SYNOPSIS Certain specificities of the human leukocyte
antigen (HLA) system have been shown to be associated with particular diseases. A review
of recent studies in schizophrenia shows inconsistent results for schizophrenia as a
whole, although a significant increase in HLA A28
remains on combining the data. There are more consistent findings for disease subtypes. In particular, HLA A9 and RLA CW4 are increased in paranoid schizophrenics, while HLA A1 and the A1-B8 haplotype are increased in nuclear forms. It is postulated that the relationship between the schizophrenias and certain HLA types could be due to an influence of the latter upon neuronal post-synaptic membrane sensitivity to central neurotransmitters such as dopamine.
THE NATURE OF THE RELATIONSHIP: THE HLA SYSTEM AND
THE DOPAMINE HYPOTHESIS
If we are now to accept that the results, although not conclusive, do suggest that associations exist between the HLA system and subtypes of schizophrenia, we must next ask what are the possible explanations for such associations? A promising lead is given by the work in Milan on the HLA system and neuroleptic drugs. It is known that chlorpromazine (CPZ) can bind to lymphocytes (Ferguson et al. 1975) and that lymphocytes have, on their surface, sites resembling adrenergic receptors (Galant & Remo, 1975).
Smeraldi &Scorza-Smeraldi (1976) have shown that CPZ and to a lesser extent dopamine (DA) and noradrenaline (NA) interfere with the specific absorption of anti HLA Al antibodies by A1 positive lymphocytes. A subsequent study in the same centre (Scorza-Smeraldi et al. 1977) has confirmed these findings, as well as showing that the same phenomenon occurs with other adrenergic binding drugs and HLA Al or its c.r.e.g.s. These in vitro findings have yet to be replicated elsewhere. However, if correct, it is possible to suggest that there might also be an in vivo affinity of certain HLA specificities for neuroleptics and that this should influence clinical response, since HLA antigens are present on the surface of all nucleated cells including neurones. This proposition receives support from a study in mice (Castellano et al. 1974), where it was shown that the effect of CPZ on acquired avoidance behaviour is strain dependent. This is probably modulated by 2 genes, one of which resides in the chromosome 9 linkage group II which contains the histocompatibility (H2) loci.
The Milan group (Smeraldi et al. 1976b) have already shown that HLA A1 positive schizophrenic patients respond better to CPZ than those who are Al negative. A more recent study of schizophrenics taking a variety of neuroleptics did not, however, show any relationship between HLA type and rated clinical response to treatment (McGuffin, 1979), but did suggest a relationship between HLA type and susceptibility to Parkinsonian side-effects.
It is probable that neuroleptic drugs exercise the major part of their anti psychotic activity byblocking the post-synaptic DA receptors in the brain (Crow & GilIbe, 1976; Crow et al. 1976). This is held to support the dopamine hypothesis of schizophrenia, which states that a relative over-activity at certain dopaminergic sites in the brain plays a part in the pathogenesis of the disorder. One of the main difficulties in sustaining the dopamine hypothesis is that such methods that are available do not indicate increased DA levels in the brains of schizophrenic patients (Post et al. 1975; Bowers, 1974). Neither do post-mortem studies provide any strong evidence of increased DA production (Bird et al. 1977; Owen et al. 1978). A possible explanation is that there is a relative deficiency of one or more neurotransmitters which normally modulate or oppose the action of DA (Perry et al. 1979). Alternatively, as some workers have proposed, there may be an increase in post-synaptic membrane sensitivity to DA in schizophrenia (Friedhoff, 1977; Crow, 1977). Recent post-mortem studies, using butyrephenones in ligand binding techniques, have demonstrated that there is an increased density of receptors in dopaminergically innervated areas of brain in schizophrenics compared with controls (Owen et al. 1978; Lee et al. 1978).
The mechanism involved in this phenomenon is obscure and cannot be accounted for purely in terms of previous neuroleptic therapy. Therefore, it does now seem likely that there may be subtle individual differences in cell surface topochemistry which differentiate schizophrenics or schizophrenia-susceptible individuals from the rest of the population and it would seem reasonable to speculate that such differences might be under genetic control.
In order to explain the association betweennon-immunological disorders and the HLA system, Svejgaard & Ryder (1976) have proposed that there may be a resemblance between HLA antigens and receptor sites for certain ligands, such as hormones or neurotransmitters. This concept receives support from the Milan work with neuroleptics, as well as from observations elsewhere on the mouse H2 system (Ivanyi, 1978). It is, therefore, clearly possible to suggest that this theory complements the dopamine hypothesis of schizophrenia in its present state, providing the 'missing link' in the latter, by proposing a basis for the apparent increase in post-synaptic membrane sensitivity to DA.
Despite inconsistencies in the studies to date, there does seem to be a reasonable prospect that associations exist between the HLA system and subtypes of schizophrenia. In the author's view, the most promising association at present looks to be that between HLA A9, HLA CW4 and the paranoid subtype, although the possibility of an association between HLA Al and AI-B8 haplotype and nuclear forms of schizophrenia warrants further investigation. The same also applies to the apparent association between HLA A28 and schizophrenia as a whole, although, as we have discussed, there are some reasons for considering that this may be an artefact. It is clearly desirable that all future studies include consideration of the C and D series antigens. Clarification, we hope, will also come from studies on the segregation of HLA haplotype and schizophrenia in families containing more than one affected member. This we now have in progress.
It will be most important in all the future studies on schizophrenia and the HLA system to use precise and replicable diagnostic criteria. This review of some of the work to date in the field, provides perhaps a salutary reminder that although we are applying an advanced and sophisticated technique to the problem of schizophrenia, the validity of our findings depends ultimately on clinical accuracy and clarity. -- H10.5.13
Suma Jacob, Martha K. McClintock, Bethanne Zelano, and Carole Ober: Paternally inherited HLA alleles are associated with women’s choice of male odor. Nature Genetics 30, 175-179, 2002
Wedekind C, and Furi S: Body odour preferences in men and women: do they aim for specific MHC combinations or simply heterozygosity? Proc R Soc Lond B Biol Sci. 264, 1471-1479, 1997
後者が、一般的に紹介されている参考文献［H20.10.19 所さんの目がテン、H21.11 松尾友香さん『最新血液型の基本としくみ』 etc.］のようで、女性は自分とＨＬＡの一致度が低い男性を好むとのことです。
どっちがホントなの？ -- H21.11.14