Autoantibodies in Human Chronic Graft-versus-Host Disease
after Hematopoietic Cell Transplantation
S. Quaranta,* H. Shulman,† A. Ahmed,‡ Y. Shoenfeld,‡ J. Peter,‡ G. B. McDonald,† J. Van de Water,*
R. Coppel,§ C. O
¨
stlund,
¶
H. J. Worman,
¶
M. Rizzetto, K. Tsuneyama,** Y. Nakanuma,** A. Ansari,††
F. Locatelli, S. Paganin, F. Rosina,‡‡ M. Manns,§§ and M. E. Gershwin*
*University of California, Davis, California 95616-8660; †Fred Hutchinson Cancer Research Center, Seattle, Washington; ‡Specialty Labs
Inc., Santa Monica, California; §Department of Microbiology, Monash University, Clayton, Australia;
¶
Departments of Medicine and
Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York;
Hospital “Molinette,” Turin, Italy; **Department of Pathology, Kanazawa University, School of Medicine, Japan;
††Department of Pathology, Emory University, Atlanta, Georgia; ‡‡Hospital “Gradenigo,” Turin, Italy;
and §§Department of Gastroenterology and Hepatology, Zentrum Innere Medizin und Dermatologie,
Medizinische Hochschule Hannover, Germany
Primary biliary cirrhosis (PBC) and graft-versus-host
disease (GVHD) are thought to have common immuno-
pathologic features and previous studies have reported
that 5.2 to 81% of patients with chronic GVHD after al-
logeneic hematopoietic cell transplant have anti-
mitochondrial antibodies (AMA). We studied a total of 89
patients with chronic GVHD and 60 controls for AMA
reactivity by ELISA and immunoblotting using recombi-
nant PDC-E2, BCOADC-E2, and OGDC-E2, immunoblot-
ting of beef heart mitochondrial proteins, and reactivity
to nuclei, smooth muscle (ASMA), ribonucleoprotein
JO-1, extractable nuclear antigen, nuclear proteins SSA/
SSB, ribonucleic P proteinase III, cardiolipin (ACA),
liver kidney microsomal, thyroid microsomal, myeloper-
oxidase, and the reactivity of rheumatoid factor. A sub-
set of 60 chronic GVHD sera were tested for reactivity to
gp210 and LBR. Finally, liver tissue from patients with
chronic GVHD and PBC was studied by immunohisto-
chemistry to determine whether there was comparable
abnormal apical staining of biliary epithelial cells using
PDC-E2-specific monoclonal antibodies. Surprisingly,
there were no AMA found in the sera from the 89 pa-
tients with chronic GVHD. Review of published data on
AMA in GVHD suggests that previous results were pri-
marily false positives. In contrast, sera from the patients
with GVHD did have a variety of other autoantibodies
and, in particular, 20/89 (22.4%) positive ANA, 23/89
(25.8%) positive ASMA, and 9/89 (10.1%) positive ACA.
The other autoantibodies assayed were not statistically
different from controls. Finally, abnormal biliary epithe-
lial luminal staining of bile ducts was found, as expected,
in liver tissue of patients with PBC but was absent in
chronic GVHD.
© 1999 Academic Press
Key Words: AMA; primary biliary cirrhosis; chronic
graft-versus-host disease; bone marrow transplantation.
INTRODUCTION
Chronic graft-versus-host disease (GVHD), a multi-
system disease that occurs after allogeneic hematopoi-
etic cell transplantation, has clinical and laboratory
findings of autoimmunity and immunodeficiency.
Chronic GVHD resembles an “overlap” syndrome with
skin changes similar to both systemic lupus erythem-
atosus and scleroderma/sicca syndrome together with
a destructive cholangiopathy with cholestasis as well
as myositis, serositis, and obliterative bronchiolitis (1,
2). Because of the similarities between chronic GVHD,
CREST, and primary biliary cirrhosis (PBC), chronic
GVHD is considered a “dry gland syndrome” which
might serve as a model for PBC (3). This hypothesis
has been strengthened by reports of frequent autoan-
tibodies in patients with chronic GVHD, ranging from
5–81% (4–6). Autoantibodies found in chronic GVHD
include anti-nuclear (ANA) (7), anti-smooth-muscle
(ASMA) (5), anti-cytoskeleton (8, 9), anti-neutrophil
cytoplasmic (10), and anti-mitochondrial antibodies
(AMA) (4–6, 11, 12). AMA are the most frequent rec-
ognized autoantibodies in chronic GVHD (4). To fur-
ther our understanding of autoantibodies in chronic
GVHD, we studied sera from 89 patients and controls
for reactivity to the 74-kDa E2 subunit of pyruvate
dehydrogenase (PDC-E2), the 56-kDa E3 binding pro-
tein or protein X (E3BP), the 52-kDa E2 subunit of
branched-chain oxo-keto acid dehydrogenase (BCO-
ADC-E2), the 48-kDa E2 subunit of 2-oxoglutarate de-
hydrogenase (OGDC-E2) (13), nuclear envelope pro-
teins, and a panel of autoantigens, including smooth
muscle, rheumatoid factor (RF), ribonucleoprotein
JO-1 (JO-1), extractable nuclear (ENA), nuclear pro-
teins SSA/SSB, ribonucleic P (RIB.P), proteinase III
(PR3), cardiolipin (ACA), gp210, LBR, liver kidney mi-
crosomal, thyroid microsomal, and myeloperoxidase
Clinical Immunology
Vol. 91, No. 1, April, pp. 106–116, 1999
Article ID clim.1998.4666, available online at http://www.idealibrary.com on
1521-6616/99 $30.00
Copyright © 1999 by Academic Press
All rights of reproduction in any form reserved.
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