Imllan ft. Pedlar., 24t 246, 1957
IMMUNOGENETICS AND PEDIATRICS*
JOYTIRMOYCHATTERJEE Calcutta In one of the earlier communications 1 the present author revie~ some genetic determinants of certain diseases of pediatric interest. fundamental mechanisms of such genetic determinations are still larg ob~ure. The object of this communication i~ to review critically the prel status of the said problem, in the light of certain fundamental conce I In doing ~ almost a virgin land--the domain of "'immunogenetics" being approached. While, generally speaking, immunity indicates subject that deals with ',.he mechanism of a host's resistance to a disease, a genetics, the science of heredity, immunogenetics is the borderland th~ draws from both the disciplines. The term "immunogenetics" was coined by CUMLVand IRWIN2 and way of a definition BARRETT3 loosely stated it as "'referring to the areas which the disciplines of genetics and immunology impinge upon or overla by reason of concept, tecl'miques or knowledge". Thus, in rather broa terms, immunogenedcs would attend to such things as resistance to disea~ offered through heredity. The genetic transmission of immunity from a pediatrician's point view is no less important. The pediatrician would not fail to dream abou the utopia, where, the group of human beings born, would be free fror so many diseases. Such a possibility, although not within the domain o feasibility, has not escaped the attention of workers in experimental genetict It is commonly known that certain mice are particularly sensitive t~ transplantation of some tumour from homologous species, while others am particularly resistant to such transplantations. It could be easily guessea that such determinants could be operating either through the genes in tho chromosomes or through certain other protein synthesis mechanism within the cell, that might give rise to the formation of immune bodies, such as y globulin. The genetic investigations about the susceptibility and resistance to transplantation of tumours have been taken up extensiveiy by SNELt. and others, i, s. 5, ~ In such studies they made a detailed analysis of the genes governing the susceptibility or resistance to transplantation. By such analysis particular genetic loci have been found. One such locus have been found to be very important and have been termed by SNVLL~ the histocompatibility gene. If there is a difference at this particular locus of the chromosomes, between the tumour and the host, the host will resist growing the particular tumour. This concept is represented diagrammatically in Fig. 1. Itself a highly specialised technicality, it might be very briefly *From the Department of Applied Immunology and Cytobiology, Indian Institute for Biochemistry and Experimental Medicine, Calcutta. Received for publication on August 3, 1957.
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tlined by mentioning tha~ the chromo.~mes of some animals and plants mice and corn, have been drawn and each particular location supposed contribute a particular character has been mapped out by statistical denee. The histocompatibility gene, as diagrammatically represented e if pre~ent in both the tumour as well as the host chromosome, will Ice the host take the turnout. ~t
HISTOCOMPATIBILITY GENE ~176176176176176176176176 ~
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H
i
TUMOUR
HOST
CHROMOSOME
CHROMOSOME
Fig. l--Diagramatically showhag the comparative locus of the histocompatibility genes in a pair of chromosomes.
From the evidence discussed it appears that at least in tumour esistance, the particular genetic locus might be holding the key to the determining mechanism involved. Through adaptive mutation the particular genetic locus appears within the cell. But the mechanism of immunogenetics is not entirely confined to the whims of the chromosome strips. This has been shown by FLEXNER and TOBtaNOs and subsequently by KnLISS et al. 9, z0, 11 The tumour take vas enhanced as shown in these experiments by previous injection of yophilised tumour extracts or even by pretreatment with lyophilised normal assue TM. The interesting finding was that while a very small dose (0.05 mg.) inhibited t h e take, a higher dose (30 to 50 mg.) enhanced the percentage of tumour take. To explain this apparent anomaly a conjecture is being made as follows: a growing tumour as also any other "disease producing ~adty" must utilise the pool of the host's protein. If somehow the host has supply of a protein, compatible or suitable for adaptation, the tumour will ~ w or disease establish itself. The mode of utilisation of this particular z0teirt pool in the host by the parasite is still a matter of conjecture, but maght be possible to draw from a parallel source, where some work has Jready been done. This is the question of combination of carcinogen and
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Indian Journal of Pedi
cell cortstituents in producing carcinogenesis. The question now raise~l viewed from different points of view by different workers. People BOV1.,~NDla have forwarded the idea that carcinogens act directly on nucleic acid of the chromosomes. This has been contradicted by wor like MXLL~Rx4 who have visualised that carcinogens combine with cer proteins in the cells producing a bunch of new cells, rather unique in th protein make-up. To derive these conclusions, these authors used di-meth amino-azo-benzene compounds, known to be liver carcinogens, and rats with these compounds. They found that a combination of these d with the liver protein occurred prior to the establishment of carcinon The chemical combination between the dye and protein of the cells befc carcinogenesis, has been established by these authors. The importance of chemical binding of the carcinogen-protein complex for carcinogenesis k been established by SALSBURG and GRAFFIN14, who have shown that ar substance that will inhibit the carcinogenic effect of these dyes will al make the liver cell not combine with these dyes. This was shown in ra made diabetic with alloxan and resisting carcinogenic effect of 3-dimethy 4-methyl-aminoazo benzene. The works cited, although they tell with certain emphasis that in ord to establish carcinogenesis a combination of the stimulant complex with tt protein of the cell was essential, they do not tell how, once such a combinatio is established, the reduplication of the necessary complex takes plar through future generations of the cell. This is the very core of the proble~ through which the immunity mechanism, inherited or acquired, operate This is also a question of replication of new or altered proteins, followi~ certain stimuli.
The replication of a protein by a cell, depends on some inheren properties of the cell. A particular type of cell will only manufacture tho protein of its own kind, type specific, species specific, so to say. This was shown by the classical work of LANSTEINER and PARKER16 that even on prolonged culture of cells in tissue culture in a media different from the original protein, the cells could retain the protein pattern, specific for th~ species. But it might be assumed that within the framework of species specificity, given a sufficient stimulus, the cells might be capable of producing, or dropping off from their production list, some protein necessary for immunogenesis or, may be, carcinogenesis. While this hypothesis of the genetic mechanism of immunity production is being forwarded, it might be worthwhile to take up the question, as to how the reduplication of the specialised protein needed in the cellular economy is made in the cell. The view of PETRIe is worth mentioning. "Since the unique type of protein", he says, "'is synthesised always in a cell, such unique specificity can be explained by assuming the presertce of a template within the cell, capable of moulding the amino acids into specific proteins." These assumptions throw into relief the following questions: Do the templates make positive or negative prints ? What role do the nucleic acids have to play ? B~0HZT ls has come forward with the proposal that the role of nucleic
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clld in protein synthesis might be as follows: (a) formation of a special ajtrix in the formation ot'proteirt molecules, (b) combination with p~otein, 11~ forming nucleoprotein, which is removed from solve thereby shifting bc kinetics of chemical equilibrium towards the newly formed protein, lupplying energy by oxidation of pentose residue or purine derivatives, furnishing material for co-enzyme formation~ ,..~., ribose adenine, phosplioric acid forming adenine nucleotide ~r pyridine nucleotide. The question of templating might here be taken up in a little detail. These proteins, as they exist, are in the form of a three dimensional folded globular protein molecule. Can the templated reproduction occur as such ? This seems to be very highly improl)ablOL The diameter of a three dimensional globular protein would be from 20 to 100 A ~ This is too long s distance for ionic or polar forces to operate. Then again, due to the Fesence of water tlae electrostatic attraction or repulsion will be even more diminished. So the direct formation of a molecule as such by intermolecular t'orce, is almost impossible. So, HAuRowITz x9 says that the reproduction of n protein molecule can only take place in an expanded state in a monomoleettlar film. This is shown in Fig. 2. This is a phenomena similar to crystallisa-
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