HLA as regulator.
Authors: J J van Rood
Journal: Annals of the Rheumatic Diseases (1984)

When Derrick Brewerton invited me to give the annual Heberden Oration he wrote that after the initial excitement about the associations of HLA and disease the impetus of the research was in danger of being lost and could I come over and tell 'what to do about it.'It is obvious first that this is the kind of invitation you simply cannot turn down and secondly that it is an impossible task to fulfil.Derrick told me also that I could 'speculate a bit,' and as he is your president, I shall take the opportunity.I would like to divide my lecture into three parts.In the first I shall briefly review recent developments on the genetics of HLA; these are hard facts.In the second I shall present to you data which indicate that HLA class I molecules might have an important role not only in immunology but also in endocrine functions, which are new facts, and their interpretation is not yet definitive.In the third and last part I shall discuss some findings in leprosy which might be useful in the study of the pathogene- sis of rheumatoid arthritis (RA) which is almost all speculation.In the two last topics HLA acts as a regulator.I realise that I shall discuss mainly topics outside the field of rheumatology, but Derrick told me to approach my topic with breadth of vision. Genetics of HLAPhase 1 is thus the genetics of HLA.Fig. 1 brings you up to date with the present situation.In the last few years the HLA region has at least doubled in size and 'grown' perhaps even much more.The broken line indicates what we today consider might encompass the HLA supergene and the closed rectangle was what it was like until a few years ago.Then only the ABC and D/DR loci were known, coding respectively for the class I antigens, which are expressed on all nucleated cells, and the class II This oration was delivered at the Annual Meeting of the Heberden Society in London on 11 November 1983.Correspondence to Dr J. J. van Rood.antigens, which express themselves on cells involved in the immune response like macrophages, activated T cells, and B cells.I will not discuss the class III genes coding for complement factors today.In recent years at least two class II loci have been added to the list; one is the DC or MB locus, which is certainly located to the left of HLA-B but of which the exact position relative to HLA-DR is uncertain.It codes for class II antigens.And to the left of D/DR, about 2 centimorgan away from it, is the locus recognised by Termijtelen, Mawas, and Shaw, the secondary B locus or SB.Thus the doubling of the size of the HLA supergene.On the top line the position of another locus is indicated, the TC-A locus.This locus represents a diallelic system coding for a product present on part of the T-gamma cells.Recent family studies performed by Van Leeuwen, who identified this locus, indicate that it is on chromosome 6 and about 15 cM away from HLA-A or even less.We can thus recognise the products of three more loci than those officially recognised so far (the official ones are HLA-ABC D/DR).Recently Termijtelen, using cellular typing tech- niques, has found evidence for yet another locus, the LB-Q locus.The number of genes identified at the chromosomal level is even greater than the number of allelic series identified at the membrane level, and this is true both for class I and class II.By typing by serology we see thus only a fraction of the complexity at the DNA level.There appear to be more than 30 genes coding for the heavy chains of class I and up to Sa and 7I genes coding for class II.The class II molecules consist of two polypeptide chains each of which is coded for by one a and one fi chain.The , genes carry the allelic specificity with the exception of DC, which is polymorphic as well.Of course not all of these need to be expressed at the cell surface.With protein chemistry techniques up to four class I and six or even seven class II molecules coded for by different genes have been 665copyright.