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Skewed distribution of IGG FC receptor iia CD32 polymorphism is associated with renal disease in systemic lupus erythematosus patients.

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ARTHRITIS & RHEUMATISM
Vol. 39, No. 12, December 1995, pp 1832-1836
0 1996, American College of Rheumatology
1832
SKEWED DISTRIBUTION OF IgG Fc RECEPTOR IIa (CD32)
POLYMORPHISM IS ASSOCIATED WITH RENAL DISEASE IN
SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS
ASHLEY J. DUITS, HENDRIKA BOOTSMA, RONALD H. W. M. DERKSEN, PETER E. SPRONK,
LOUIS KATER, CEES G. M. KALLENBERG, PETER J. A. CAPEL, NOMDO A. C. WESTERDAAL,
GERRIT TH. SPIERENBURG. FRITS H. J . GMELIG-MEYLING, and JAN G. J. VAN DE WINKEL
Objective. Fcy receptors of class IIa (FcyRIIa)
occur in 2 allelic forms, with either a low (IIa-R131) or
a high (IIa-H131) affinity for complexed IgG2 and IgG3.
This polymorphism might have implications for the
handling of immune complexes. Therefore, we determined the distribution of the FcyRIIa allotypes in
patients with systemic lupus erythematosus (SLE), with
or without a history of lupus nephritis.
Methods. We studied 95 unrelated white European patients with SLE, as defined by the American
College of Rheumatology criteria, 50 of whom had a
history of lupus nephritis, and 69 healthy white European control subjects. Fc yRIIa allotypes were determined by immunophenotyping of blood monocytes.
Results. It was found that lupus nephritis was
significantly associated with the “low affinity” FcyRIIa
WR131 allotype and with the R131 allele, compared
with healthy controls. No significant association was
found upon comparison of groups with and without
nephritis.
Conclusion. SLE patients with a history of lupus
nephritis have an abnormal distribution of FcyRIIa
allotypes. FcyRIIa may well play a role in the pathogenesis of lupus nephritis, since IIa-R/R131 SLE paPresented in part at the 58th National Meeting of the
American College of Rheumatology, Minneapolis, MN, October
1994.
Ashley J. Duits, PhD, Hendrika Bootsma, MD, Ronald
H. W. M. Derksen, MD, PhD, Louis Kater, MD, PhD, Peter J. A.
Capel, PhD, Nomdo A. C. Westerdaal, MSc, Gerrit Th. Spierenburg, MSc, Frits H. J. Gmelig-Meyling, PhD, Jan G. J. van de
Winkel, PhD: University Hospital, Utrecht, The Netherlands; Peter
E. Spronk, MD, PhD, Cees G. M. Kallenberg, MD, PhD: University
Hospital, Groningen, The Netherlands.
Address reprint requests to Frits H. J. Gmelig-Meyling,
PhD, Department of Immunology, F03.821, University Hospital,
Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Submitted for publication December 30, 1994; accepted in
revised form July 21, 1995.
tients seem to have a higher incidence of developing this
complication.
Abnormal handling of immune complexes (IC)
is considered to be an important factor in the pathogenesis of systemic lupus erythematosus (SLE). It has
been proposed that clearance of IC by the mononuclear phagocyte system (MPS), in which complement
and IgG Fc receptors (FcyR) play a pivotal role, is
impaired in SLE; this may result in tissue deposition of
IC (1). Such phenomena could not be explained merely
by IC saturation of the receptors (2); indeed, it was
postulated as long ago as 1984 that an FcyR, unable to
effectively trigger ingestion, might be involved in SLE (3).
FcyR are instrumental in the elimination of IC
and infectious agents by phagocytosis (3). Three main
classes of FcyR have been defined in humans: FcyRI
(CD64), FcyRII (CD32), and FcyRIII (CD16). They
serve important functions in the immune response (4).
The FcyRII, which binds IgG only in the complexed
form, has the broadest cell distribution. The FcyRIIa
subclass is predominantly expressed on myeloid cells.
This receptor has been shown to be crucial (and
sufficient) for the binding and internalization of IC (5).
FcyRIIa displays a genetic polymorphism, comprising
2 allotypes that can be discerned by a variation of 1
amino acid in the second Ig-like domain: H (histidine)
or R (arginine) at amino acid position 131 (6). Individuals can therefore be categorized as FcyRIIa-HIH131,
-R/H131, or -R/R131. This polymorphism has major
implications for the handling of IC, especially those
involving human IgG2 and IgG3: whereas the IIa-H13 1
allotypic form interacts efficiently with IC, the IIaR131 form does not (7).
We sought to determine whether the FcyRIIa
polymorphism would have consequences for SLE and
IgG FcyRIIa ALLOTYPE AND RENAL DISEASE IN SLE
cr
1833
Log Fluorescence intensity (Arbitrary Units)
Figure 1. Allotyping of Fcy receptor IIa (FcyRIIa) polymorphism by flow cytometry. Mononuclear cells from 3
representative donors were incubated with buffer alone (shaded area), with buffer supplemented with anti-FcyRIIa
monoclonal antibody (MAb) IV3 or with anti-FcyRIla R131-specific MAb 41H16. CD32 MAb binding was detected by
F(ab’), fragments of a fluorescein isothiocyanate-labeled secondary antibody.
its clinical manifestations. Specifically, we tested the
hypothesis that the “low-affinity” R131 allotype of the
FcyRIIa is associated with renal involvement, because
suboptimal clearance of IC may contribute to this
complication (1,2). Therefore, we analyzed the distribution of the FcyRIIa allotypes in SLE patients with
and without a history of renal disease, as well as in a
control group of healthy individuals. We found that
SLE patients with renal involvement exhibited a significantly increased frequency of the R131 FcyRIIa
allotype.
PATIENTS AND METHODS
Study population. Ninety-five unrelated white European patients with SLE followed at the University Hospitals
of Utrecht and Groningen were included in this study. All
patients fulfilled at least 4 of the American College of
Rheumatology (ACR) 1982 revised criteria for the classification of SLE (8). Their mean age was 36.3 years (range
20-74); 85 were women and 10 were men.
Fifty of the SLE patients had developed (symptoms
of) lupus nephritis between the time of diagnosis of SLE and
the current study. Lupus nephritis was defined by criteria
which were somewhat narrower than those of the ACR, as is
usual in our clinics. The criteria used were proteinuria of at
least 500 mgI24 hours plus active urinary sediment andlor
decreased creatinine clearance by >25% within 4 months. In
45 of these 50 patients, a kidney biopsy was also performed.
Histopathologic findings were recorded according to the
World Health Organization (WHO) classification criteria,
which are based primarily on the characteristics of glomerular lesions (9). Proliferative changes (class 111, IV, Vd) were
present in 33 patients, mesangioproliferative changes (class
11) in 5 patients, membranous changes (class Vnon-d)in 6
patients, and advanced sclerosing glomerulonephritis (class
VI) in 1 patient. In the other 5 patients, biopsy was not
performed because of such contraindications as severe
thrombocytopenia.
The median duration of disease was 9 years (range
1-31 years) for those with nephritis and 7 years (range 1-34
years) for those without nephritis. Sixty-nine healthy unrelated white European volunteers served as a control group
(7). Their mean age was 29 years (range 2445); 38 were men
and 31 were women.
FcyRIIa allotyping. FcyRIIa allotypes were assigned
in all patients by quantitative flow cytometric immunophenotyping on monocytes isolated from blood samples. The
following monoclonal antibodies (MAb) were used: IV3
(mouse subclass IgG2b; Medarex, Annandale, NJ), which
reacts with both of the FcyRIIa (CD32) allotypic forms, and
MAb 41H16 (IgG2a; generously provided by Dr. B. Longenecker, University of Alberta, Edmonton, Alberta, Canada),
which selectively recognizes the Fc yRIIa-R13 1 allotypic
form (4,7). Results of flow cytometry were analyzed as
previously described (7), based on the binding ratios of MAb
41H16IIV3 (ratio for FcyRIIa-HIH131 < 0.4, for IIa-RlH131
between 0.4 and 0.8, and for IIa-R/R131 > 0.8) (Figure 1).
In 37 of the patients, the FcyRIIa allo-immunophenotyping was confirmed by T cell activation of isolated blood
mononuclear cells (results not shown in detail), using
monocyte-focused anti-CD3 MAb of various IgG subclasses
as a mitogen (4,7). This approach is based on the differential
binding affinity of monocytes toward mouse (and human)
IgG subclasses, through the FcyRIIa allotypic forms. Thus,
FcyRIIa-RIR131 cells are only responsive to mouse IgGl
(mIgG1) anti-CD3 MAb (WT31; kindly provided by Dr. W.
Tax, University Hospital, Nijmegen, The Netherlands),
HIH131 cells only to humanized IgG2 (HuIgG2) anti-CD3
MAb (CLB-T3/4.h2; a kind gift from Dr. L. Aarden, CLB,
Amsterdam, The Netherlands), and R/H131 cells support
proliferation triggered by both mIgG 1 and HuIgC2 anti-CD3
MAb. In the presence of mIgG2a anti-CD3 (WT32; from Dr.
Tax), monocytes from all donors support the induction of T
cell proliferation.
Previously, we had established that there is complete
concordance between allotype analysis by flow cytometric
immunophenotyping, T cell activation using anti-CD3 antibodies (see ref. 7), and a polymerase chain reaction-based
DUITS ET AL
1834
Table 1. Distribution of FcyRIIa allotypes in SLE patients with
and without a history of nephritis, and in healthy control subjects*
Fc yRIIa allotype
FUR131
R/H131
H/H131
27
8
19
50
26
24
18
11
7
11
1
4
18
4
1
4
All SLE patients (n = 95)
Patients without nephritis (n = 45)
Patients with nephritis (n = 50)
Renal biopsy findings
WHO class 111, IV, Vd (n = 33)
WHO class I1 (n = 5)
WHO class Vnon-d(n = 6)
WHO class VI (n = 1)
Renal biopsy not done (n = 5)
Control subjects (n = 69)
1
1
3
11
36
2
22
* FcyRIIa = Fc receptor subclass IIa; SLE = systemic lupus
erythematosus; WHO = World Health Organization.
approach (as tested in more than 400 individuals) (Duits et al:
Unpublished observation).
FcyRIIIb allotyping. There is another (sub)class of
allotypically polymorphic FcyR, notably the FcyRIIIb
(CD16b) which is selectively expressed on neutrophils. This
bi-allelic polymorphism, designated neutrophil antigen 1 and
2 (NA1 and NA2) is associated with allo- or autoimmune
neutropenias and blood transfusion reactions (10). To assess
the specificity of potential differences in Fc yRIIa allotype
frequencies between the patients and the controls, we also
studied the allotype distributions of FcyRIIIb. This was
done by flow cytometric allo-phenotyping on isolated blood
polymorphonuclear granulocytes. We used MAb CLBGranll (mIgG2a; CLB), which selectively recognizes the
Fc yRIIIb-NA1 allotypic form, GRMl (mIgG2a; provided by
Dr. F. Garrido, Hospital Las Nieves, Granada, Spain),
which specifically reacts with FcyRIIIb-NA2, and CLBGran 1 (mIgG2a; CLB), which recognizes all FcyRnI forms (4).
Statistical analysis. The allo-phenotype frequencies
among the various groups of subjects were subjected to
logistic regression analysis (2-tailed) with Bonferroni correction for multiple comparisons, using the IUR 131 and R/H 131
phenotypes as potential predictors of nephritis, or SLE in
general, and the H/H 131 phenotype as the baseline group.
Age, sex, and disease duration were also analyzed as potential determinants.
Gene frequencies of the IIa-R131 and IIa-H131 alleles in the different groups were analyzed by 2-tailed Pearson's chi-square test, using the continuity correction.
RESULTS
The distribution of FcyRIIa allotype frequencies in the different study groups are shown in Table 1.
Among the 69 healthy individuals, the frequencies of
the FcyRIIa-WR131, -R/H131, and -H/H131 allotypes
were 16%, 52%, and 32%, respectively. For the total
group of 95 SLE patients, the distribution was IIa-R/
R131 in 28%, IIa-WH131 in 53%, and IIa-HIH131 in
19%. The distribution of FcyRIIa allotypes among the
45 SLE patients without nephritis was RlR131 in 18%,
WH131 in 58%, and H/H131 in 24%.
Among the group of 50 SLE patients with
nephritis, 38% were FcyRIIa-WR131, 48% were heterozygous (WH131), and only 14% were H/H131. The
allotypes of the 17 patients with nephritis of WHO
classes 11, Vnon-d,and VI, or with nonclassified nephritis, are shown separately in Table 1. Because these
subgroups were too small to allow for separate analysis, the patients with renal disease were analyzed as
one group.
Logistic regression analysis showed that the
FcyRIIa allotype was not a predictor of SLE in
general. There was also no association between the
allotype and SLE patients without nephritis, as compared with the healthy control group. Furthermore,
the allotype was not a significant predictor of nephritis, as compared with SLE patients without renal
involvement. However, the Fc yRIIa allotype was a
significant predictor of nephritis compared with the
healthy control group (overall analysis P = 0.03); the
WR131 allotype appeared to be associated with SLE
nephritis (odds ratio 3.7, 95% confidence interval
1.6-18.5, Bonferroni corrected P = 0.01), when compared with the H/H131 allotype. By similar analysis,
no significant association with nephritis was found for
comparison of the WH131 with the H/H131 allotype,
or for comparison of the WR131 with the WH131
allotype.
We also calculated the gene frequencies of the
FcyRIIa-R131 and -H131 alleles in these 2 groups:
these were, respectively, 62 (62%) and 38 (38%) in the
patients with nephritis, and 58 (42%) and 80 (58%) in
the healthy control subjects. In this analysis, both
groups differed significantly (P = 0.01 1).
Finally, we studied the frequencies of the
FcyRIIIb allo-phenotypes NA1 and NA2. The distribution among the SLE patients with renal disease was
23% with FcyRIIIb-NA1/1, 46% with NA1/2, and 31%
with NA2/2. Among those without renal disease, 26%
had NA111, 47% had NA1/2, and 27% had NA2/2.
Among the healthy controls (see ref. lo), 14% had
NA1/1, 47% had NA112, and 39% had NA2/2. Statistical analysis showed that the FcyRIIIb allotype was
not associated with SLE or with either of its subgroups
studied.
DISCUSSION
Fcy receptors play an essential role in the
clearance of immune complexes. Impaired handling
1835
IgG FcyRIIa ALLOTYPE AND RENAL DISEASE IN SLE
and removal of IC by the mononuclear phagocyte
system, resulting in deposition of IC and inflammatory
processes in organs and tissues, is considered to be of
crucial pathogenic importance in SLE (1). However,
the underlying basis of such defective immune complex clearance and its relation to the observed clinical
manifestations has not heretofore been defined. Downregulation of FcyR expression and function by IC,
effects on signal transduction, and anti-Fc yR autoantibodies have all been implicated as factors in aberrant
FcyR functioning (I ,2,3,11). In addition, qualitative
differences in FcyR on mononuclear cells have been
postulated to explain nonoptimal IC handling in SLE
(3). In this regard, both FcyRI (CD64) (12) and
FcyRIIIa (CD16) (13) were implicated to be involved
in the process of IC uptake by macrophages. Recent
reports strongly suggest a genetic polymorphism of
Fc yRIIa to affect effective handling and clearance of
immune complexes and opsonized microorganisms
(4,5,14). Furthermore, the FcyRIIa polymorphism
also proved important for the clearance of T cells in
kidney allograft recipients treated with mouse IgGl
anti-CD8 MAb (15).
This study shows that there is considerable
skewing in the distribution of the FcyRIIa allotypes
among SLE patients with renal disease: we observed
an overrepresentation of the RiR131 allotype in this
group, compared with the H/H131 allotype. In terms
of the total H131 and R131 allele frequencies, the same
was observed. Remarkably, patients without nephritis
had an allelic distribution of FcyRIIa that was comparable to that in the healthy controls; apparently, the
observed skewing seems to be related to renal disease.
Furthermore, the observed differences in distribution
proved specific for FcyRIIa, since the FcyRIIIb phenotype distribution (NAl/NA2) was comparable in
both groups of SLE patients and the control population. The interaction of phagocytes expressing
FcyRIIa-H131 with IC containing IgG2 and IgG3 is
much more effective than with IIa-R131 cells (4,5,14).
The altered distribution observed for Fc yRIIa allotypes, therefore, seems consistent with a diminished
capacity to handle IC in SLE patients, which may be
important for the development and extent of renal
disease.
Although the development of SLE as such
seems not to be associated with FcyRIIa polymorphism, in our study population, the data strongly
support the assumption that FcyRIIa allotypic variation is related to the occurrence of lupus nephritis. In
order to test this supposition, more patients with
various types of nephritis should be studied. Interestingly, one type of autoantibody that has been related
to renal disease in SLE patients, anti-Clq, has IgG2
and IgG3 as its predominant subclasses (16). Thus far,
it is still unknown if it is the interaction between such
antibodies and Fc yRIIa that might play a role in the
development of renal disease. Such a relationship may
be particularly expected in patients with proliferative
forms of nephritis, because this type is strongly associated with immune complex nephritis.
In conclusion, an abnormal distribution of the
FcyRIIa (CD32) allotypes may contribute to the pathogenesis and/or the development of clinical manifestations of renal disease in SLE, and determination of
Fc yRIIa phenotypes could have implications for patient care. Therefore, future work on the relationship
between FcyR and lupus nephritis should also include
prospective studies.
In a recent study of African-American SLE
patients, an FcyRIIa allotype skewing was found, both
for SLE in general and for lupus nephritis (Salmon JE:
personal communication).
ACKNOWLEDGMENTS
We wish to thank Mrs. I. van der Tweel and Dr. J. A.
J. Faber (Center for Biostatistics, Utrecht University) for
their help with the data analysis.
REFERENCES
1. Emlen W: Immune complexes in systemic lupus erythematosus.
2.
3.
4.
5.
6.
7.
In, Dubois’ Lupus Erythematosus. Edited by DJ Wallace, BH
Hahn. Philadelphia, Lea & Febiger, 1993
Davies KA, Peters AM, Beynon HLC, Walport MJ: Immune
complex processing in patients with systemic lupus erythematosus. J Clin Invest 90:2075-2083, 1992
Salmon JE, Kimberly RP, Gibofsky A, Fotino M: Defective
mononuclear phagocyte function in systemic lupus erythematosus: dissociation of Fc receptor-ligand binding and internalization. J Immunol 133:2525-2531, 1984
Van de Winkel JGJ, Capel PJA: Human IgG Fc receptor
heterogeneity: molecular aspects and clinical implications. Immunol Today 14:215-221, 1993
Tuijnman WB, Capel PJA, van de Winkel JGJ: Human low
affinity IgG receptor FcyRIIa (CD32) introduced into mouse
fibroblasts mediates phagocytosis of sensitized erythrocytes.
Blood 79:1651-1656, 1992
Warmerdam PAM, van de Winkel JGJ, Gosselin EJ, Capel PJA:
Molecular basis for a polymorphism of human Fcy receptor I1
(CD32). J Exp Med 172:1!3-25, 1990
Parren PWHI, Warmerdam PAM, Boeije LCM, Arts J, Westerdaal NAC, Vlug A, Capel PJA, Aarden LA, van de Winkel
JGJ: On the interaction of IgG subclasses with the low affinity
Fc*IIa (CD32) on human monocytes, neutrophils, and plate-
DUITS ET AL
1836
8.
9.
10.
11.
12.
lets: analysis of a functional polymorphism to human IgG2. J
Clin Invest 90: 1537-1546, 1992
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield
NF, Schaller JG, Tala1 N, Winchester RJ: The 1982 revised
criteria for the classification of systemic lupus erythematosus.
Arthritis Rheum 25:1271-1277, 1982
Churg J, Sobin LH: Lupus nephritis. In, Renal Disease: Classification and Atlas of Glomerular Diseases. Edited by J Churg,
LH Sobin. Tokyo, Igaku-Shoin, 1982
Fromont P, Bettaieb A, Skouri H, Floch C, Poulet E, Duedari
N, Bierling P: Frequency of the polymorphonuclear neutrophil
Fcyreceptor I11 deficiency in the French population and its
involvement in the development of neonatal alloimmune neutropenia. Blood 79:2131-2134, 1992
Boros P, Muryoi T, Spiera H, Bona C, Unkeless JC: Autoantibodies directed against different classes of FcyR are found in
sera of autoimmune patients. J Immunol 5:218-224, 1993
Ruiz P, Gomez F, Schreiber AD: Impaired function of macro-
13.
14.
15.
16.
phage Fcy receptors in end-stage renal disease. N Engl J Med
3229 17-722, 1990
Clarkson SB, Bussel JB, Kimberly RP, Valinski JE, Nachman
RL, Unkeless JC: Treatment of refractory immune thrombocytopenic purpura with anti-Fcyreceptor antibody. N Engl J Med
3 1 4 1236-1 239, 1986
Salmon JE, Edberg JC, Brogle NL, Kimberly RP: Allelic
polymorphisms of human Fcy receptor IIA and Fcy receptor
IIIB: independent mechanisms for differences in human phagocyte function. J Clin Invest 89:1274-1281, 1992
Wee SL, Colvin RB, Phelan JM, Preffler FI, Reichert TA, Berd
D, Cosimi AB: Fc receptor for mouse IgCl (FcyRII) and
antibody-mediated cell clearance in patients treated with Leu2a
antibody. Transplantation 48: 1012-1017, 1989
Prada AE, Strife CF: IgG subclass restriction of autoantibody to
solid-phase C lq in membranoproliferative and lupus glomerulonephritis. CIin Immunol Immunopathol 63:8448, 1992
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