By
From the * Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin 43226; The Jackson Laboratory, Bar Harbor, Maine 04609; and the § Department of Internal Medicine and
the
Department of Pathology, The Ohio State University, Columbus, Ohio 43210
Recent understanding of the mechanism of immunoglobulin G (IgG) catabolism has yielded
new insight into antibody-mediated diseases. We proposed that 2-microglobulin (
2m)-deficient mice have been protected from systemic lupus erythematosis (SLE)-like syndromes because they lack the
2m-associated IgG protection receptor (FcRn) and therefore catabolize
IgG, including pathogenic IgG autoantibodies, considerably more rapidly than normal mice. Such an hypothesis would predict that
2m-deficient mice would also be resistant to experimental bullous pemphigoid, a disease with a pathogenesis thought to be much simpler than
SLE, being the result of antibody directed toward a pathogenic epitope on the epidermal
hemidesmosome that anchors basal keratinocytes to the basement membrane. To test this hypothesis, we administered pathogenic rabbit antibody directed toward the hemidesmosome to
2m-deficient mice and to normal control mice, both intraperitoneally and intradermally, and
assessed the mice clinically, histologically, and immunologically for manifestations of skin disease. We found that the
2m-deficient mice were protected when the antibody was given intraperitoneally whereas intradermal administration resulted in blisters only slightly less severe
than those seen in normal mice. These data would indicate that autoantibody-mediated inflammation might be prevented or controlled by appropriate modulation of FcRn function.
More than 30 years ago, Brambell postulated that the
mechanisms by which the catabolic rate of IgG is
controlled and by which IgG is transported from mother to
young were remarkably alike and were mediated by similar
Fc receptors (1). Assessing today the data available to him
we would say the putative receptors were virtually identical. The receptors, present in the walls of intracellular vesicles, he envisioned as binding pinocytosed IgG and transporting it either back to the surface or across the cell,
thereby protecting it from the usual fate of catabolic degradation and regulating its concentration in blood and tissues.
Such a mechanism accounted for all that was known about
these two processes, including the relatively long lifespan of
IgG and the paradoxically inverse relationship of IgG concentration to lifespan (2). It has recently become clear that
the Brambell receptor, responsible for both IgG transport
and protection from degradation, is in fact the pH-dependent IgG transporter (Fc receptor neonatal, FcRn)1 initially
described as the molecule that moves IgG across the neonatal rat gut (3).
The structure of FcRn is now known in great detail. It is
a heterodimer of The crucial link between Brambell's receptor and FcRn
has been provided by recent studies of It was noted recently that the severity of experimental
systemic lupus erythematosus (SLE) is greatly attenuated in
A more direct test of the hypothesis, that the absence of
FcRn protects against autoantibody-mediated disease, would
be to determine whether We subjected Animals.
Breeding pairs of BALB/ByJ and C57BL/6J mice
were obtained from The Jackson Laboratory (Bar Harbor, ME).
Preparation of Pathogenic Rabbit Anti-murine BP180 IgG.
The preparation of recombinant mBP180 and the immunization of rabbits
were performed as previously described (29, 32). In brief, a segment of the mBP180 antigen containing the pathogenic epitope
was expressed, purified to homogeneity by affinity chromatography (33), and used to immunize New Zealand White rabbits.
The IgG fraction from the sera (referred to as R621) was purified
as previously described (29). The titer of rabbit anti-mBP180 antibodies was assayed by indirect IF using mouse skin cryosections
as substrate (29). The pathogenicity of the IgG preparations was
tested by passive transfer experiments as described below.
Induction of Experimental BP and Animal Evaluation.
A 50 µl
dose of sterile IgG in PBS was administered to neonatal mice by
intraperitoneal injection (2.5 mg IgG/g body weight) or intradermal (2.5 mg IgG/g body weight). The skin of neonatal mice from
the test and control groups was examined 12 or 24 h after the IgG
injection. The extent of cutaneous disease was scored as follows:
minus, no detectable skin disease; 1+, mild erythematous reaction with no evidence of the epidermal detachment sign elicited by gentle friction of the mouse skin, which, when positive, produced fine, persistent wrinkling of the epidermis; 2+, intense
erythema and epidermal detachment involving 10-50% of the
epidermis in localized areas; and 3+, intense erythema with frank
epidermal detachment involving more than 50% of the epidermis.
The animals were then sacrificed and skin sections were taken for
light microscopy (hematoxylin and eosin, H/E) and for direct
immunofluorescence (IF) to detect rabbit IgG and mouse C3
deposition at the BMZ. Sera of injected animals were assayed by
indirect IF to determine the circulating titers of anti-mBP180
IgG (29). Monospecific FITC-conjugated goat anti-rabbit IgG
was obtained commercially (Kirkeggard & Perry Laboratories,
Inc., Gaithersburg, MD). Monospecific goat anti-mouse C3 was
purchased from Cappel Laboratories (Durham, NC). Both anti-rabbit IgG and anti-C3 antibodies were used at a 1:100 dilution.
Quantitation of Skin Site PMN Accumulation.
Tissue MPO activity in skin sites of the injected animals was assayed as described
(34, 35). A standard reference curve was first established using
known concentrations of purified myeloperoxidase (MPO). The
skin samples were extracted by homogenization in an extraction
buffer containing 0.1 M Tris-HCl, pH 7.6, 0.1 M NaCl, 0.5%
hexadecyltrimethylammonium bromide. MPO activity in the supernatant fraction was measured by the change in optical density
at OD 460nm resulting from decomposition of H2O2 in the presence of O-dianisidine. MPO content was expressed as units of
MPO activity/mg protein. These numbers were subtracted from
background MPO activity of skin of mice injected with PBS
alone and sacrificed at the same timepoints as the test mice. Protein concentrations were determined by the Bio-Rad dye binding
assay using BSA as a standard.
Determination of Serum Rabbit IgG Levels.
The concentration
of serum rabbit IgG was measured by ELISA relative to purified
rabbit IgG (Sigma Chemical Co., St. Louis, MO). Microtiter
plates were coated with polyclonal goat anti-rabbit IgG Fc antibody (Cappel Laboratories, Durham, NC), incubated with dilutions of serum, and then developed with horseradish peroxidase- conjugated goat antibodies specific for rabbit IgG F(ab Statistical Analysis.
The data were expressed as mean ± SEM
and were analyzed using the Student's t-test. A P value <0.05
was considered significant.
Pathogenic anti-mBP180 antibodies administered intraperitoneally do not induce experimental BP in
Table 1.
Experimental BP in
Indirect IF showed a lower level of circulating rabbit
IgG in
Intradermal injection of pathogenic anti-mBP180 IgG
induced subepidermal blisters in
Our data show that mice deficient in The hypothesis accounts for additional findings. We
note that pathogenic antibody given intradermally caused
lesions slightly less severe in the Although these studies were performed in neonatal mice,
there is no reason why the observations should not be applicable to the adult. Certainly, the murine model of experimental BP is valid in adult mice (Liu, Z., unpublished
observations); neonates are used experimentally only to
conserve pathogenic antibody and to inspect more readily
the hairless skin for blisters. Likewise, the IgG catabolic
studies have been done only in adult mice, but we can
think of no reason why neonates would behave any differently with respect to IgG degradation (20).
We would suggest that FcRn, appearing to be a critical
molecule in antibody-mediated immunity, might be manipulated pharmacologically to decrease pathogenic levels
of IgG in various antibody-mediated human diseases, thereby
modulating the inflammatory process.
2-microglobulin (
2m) and a 45-kD
chain closely related to MHC class I (6) that is expressed in
virtually all tissues of the body (7, 8) (Sedmak, D.D.,
manuscript submitted) and at least in mammals and birds
(9). Its crystal structure shows that the peptide groove is too
narrow to bind ligand; rather, Fc fragments interact with an
adjacent surface of the molecule in a manner that may, under appropriate circumstances, permit two receptors to bind
a single IgG ligand (10). The 100-fold gain in affinity
between pH 7 and 6 is accounted for by critical histidines
near the site of ligand-receptor interaction (13).
2m-deficient mice.
These mice are FcRn deficient as well (14), and because of
this deficiency are unable to absorb IgG from milk as neonates (15), are IgG deficient as adults (15), and catabolize IgG several times the normal rate (20) (Roopenian,
D.C., manuscript submitted), but apparently have normal
concentrations of the other Ig classes and normal rates of
IgG synthesis (21). The broad outline and many details of
IgG catabolism and FcRn-mediated transport have recently
been reviewed (23). An important point that needs now to
be established is how this receptor might participate in certain diseases.
2m-deficient mice. In the genetically determined lpr/lpr
model, wherein the affected mice develop both marked
lymphoproliferation and an SLE-like syndrome consisting
of hypergammaglobulinemia, autoantibody production, and
glomerulonephritis, the lack of
2m appears to protect
against both the SLE syndrome and the lymphoproliferative response (18, 19, 24). Although the absence of
MHC class I molecules sufficiently explains abrogation of
the lymphoproliferative response, it has never satisfactorily
accounted for protection from the SLE syndrome (19).
Similarly, in a second model of SLE, induced by the infusion of a specific anti-idiotype antibody, the absence of
2m protects against the disease (27). Noting that
2m-deficient mice are IgG deficient (15), we propose that
they are protected against the SLE syndrome because, lacking FcRn, they rapidly catabolize their pathogenic IgG autoantibodies.
2m-deficient mice are resistant
to experimental bullous pemphigoid (BP). BP is an autoimmune skin disorder characterized by subepidermal blisters
and autoantibodies directed against two hemidesmosomal
antigens, BP230 and BP180 (28). The experimental mouse
model of BP that involves the passive transfer of anti-mBP180 antibodies into neonatal BALB/c mice reproduces all key immunopathological features of human BP;
namely, IgG and complement deposition at the basement
membrane zone (BMZ), inflammatory infiltration of the
upper dermis, and subepidermal blister formation (29). The subepidermal blistering in experimental BP is initiated by
anti-mBP180 IgG and is dependent on complement activation and neutrophil recruitment (30, 31, 31a).
2m-deficient and normal mice to experimental BP and compared the clinical, histological, and immunological manifestations. Herein, we describe those experiments.
2m
/
MRL/MpJ-B2mtm1Unc/Dcr and C57BL/6J-B2mtm1Unc/
Dcr mice were produced as described (19).
2m
/
neonates
were produced from an F1 cross of MRL/MpJ-B2mtm1Unc × C57BL/6J-B2mtm1Unc mice. Genetically matched
2m+/
(wild-type) mice were produced from an F1 cross of MRL/MpJ-
B2mtm1Unc × C57BL/6J-B2m+/+ mice. The animals were bred at
The Jackson Laboratory and litters were delivered at the Medical
College of Wisconsin Animal Resource Center. Neonatal mice
(24-36 h old with body weights between 1.4 and 1.6 g) were
used for passive transfer experiments.
)2 (Cappel Laboratories, Durham, NC) and read at OD492nm against a standard curve (Bio-Rad EIA reader, model 2550).
2m
/
mice. When neonatal BALB/c (n = 5), C57BL/6J (n = 5),
and
2m+/
(n = 5) mice were injected intraperitoneally
with pathogenic anti-mBP180 IgG (2.5 mg/g body
weight), as expected, these animals developed extensive
blisters 24 h after injection (Fig. 1 A; Table 1). The skin of
these animals was markedly erythematous and, upon gentle
friction, developed persistent epidermal wrinkling due to
epidermal detachment from underlying dermis. Direct IF of cryosections of lesional and peri-lesional skin showed in
vivo deposition of rabbit IgG and mouse C3 at the dermal-
epidermal junction (Fig. 1 B). H/E stained sections from
these mice showed dermal-epidermal separation with neutrophilic infiltration (Fig. 1 C). In contrast,
2m
/
mice
(n = 5) exhibited no blisters 24 h after injection with an
identical dose of pathogenic anti-mBP180 IgG (Fig. 1 D).
Direct IF also showed a significant reduction in in situ deposition of rabbit IgG and mouse C3 at the BMZ (Fig. 1 E).
H/E staining of the skin sections from injected mice exhibited no epidermal detachment from the dermis and a neutrophilic infiltrate milder (Fig. 1 F) than positive control
mice. Quantitation of neutrophilic infiltration with the
MPO assay showed significant changes in the extractable enzyme activity at the injected site at 24 h after injection, with 0.06 ± 0.01 in
2m
/
mice versus 0.41 ± 0.04 in
BALB/c, 0.38 ± 0.04 in C57BL/6J, and 0.38 ± 0.03 in
2m+/
mice (P <0.001) (Fig. 2). However, there was no
difference in tissue MPO activity in both
2m
/
and
control mice 4 h after intraperitoneal administration of anti-mBP180 IgG (Fig. 2), suggesting that lack of
2m expression did not interfere with neutrophil migration from
circulation into the site of tissue inflammation.
Fig. 1.
Clinical, immunofluorescence,
and histological examination of neonatal
2m
/
and
2m+/
mice injected intraperitoneally with pathogenic rabbit anti-mBP180 IgG. The anti-mBP180 IgG induced extensive blistering disease in
2m+/
mice (A). The skin of these animals showed
linear deposition of rabbit IgG (B) at the
BMZ, as determined by direct IF. Hematoxylin and eosin staining showed epidermal-dermal separation with a neutrophilic infiltrate (C). In contrast, neonatal
2m
/
mice showed no evidence of skin disease
(D). Direct IF showed faint BMZ deposition of rabbit IgG (E). Histologic examination showed no epidermal-dermal separation and little inflammation (F). Dermis (D);
epidermis (E); vesicle (V); site of antibody labeling (arrow). Original magnification, ×400.
[View Larger Version of this Image (137K GIF file)]
2-microglobulin-deficient Mice
Host mice
Injection
route*
Incubation
time (h)
Number
of mice
Disease
activity
BALB/c
i.p.
24
5
2+
BALB/c
i.d.
12
5
3+
C57BL/6J
i.p.
24
5
2+
C57BL/6J
i.d.
12
5
3+
2m+/
i.p.
24
5
2+
2m+/
i.d.
12
5
3+
2m
/
i.p.
24
5
2m
/
i.d.
12
5
2+
*
24 to 36-h-old neonatal 2-microglobulin-deficient (
2m
/
), genetically matched wild-type (
2m+/
), and normal control BALB/c and
C57BL/6J mice were injected intraperitoneally ([i.p.] 2.5 mg IgG/g
body weight) or intradermally ([i.d.] 2.5 mg/g body weight).
Disease activity is scored on a scale of
to 3+. Minus means no detectable skin lesion; 2+ means intense erythema with frank epidermal
detachment sign involving 10-20% of the epidermis in intraperitoneally
injected animals or 10-50% of the epidermis in intradermally injected
animals; 3+ means frank epidermal detachment sign involving 20-50%
of epidermis in intraperitoneally injected animals or >50% of epidermis
in intradermally (i.d.) injected animals. See Materials and Methods for
details.
Fig. 2.
MPO activity (mean ± SEM) of skin extracts from 2m
/
and
2m+/
mice injected intraperitoneally with pathogenic rabbit anti-mBP180 IgG. Neonatal
2m
/
(bars 1 and 2),
2m+/
(bars 3 and 4),
C57BL/6J (bars 5 and 6), and BALB/c (bars 7 and 8) mice received 2.5 mg/g body weight anti-mBP180 IgG. Tissue MPO activity in skin at the
back were determined 4 h (open bars) or 24 h (hatched bars) after IgG administration. n = 5 for each group. *P <0.001, Student's t test for paired
samples (bar 1 versus 3).
[View Larger Version of this Image (41K GIF file)]
2m
/
mice (titer = 1:1,280) than control groups
(titer >1:5,120 for all three groups of mice). ELISA further
demonstrated significant changes in circulating R621 IgG
in
2m
/
mice at different timepoints after injection (Fig.
3). R621 IgG levels in
2m+/
mice were 1.18 ± 0.09, 2.32 ± 0.06, 1.83 ± 0.19, at 6 h, 12 h, 24 h, respectively,
after intraperitoneal injection. In contrast, R621 IgG levels
in
2m
/
mice were 0.89 ± 0.08, 1.40 ± 0.14, 1.04 ± 0.10, at 6 h, 12 h, 24 h, respectively, after intraperitoneal
IgG injection. There were significant reductions of circulating R621 IgG between
2m
/
and
2m+/
at 12 h
(40%; P <0.001) and 24 h (43%; P <0.001) after injection.
Fig. 3.
Time course (6-24 h after injection) of anti-mBP180 IgG
survival in 2m
/
mice.
2m
/
(closed squares) and
2m+/
(closed circles)
mice were injected intraperitoneally with pathogenic rabbit anti-mBP180
IgG and serum samples were collected at 6, 12, and 24 h after injection
and assayed for rabbit IgG by ELISA. n = 5 for each point. *P <0.001,
Student's t test for paired samples.
[View Larger Version of this Image (16K GIF file)]
2m
/
mice. To demonstrate that anti-mBP180 IgG is pathogenic in
2m
/
mice
if it binds to its target antigen sufficiently, neonatal
2m
/
(n = 5),
2m+/
(n = 5), BALB/c (n = 5), and C57BL/6J
(n = 5) mice were administered intradermally pathogenic
anti-mBP180 IgG (5 mg/g body weight). After 12-h incubation, like normal control mice,
2m
/
mice developed
subepidermal blisters, along with in vivo deposition of rabbit IgG and murine C3 at BMZ and neutrophilic infiltration (see Table 1). However, clinical examination showed
that disease activity in
2m
/
mice (2+) was less severe
than in control mice (3+) (Table 1). Direct IF revealed a
less intense staining of BMZ in
2m
/
than in control
mice (data not shown). Quantitation of neutrophilic infiltration by the MPO assay also showed a similar trend, with 0.77 ± 0.08 in
2m
/
mice versus 0.89 ± 0.09 in
2m+/
mice (Fig. 4). At 12 h after injection, circulating anti-mBP180 IgG levels in
2m
/
were 77% of those in
2m+/
mice (Fig. 5). Indirect IF of sections of skin from uninjected
2m
/
and normal control mice indicated that the
pathogenic rabbit antibody bound the basement membrane
zone with equal intensity and pattern (data not shown), indicating that the absence of
2m did not prevent binding of
the pathogenic antibody to its target.
Fig. 4.
MPO activity (mean ± SEM) of skin extracts from 2m
/
and
2m+/
mice injected intradermally with pathogenic rabbit anti-mBP180 IgG. Neonatal
2m
/
(bar 1),
2m+/
(bar 2), C57BL/6J (bar
3), and BALB/c (bar 4) mice received 2.5 mg/g body weight anti-mBP180 IgG. Tissue MPO activity in skin at the back were determined
12 h after IgG administration. n = 5 for each group. *P <0.001, Student's
t test for paired samples (bar 1 versus 2).
[View Larger Version of this Image (69K GIF file)]
Fig. 5.
Serum anti-mBP180 IgG levels in 2m
/
mice after intradermal injection. Neonatal
2m
/
(bar 1),
2m+/
(bar 2), C57BL/6J (bar
3), and BALB/c (bar 4) mice were injected intradermally with 2.5 mg/g
body weight anti-mBP180 IgG and serum samples were collected 12 h after injection and assayed for rabbit IgG by ELISA. n = 5 for each point.
[View Larger Version of this Image (67K GIF file)]
2m expression
were protected from experimental BP when the pathogenic antibody was administered intraperitoneally, whereas
the skin of these mice was readily susceptible to the inflammatory effects of the antibody given intradermally. These
findings are predicted by the hypothesis that in
2m-deficient mice, the amount of pathogenic anti-BP antibody reaching the epidermal target site is greatly reduced because the antibody is eliminated rapidly by systemic catabolic
mechanisms. A milder pathologic reaction thus ensues.
Conversely, the systemic expression of FcRn in
2m-intact
mice protects IgG, including the pathogenic antibody,
from catabolism, thereby maintaining an effective pathogenic dose. The cellular mechanism for IgG degradation postulated by Brambell (1) and subsequently elaborated (reviewed in reference 23) sufficiently explains this observation. It is proposed that IgG is pinocytosed nonspecifically
into an acidic endosomal compartment where it encounters
and binds FcRn at low pH. At this point the transport
pathway forks. Those endosomes bearing FcRn complexed
with IgG move through the cell to be expressed on the cell
surface where at physiologic pH the ligand dissociates from
FcRn and is free to circulate in the animal or to be pinocytosed by the cell again for recycling. Pinocytosed IgG that
does not bind to the endosomal FcRn (because of receptor
saturation or by chance) is moved to lysosomes for enzymatic degradation. It has been calculated that an IgG molecule is degraded every eighth pass through this recycling
pathway (21). Which cells might be responsible for IgG
degradation is not yet clear. To date, a variety of cells of
humans have been shown to express the receptor including
endothelium and the syncytiotrophoblast (8, 36) (Sedmak,
D.D., manuscript submitted). We know of no data suggesting that our findings on experimental BP could be the result of other functional defects of the
2m-deficient mice;
specifically, those defects resulting from the lack of MHC
class I, CD1 (37), HFE (38), and perhaps others.
2m-deficient mice than in
normal mice. In the absence of FcRn, such antibody would
be expected to be degraded more rapidly, and therefore be
less damaging, than when given to normal mice. Considering the findings of others, we would propose that FcRn
deficiency accounts for several observations in
2m-deficient mice; viz, both acute (19) and chronic (18, 26, 27)
(Roopenian, D.C., manuscript submitted) forms of the
SLE syndrome, the low titers of virus-specific IgG seen after vaccinia inoculation (16), and DNP-specific IgG responses generated to both T-dependent and -independent
antigens (Roopenian, D.C., manuscripts submitted).
Address correspondence to Dr. Liu, 8701 at the University of Wisconsin, Watertown Plank Rd., Milwaukee, WI 53226. Phone: 414-456-4082; FAX: 414-266-8673; E-mail: zhiliu{at}post.its.mcw.edu; Dr. Roopenian, The Jackson Laboratory, Bar Harbor, ME 04609. Phone: 207-288-6396; FAX: 207-288-6079; E-mail: dcr{at}aretha.jax.org; and Dr. Anderson, 2054 Davis Research Center, 480 West Ninth Ave. Phone: 614-293-4819; FAX: 614-293-5631; E-mail: anderson.48{at}osu.edu
Received for publication 18 March 1997 and in revised form 27 May 1997.
1 Abbreviations used in this paper:This work was supported in part by United States Public Health Service grants R29-AI40768 (Z. Liu), RO1-AR32599 (L.A. Diaz), R37-AR32081 (L.A. Diaz), RO1-AI24544 (D.C. Roopenian), RO1-AI32744 (D.D. Sedmak and C.L. Anderson), and RO1-HD35121 (C.L. Anderson) from the National Institutes of Health, a Dermatology Foundation Research Grant (Z. Liu), and a grant from the Pediatrics AIDS Foundation (C.L. Anderson).
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