HLA and
Personality TraitsI found two papers:
I finally got the former one. Ceartain HLA types might affect neuronal post-synaptic membrane sensitivity to central neurotransmitters such as dopamine ...
ABSTRACT
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 ofneuroleptics 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.
CONCLUSION
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.
E-mail: abofan@js2.so-net.ne.jp
