost all the Gm phenotypes of the Black children indicate White admixture (table II). After correction for the number of comparisons made, no phenotype was significantly associated with immune responsiveness. DISCUSSION

A probable explanation for these results is that there exist in man Ir genes (on human chromosome 6) which regulate the immune responses to H. influenxe and meningococcus C polysaccharides, and that alleles of these genes are in linkage disequilibrium with the Km alleles and, for H. influenzae, also with Gm(1, 2, 3, 17; 5, 13, 14, 21). However, conclusive evidence of genetic control of these immune responses can be obtained only after

i

i

i

i

i

i

i

family studies, which are currently being done. The nature of the selective mechanisms that maintain Gm and Km polymorphism is unknown. Associations between these allotypes and specific antibody responses could be a selective force for the maintenance of the various haplotypes and their frequencies.19 Selection may operate through the purported Ir genes, with Gm and Km antigens serving merely as markets. More extensive studies of the type described here, with natural immunogens, would shed further light on the nature of such a selective force. One way to corroborate the results reported here would be to determine Km(l) allotypes in children who had been immunised with H. influenzce and nevertheless had meningitis. So far, we have typed 10 such children, of whom 4 were positive for Km(l). In this admittedly small sample, the frequency of Km(l) is thus four times that of the normal population. Moreover, in 1 family, the mother and 1 child, who were Km(l) positive, had H. influenza infections, whereas the father and 3 other children, who lacked this antigen, did not. Our results may prove to have wider implications in terms of the effectiveness of vaccination against a variety of microorganisms. We thank Ms Beth Phifer and Ms Alice

Gorham-Alexy for technical

assistance, Dr John B. Robbins for valuable discussions, and Charles L. Smith for editorial assistance. We also thank Dr Harrison Peeples for his collaboration in arranging the vaccination programme. This research was supported in part by U.S.P.H.S. grants HD-09938 and AI-13484. This is publication No. 235 from the Department of Basic and Clinical Immunology and Microbiology, Medical University of South Carolina. Reprint requests should be addressed to J. P. P., Department of Basic & Clinical Immunology & Microbiology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina

29403, U.S.A.

192

Reviews of Books A&bgr;atoxins Chemical and Biological Aspects-Developments in Food Science, Vol. I. J. G. HEATHCOTE, The University, Salford, and J. R. HIBBERT, Manchester Polytechnic. Amsterdam and New York: Elsevier. 1978. Pp. 212. D.fl. 120;$53. THE discovery of aflatoxin nearly two decades ago heralded the modern era of mycotoxicology. Although other mycotoxins have been recognised and studied, aflatoxins remain the focal point of interest, and much information has been gained about these most potent of naturally occurring carcinogens. This monograph is intended to provide a comprehensive account of their chemistry and biology; it covers the discovery

of individual aflatoxins, their occurrence in nature and production in the laboratory, chemistry, assay, pathological and biochemical effects, metabolism, biosynthesis, and control. Separate subject and author indexes are provided, together with more than 954 references. The text is clearly presented and informative. Many of the references are recent, up to 64% of the citations at the end of individual chapters being work published in the 1970s. Despite the enormous increase in knowledge about aflatoxin over the past decade, there is still comparatively little known about the precise mechanisms responsible for damage to susceptible mammalian cells. Evidence linking tumour induction in man with ingestion of aflatoxin is circumstantial and sparse, although a recent report describing the development of colonic cancer in two research scientists who had been working with aflatoxin for a number of years emphasises the need for additional information on the relation between mycotoxins and disease of man. The authors have succeeded in producing a concise, up-to-date account of the aflatoxins.

Physiological Tremor, Pathological Tremors and Clonus Progress in Clinical Neurophysiology, Vol. V. Edited by J. E. DESMEDT, University of Brussels, Basle, London, and New York:

many years. Although there is still much to be learnt, it is becoming clear ’that physiological tremor is a function of a number of factors acting concurrently. These include the weight and mechanical resonance properties of the limb, ba1_1_=stic oscillations induced by the heart-beat, motor-unit activity, stretch-reflex sensitivity, visual feedback, and the effect of catecholamines in altering dynamic properties of muscle nbres. The recruitment order of motor units is important in determineing tremor-rate, particularly in disorders such as thyrotoxicosis and anxiety, in which the movements resemble physiological tremor. Central mechanisms in the generation of tremor, as in patients with alcoholic tremor or Parkinsonian tremor, are still less well understood, and the reviews of these topics in the book reflect the speculative nature of current ideas. In Parkinson’s disease, results of recordings in the nucleus ventralis intermedius of the thalamus, motor-unit recordings in muscle,

single-fibre neurographic recordings of spindle primary afferents suggest that the tremor is due to an abnormal release of programmed motor behaviour normally used for voluntary purposeful contractions. and

Adverse Mechanical Tension in the Central Nervous

System ALF

don :

BREIG, Karolinska Institute, Stockholm. New York ,U::l LÜ!1-

Wiley. Stockholm: Almqvist $86.70; Sw.kr. 282.

and Wiksell. 1978.

Pp. 264.

THIS splendidly-produced book is an act of faith by its author. Professor Breig has set out at length his views about the mechanical influences acting on the central nervous system. The central nervous system tends to be regarded in neurological terms, but a surprising number of conditions can be the result of mechanical deformation of the supporting tissues. The lavish illustrations show how mobile and extensible the axial nervous system must be when, for instance, the neck is put through its full range of movements. This book describes in essence the orthopsedics of the central nervous system. A variety of specialists will find the wealth of practical suggestions on rehabilitation most helpful.

S. KARGER. 1978. DM 98;$49.

THIS volume contains 15 reviews of various aspects of physiological tremor and of tremor in neurological disease. The first part of the book is concerned with the mechanisms underlying physiological tremor, which have excited controversy for

1. Snell, G. D.,

Dausset, J., Nathenson, S. Histocompatibility ; p. 133. New York, 1976. 2. Blomberg, B., Geckeler, W. R., Weigert, M. Science, 1972, 177, 178. 3. McKenzie, I. F. C. Immunogenetics, 1975, 1, 529 (abstr.). 4. Taylor, B. A., Cherry, M., Bailey, D. W., Shapiro, L. S. ibid. 1975, 1, 529(abstr.). 5. Levine, B. B., Stember, R. H., Fotino, M. Science, 1972, 178, 1201. 6. Buckley, C. E., Dorsey, F. C., Corley, R. B., Ralph, W. B., Woodbury, M. A., Amos, D. B. Proc. natn. Acad. Sci. U.S.A., 1973, 70, 2157. 7. Marsh, D. G., Bias, W. B., Hsu, S. H. Science, 1973, 179, 691. 8. Blumenthal, M. N., Amos, D. B., Noreen, H., Mendell, N. R., Yunis, E. J. ibid. 1974, 184, 1301. 9. Spencer, M., Cherry, J. D., Terasaki, P. I. New Engl. J. Med. 1976, 294, 13.

Vries, P. R. P., Lai A Fat, R. F. M., Nijenhuis, L. E., van Rood, J. J. Lancet, 1976, ii, 1328. 11. Wells, J. V., Fudenberg, H. H., Mackay, I. R. J. Immun. 1971, 107, 1505. 12. Mackay, I. R., Wells, J. V., Fudenberg, H. H. Clin. Immun. Immunopath. 1975, 3, 408. 13. Nevo, S. Prot. biol. Fluids, 1975, 22, 649. 14. Morell, A., Scherz, R., Käser, H., Skvaril, F. Lancet, 1977, i, 23. 15. Hoyerall, H. M., Vandvik, B., Mellbye, O. J. J. immun. Methods, 1975, 6, 10. de

385.

16. 17.

Gotschlich, E. C. J. Immun. 1971, 107, 910. Vyas, G. N., Fudenberg, H. H., Pretty, H. M., Gold,

E. R. ibid.

1968, 100,

274. 18. 19.

Johnson, W. E., Kohn, P. H., Steinberg, A. G. Clin. 1977, 7, 97. Steinberg, A. G. Ann. Rev. Genet. 1969, 3, 25.

Immun.

Immunopath.

Hemolytic Anemia in Disorders of Red-Cell Metabolism Topics in Hematology. ERNEST BEUTLER. New York and Plenum. 1978. Pp. 266.$14.80.

Lordcr :

THE main part of this book reflects the author’s interest in the scientific aspects of hxmolytic anaemia and contains detailed description of the properties of the various normal and abnormal red-cell enzymes. Less space is given to the clit!ica° features of the various conditions causing hsemolytic anaonia, and to their diagnosis and management. Moreover, it is a pity that although Dr Beutler reviews the literature on the effect of splenectomy in some of these syndromes it is often impossible to tell what the best course of action is or what his views are. The best section in the book (which, because of the frequency and clinical importance of its topic, quite rightly occupies more than half the volume) is that on glucose-6-phosphate dehydrogenase deficiency. There is a detailed compilation of the incidence of the condition in various populations, its genetics, and its clinical features. The clinically most useful section is that on drug sensitivity. The author’s main argument is common sense-because a drug reaction has been reported to occur in a patient with G.-6-P.D. deficiency, individuals with G.-6-P.D. deficiency are not necessarily more sensitive to the drug than the rest of the population, and careful assessment of the evidence for each drug must be made. If this argument is followed the list of drugs contraindicated shrinks appreciably and can be further subdivided into those causing (potentially) severe or mild reactions. It is for reference to this section" that the book will be used most often: anyone concerned with the management of patients’ with G.-6-P.D. deficiency should have access to a copy.