(Circulation. 1998;97:1111-1113.)
© 1998 American Heart Association, Inc.
High-Altitude Pulmonary Edema
An Immunogenetically Mediated Disease?
Frank C. Arnett, MD
From the Division of Rheumatology (Elizabeth Bidgood Chair in
Rheumatology) and Clinical Immunogenetics, Department of Internal Medicine,
and Department of Pathology and Laboratory Medicine, University of
Texas–Houston Medical School.
Correspondence to Frank C. Arnett, MD, Division of Rheumatology, University of Texas–Houston Medical School, 6431 Fannin, Room 5.268 MSB, Houston, TX 77030.
Key Words: Editorials • genetics • hypertension, pulmonary • immune system • risk factors
High-altitude
pulmonary edema (HAPE), a potentially life-threatening
complication of acute mountain sickness, is postulated to be a
noncardiogenic permeability edema caused by acute pulmonary
arteriolar vasoconstriction and resultant pulmonary
hypertension in response to the hypoxia of rapid ascent to high
altitudes.1 2 3 4 HAPE typically occurs unexpectedly
in young, otherwise healthy mountaineers. A constitutional
susceptibility has been noted for some time5 6 ;
the disease tends to recur in the same individuals on reexposure to
high altitude, whereas others appear not to be susceptible at all. The
basis for this predisposition to HAPE, whether genetic or
environmental, and its underlying pathophysiology remain poorly
understood.
In this issue of Circulation, Hanaoka and
colleagues7 present interesting new evidence
that certain human leukocyte antigens (HLA) are increased in Japanese
patients with HAPE, especially those with recurrent disease. HLA-DR6
and/or HLA-DQ4 were found to each occur significantly more often in
Japanese patients with HAPE than in a large number of normal Japanese
control subjects. Moreover, the HLA-DR6–positive patients with HAPE
had significantly higher pulmonary arterial
pressures than did their HLA-DR6–negative counterparts with HAPE. The
authors speculate that at least some cases of HAPE are
immunogenetically mediated, perhaps through an inherent HLA-associated
susceptibility to pulmonary hypertension. They cite several
recent studies reporting HLA associations, specifically HLA-DR6, with
pulmonary hypertension complicating other diseases, namely
scleroderma and human immunodeficiency virus (HIV)
infection.8 9
What is implied by the finding of an HLA association with a disease?
First, HLA antigens are cell surface molecules encoded by a cluster of
highly polymorphic linked genes located on human chromosome 6
termed the major histocompatibility complex, or MHC
(Figure
).10 A significant correlation between one
or more HLA antigens (or alleles) and a disease means that there is
a significant genetic contribution to disease susceptibility. A large
number of human diseases have been associated with different
alleles (or HLA antigens) of the MHC11
(Figure). Many of these diseases are considered to be "autoimmune"
in origin, but, increasingly MHC influences on host responses to
infectious and neoplastic diseases are being recognized. Such disease
associations are not surprising given that MHC alleles are specific
immune response genes, and one's inherited MHC repertoire largely
dictates how the immune system interacts with a hostile environment.
Increasingly, however, it is becoming apparent that MHC genes alone
cannot account for the genetic susceptibility to the diseases with
which they are associated. Most of these disorders appear to be complex
genetic traits where the MHC is only one of several (or many)
interacting genes, which along with environmental stimuli, ultimately
lead to a pathological condition.12 The genetic
complexity of such diseases as insulin-dependent diabetes mellitus,
multiple sclerosis, and systemic lupus
erythematosus, to name but a few, is increasingly
being recognized as human genome-wide scans for susceptibility genes
are being conducted.13 14 15 For most of the
complex disorders recently studied, it appears that the MHC
contribution to risk constitutes less than 50% of the overall genetic
liability. Thus if there is genetic susceptibility to HAPE, HLA is
likely to be only part of the genetic equation. Of potential interest
in this regard is a recent report of the genetic mapping of a locus on
human chromosome 2 predisposing to familial primary pulmonary
hypertension.16
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Figure 1. Genes of the major histocompatibility complex (MHC) on human
chromosome 6p. Associated diseases are shown below their relevant gene
loci. JRA indicates juvenile rheumatoid arthritis; IDDM,
insulin-dependent diabetes mellitus; MS, multiple sclerosis; RA,
rheumatoid arthritis; SLE, systemic lupus
erythematosus; SSc, systemic sclerosis or
scleroderma; AS, ankylosing spondylitis; and C, centromere.
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The HLA antigens associated with HAPE in this study are MHC class II
alleles (Figure
). What clues to the underlying pathophysiology of
HAPE or pulmonary hypertension might this information provide?
MHC class II molecules (HLA-DR, DQ, and DP) are normally expressed on
antigen presenting cells, such as macrophages and B
lymphocytes, although many other cell types, including
endothelial cells, can be induced by various stimuli to
express class II MHC molecules.17 18 The major
function of class II MHC molecules is to present intracellularly
processed exogenous or self-peptides to CD4 positive helper or inducer
T lymphocytes, thus initiating a specific immune response to those
peptides recognized by the T cell as being foreign. Each HLA molecule,
on the basis of its polymorphic amino acid composition, possesses
its own unique "peptide-binding motif" configured into a groove at
the most external end of the molecule.17 Only
peptides composed of amino acids meeting specific requirements in size
and charge can be bound by a specific HLA molecule for
presentation to a T cell. Once such an
MHC–T-cell–mediated immune response is initiated, it is amplified by
the release of a cascade of various cytokines, growth factors,
and other inflammatory mediators.18
Might such an immunologic reaction be occurring in the
pulmonary arterioles of patients with HAPE, perhaps as a result
of the upregulation and expression of HLA-DR6 and/or DQ4 molecules on
endothelial cells as a response to hypoxia?
Might such a scenario not produce an inflammatory response and/or
endothelial proliferation leading to pulmonary
hypertension? The authors of this report raise such possibilities,
which are certainly viable and testable hypotheses. On the other hand,
the HLA associations described here could simply be markers of another
non-HLA gene tightly linked to the MHC that plays a role in
pulmonary hypertension. After all, hemochromatosis, a genetic
disease caused by increased gut absorption of iron and not believed to
be immunologic in origin, is linked to the
MHC.19
There are many potential pathogenetic implications raised by this study
that should lead to new investigations and insight into HAPE
specifically and perhaps into other disorders in which
pulmonary hypertension plays a central role, such as
scleroderma or primary pulmonary hypertension. First, however,
these results need to be confirmed, especially in additional
populations. There are many vagaries to HLA and disease association
studies, especially in the selection of cases and controls, which could
lead to false-positive results. No such problems are obvious in this
study; however, the Japanese population is, relatively speaking, a
genetic isolate with a more restricted pool of HLA alleles than
many other ethnic groups. Proven MHC associations with other diseases
tend to cross ethnic lines. For some diseases, the same HLA antigen
(allele) association is found in many populations, the best example
being HLA-B27 and ankylosing spondylitis; but for other disorders,
different HLA correlations have been found in various ethnic groups. In
the latter situation, the different disease-associated HLA alleles
have been found to share similar polymorphic sequences in the
antigen-binding cleft (the shared epitope
hypothesis).20 Thus it will be of interest to see
whether these or other investigators find the same or different HLA
alleles associated with HAPE in other ethnic groups.
In addition, a limitation of this study is the use of serological
methods to detect HLA antigens. More accurate DNA typing is available
for MHC class II alleles that can reveal more specific molecular
information about the alleles associated with HAPE. In fact, 60
different HLA-DR6 alleles, which have been redesignated as HLA-DR13
or DR14 alleles on the basis of molecular structure, and two DQ4
alleles are now recognized,10 each having its
own unique sequence and peptide-binding motif, and, importantly,
population frequency. Some of these HLA alleles are relatively
unique to the Japanese population, whereas others are more ubiquitous
in their ethnic distributions. Thus it would be useful for this group
of investigators to perform molecular MHC class II typing of their HAPE
cases and control subjects, so as to define better the specific
alleles that confer susceptibility. Equally interesting would be a
comparison of HLA alleles in persons who have developed HAPE versus
mountain climbers who have proven not to be susceptible to this
disorder. In other HLA-associated diseases, most notably
insulin-dependent diabetes mellitus, some HLA alleles show
decreased frequencies and have proven to be "protective," whereas
others are increased and tend to be "promotive" of disease
expression.20 From a clinical viewpoint, it even
might be possible by HLA typing to determine which individuals are at
risk for HAPE before they are exposed, so as to provide them the
appropriate counseling and/or preventive measures if they choose to
ascend to high altitudes.
This interesting study raises more questions than it answers. If
subsequent investigations confirm a link between susceptibility to HAPE
and MHC alleles, a new dimension will have been opened in the
exploration for mechanisms underlying this seemingly nonimmunologic
disease as well as potentially other forms of pulmonary
hypertension.
Acknowledgments
This work was supported by an NIAMS Specialized Center of
Research (SCOR) in Scleroderma Grant (IP50 AR44888) and the RGK
Foundation.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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