Molecular Genetics of Histocompatibility 
David D. Chaplin, M.D., Ph.D. — Associate Investigator 
Dr. Chaplin is also Assistant Professor of Medicine, Genetics, and Molecular Microbiology at Washington 
University School of Medicine and Assistant Physician at Barnes Hospital, St. Louis. He received his A.B. 
degree in biochemistry from Harvard University and his M.D. and Ph.D. degrees in cellular and develop- 
mental biology from Washington University. Following a medical residency in internal medicine at Park- 
land Memorial Hospital, Dallas, he received postdoctoral training in genetics at Harvard Medical School 
with Jonathan Seidman. 
THE immune system acts in a critically impor- 
tant fashion to protect the organism from a 
vast array of infectious and parasitic agents. To 
execute this function the immune system has 
evolved potent mechanisms to eliminate or de- 
stroy invading organisms. Because these effector 
mechanisms are so potent, stringent regulation of 
the activation of the immune response is very im- 
portant. Inappropriate activation of immune ef- 
fector systems or failure of the immune system to 
distinguish self tissues from invading pathogens 
can lead to serious damage to the host. Examples 
of such failures of normal immune regulation are 
insulin-dependent diabetes mellitus (in which 
the immune system participates prominently in 
the destruction of the insulin-producing cells of 
the pancreas) , rheumatoid arthritis (in which ab- 
normal self-reactive antibodies cause destructive 
inflammation in joints), and systemic lupus er- 
ythematosus (in which a broad spectrum of self- 
reactive antibodies induce inflammatory damage 
in many tissues) . 
Proper regulation of immune defenses depends 
on the coordinate action of an array of different 
host mechanisms. Many of these mechanisms are 
influenced in fundamental ways by genes of the 
major histocompatibility complex (MHC). Our 
laboratory studies the structure and molecular bi- 
ology of this important gene complex. These stud- 
ies are motivated by a desire both to understand 
the nature and regulation of the genes in the MHC 
and to use the MHC as a model system to test 
methods for analysis of large gene complexes in 
general. 
The MHC encodes genes that determine 
whether tissue grafts between unrelated individ- 
uals are accepted or rejected. The products of 
these genes determine each individual's tissue 
type (also called HLA type). These HLA mole- 
cules also serve other important, perhaps more 
biologically relevant, functions, as they partici- 
pate in the regulation of most immune reactions. 
The MHC comprises a cluster of at least 60 
closely linked genes, which can be divided into 
three classes on the basis of their structures and 
their functions. Class I genes encode proteins 
that are present on the surfaces of all nucleated 
cells, where they participate in a number of im- 
mune responses. Importantly, when a host cell is 
infected with a virus, fragments of viral proteins 
associate with the class I molecules. This com- 
plex of viral protein and class I molecule is recog- 
nized by host cytotoxic T lymphocytes, which 
then act to destroy the virally infected cell. 
Class II MHC genes encode cell surface pro- 
teins that share some structural features with the 
class I molecules, indicating evolution from a 
common ancestral gene. Class II molecules are 
present on the surfaces of only a few cell types, 
where they also bind fragments of foreign anti- 
gens. In this case the complex of foreign antigen 
and class II molecule is recognized by host helper 
T lymphocytes, resulting in the initiation of an 
active immune response to those antigens. 
Class III genes encode molecules with diverse, 
and in some cases unknown, functions. Four of 
the class III genes specify soluble proteins that 
circulate in the blood, where they form part of 
the most primitive portion of the immune system, 
the complement system. They provide an initial, 
nonspecific barrier to invading microorganisms, 
before a specific immune response is developed. 
In addition to the complement genes, this region 
contains the genes encoding two potent, white 
blood cell-derived inflammatory molecules (tu- 
mor necrosis factor and lymphotoxin) . The class 
III region also contains several additional genes, 
some with as yet unknown functions. 
An important feature of most of the MHC genes 
is their marked variability in structure between 
different individuals in the population. This indi- 
vidual-to-individual (or allelic) variation confers 
an immunologic fingerprint that makes up each 
individual's tissue type and is the basis for recog- 
nition and rejection of foreign tissue grafts. More 
generally, this fingerprint permits very sensitive 
discrimination of self from nonself. 
It has been apparent for over a decade that sus- 
ceptibility to a large number of immunologically 
mediated diseases is determined by an individ- 
ual's tissue type. In some cases, disease suscepti- 
bility appears to be conferred by an allelic variant 
of a single MHC gene. In other cases, susceptibil- 
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