MECHANISMS OF ALLERGIC HYPERSENSITIVITY 
Charles W. Parker, M.D., Investigator 
The importance of genetic influences on human 
respiratory allergy has been known for more 
than 60 years and indeed was suggested long be- 
fore that. Human beings show marked differences 
in their immunoglobulin E (IgE) levels, which 
are an important factor in determining whether 
they develop respiratory allergy IgE-mediated 
allergy is the most common genetic problem in 
the world, but little is known about its genetic 
control. 
Dr. Parker and his colleagues have been study- 
ing the genetic control of IgE production in hu- 
mans and inbred mice. Up to 10-fold variations in 
basal levels of IgE in serum have been found in dif- 
ferent mouse strains. Two independently segregat- 
ing genes that selectively regulate IgE levels have 
been identified. One of the genes is X-linked, and 
the other is autosomal. The autosomal gene has at 
least three alleles. In Fl hybrids and their back- 
crosses to parental strains, alleles for the intermedi- 
ate and low IgE phenotypes are dominant over the 
high serum IgE phenotype. The gene has been 
mapped to chromosome 8. This localization ex- 
cludes major histocompatibility antigens and struc- 
tural genes for immunoglobulins and hormonal 
regulators of IgE production, such as interleukin-4 
and interferon-7, as the site of genetic control in 
the mouse. In vitro studies of IgE synthesis and 
finer genetic mapping studies are under way to lo- 
calize and identify the gene and its protein product 
more precisely, determine their structures, and elu- 
cidate their role in the regulation of IgE produc- 
tion. Breeding studies are being undertaken to de- 
termine if the X-linked and autosomal genes can 
complement one another to produce still higher 
basal IgE levels. IgE levels will also be examined in 
animals stimulated with anti-IgD antibodies or in- 
fection with a helminthic parasite to determine if 
the genes controlling basal and stimulated IgE 
levels are the same. 
Another major emphasis in Dr. Parker's labora- 
tory has been on hormonal effects in autoimmunity. 
Of the common autoimmune conditions affecting 
human beings, ankylosing spondylitis is much more 
common in males than females, whereas systemic 
lupus erythematosus (SLE), rheumatoid arthritis, 
Sjogren's syndrome, Hashimoto's disease, Graves' 
disease, and pernicious anemia are substantially 
more frequent in females. Although the reason for 
the male or female predilection in most of these 
diseases is uncertain, in SLE, estrogenic hormones 
appear to be involved directly. Kunkel and his col- 
leagues showed about a decade ago that estrogen 
metabolism in vivo is altered in lupus patients and 
their relatives, with increased hydroxylation of es- 
tradiol at position 16 (compared with controls with 
and without other diseases). Previous studies with 
SLE have indicated that suppression of estrogenic 
effects by castration or administration of male hor- 
mones may considerably ameliorate the disease. 
However, the basis for the estrogen effect is un- 
certain, and less-radical means of treatment are 
needed. 
Dr. Parker and his colleagues have been study- 
ing estrogen metabolism in the NZB/NZW and 
NZB/SWR mouse hybrid models for SLE. These 
animals spontaneously develop autoantibodies 
and nephritis and die prematurely of renal failure. 
Each of the parental strains provides several genes 
that predispose to the disease. Hybrids of NZB mice 
with other strains are much less affected by auto- 
immune manifestations. Both of the susceptible 
hybrids show earlier and more marked manifes- 
tations of disease in females than males, sugges- 
ting their usefulness as an animal model to eluci- 
date the role of sex hormones in this disease. The 
increased susceptibility of females of these hy- 
brids to SLE appears to involve genes from the 
SWR and NZW strains rather than the NZB strain. 
Dr. Parker and his colleagues have studied the 
estrogen l6-hydroxylase P450 enzyme in the liver 
of various mouse strains. This enzyme produces 
multiple products and is highly polymorphic. A 
shared polymorphism of the enzyme in the NZW 
and SWR strains, which is lacking in seven of the 
eight other strains studied, including the NZB 
strain, has been identified. The next step is to de- 
termine if the alleles for the NZW and SWR enzyme 
are correlated with the presence of disease in 
NZB/W X NZB backcrosses, which have inherited 
other genes predisposing to the disease. If a re- 
lationship can be estabfished, the structure and 
regulation of this enzyme will be studied, in an at- 
tempt to determine how and at what level the al- 
teration in estrogen metabolism affects immune 
responsiveness. 
A new protein-sequencing method is also being 
developed. An increase in sensitivity of at least 10- 
to 100-fold over previous methods is anticipated. 
Because there are many proteins that remain to be 
Continued 
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