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* The Jackson Laboratory, Bar Harbor, ME 04609; and
Ohio State University, Columbus, OH 43210
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1–2 days). In contrast, the t1/2 of most IgG Abs is considerably longer (6–8 days in mice (1) and 22–23 days in humans (2)), increasing the availability of sufficient specific IgG to resolve infection. This homeostatic mechanism is absolutely dependent on the Fc region of IgG (reviewed in Ref. 3). Exploiting this mechanism has additionally proven to be an important component of drug design in that the coupling of IgG Fc to therapeutic proteins considerably extends their pharmacokinetics (3).
Brambell (4) hypothesized many years ago that perinatal transport and IgG homeostasis were consistent with receptor-mediated events, and proposed that a similar receptor might be responsible for both functions. The best candidate for Brambell’s common receptor is the so-called neonatal FcR (FcRn),3 originally identified by Simister and colleagues (5, 6). FcRn is a distant member of the MHC class I protein family, most members of which act as ligands for T cell and NK receptors. However, FcRn has diverged evolutionarily to bind the hinge region of IgG Fc at a low pH (6–6.5) (7). FcRn is highly expressed in the neonatal rodent gut and, more weakly, in adult tissues such as the vascular endothelium, where it is thought to perform its IgG protection function (8). Intracellularly, FcRn resides primarily in the early acidic endosomal vesicles, where it is thought to bind and then recycle endocytosed IgG normally destined for endosomal degradation (9, 10, 11).
Because a functional FcRn molecule is dependent on dimerization with 
2-microglobulin (2m), the obligate L chain of all class I proteins, 2m-deficient mice have been used as a model for understanding the in vivo biology of FcRn. However, this model is encumbered by the many immunological and nonimmunological processes dependent on this common class I L chain, including the elaboration of CD8 T cells, natural T cells, conventional NK cells (reviewed in Ref. 12), the control of serum iron concentration (13), and neuronal plasticity (14). 2m-deficient neonatal mice fail to take up maternal IgG (15), and their adult counterparts have an abnormally short IgG t1/2 and reduced homeostatic IgG levels (16, 17, 18). Studies have variably reported that IgG responses to antigenic stimuli are reduced (16, 19) or increased (20, 21) in 2m-deficient mice, and similarly variable effects have been reported in mouse models for autoimmune diseases with an Ab etiology (16, 22, 23, 24, 25, 26) (D. Roopenian, manuscript in preparation). The phenotypes imposed in vivo as a direct consequence of FcRn thus remain to be established.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To produce a standard FcRn targeting vector, a 2.7-kb 129/J-derived genomic BamHI fragment carrying sequences 5' of the FcRn transcriptional start site was inserted upstream of PGK-Neor into a pGTN/28 targeting vector (New England Biolabs, Beverly, MA), and a 5.2-kb fragment starting at the ApaI site in exon 2 was inserted 3'. The 129/SvJ-derived ESV/J-1182 embryonic stem cells (Genome Systems, St. Louis, MO) were electroporated with the NotI-linearized targeting construct. DNAs from clones surviving G418 selection were digested with EcoRV for Southern blot screening for homologous recombination of the 5' targeting vector arm and with EcoRV + HindIII for recombination of the 3' arm. PCR amplicons based on DNA sequences immediately 5' and 3' of the targeting vector arm were then used as probes for Southern blotting, and identified embryonic stem cell clone 573 carried the predicted 5' and 3' restriction fragment. After genotypic confirmation, clone 573 was injected into C57BL/6J (B6) blastocysts and implanted into pseudopregnant B6 mice by The Jackson Laboratory Cell Biology and Microinjection Service. Chimeric mice and their germline transmitting progeny were typed by PCR using primers designed to distinguish the targeted from the wild-type (wt) FcRn alleles: FcRn o393 F-GGGATGCCACTGCCCTG, FcRn vs o394 R-CGAGCCTGAGATTGTCAAGTGTATT, 248-bp wt allele; targeting vector o395 F-GGAATTCCCAGTGAAGGGC vs o394, 378-bp targeted allele. Protein expression of both mouse FcRn and the human FcRn transgene (see below) was determined by Western blot analysis using an antiserum produced by immunizing FcRn-deficient mice with recombinant, bacterially expressed human FcRn in CFA, followed by boosts with the same protein in IFA. Protein extracts (25 µg) from neonatal small intestine were separated on a 4–20% gradient gel, transferred to polyvinylidene difluoride membrane, and incubated with antiserum against FcRn as a primary Ab and HRP-conjugated goat anti-mouse Ig (BD Biosciences, San Diego, CA) as a secondary Ab. -actin was revealed using a rabbit anti-mouse -actin antiserum (Sigma-Aldrich, St. Louis, MO) and a HRP-conjugated donkey anti-rabbit F(ab')2 (Amersham Biosciences, Piscataway, NJ) as a secondary Ab. Bands were visualized by ECL detection. To produce mice transgenically expressing a complete human FcRn gene, a 34-kb XhoI fragment was excised from a human-derived bacterial artificial chromosome (Genome Systems) and cloned into a SuperCos vector (Stratagene, La Jolla, CA). This fragment, which encompasses the complete 11-kb FcRn gene plus 10-kb 5' and 3', was microinjected into zygotes from C57BL/6J female mice, and implanted into pseudopregnant female mice. A chimeric, germline transmitting male founder was used to establish the C57BL/6J-human FcRn transgenic line 44. Expression of human FcRn was confirmed by RT-PCR (not shown) and by Western blot analysis. Unless otherwise indicated, mice ranged from 6 to 12 wk of age and were age and sex matched within each experiment. FcRn-/- mice used as indicated were either mixed 129:B6 stocks, congenic B6 background (generated after five backcross generations), or isogenic 129/J background stocks. FcRn-/- human FCRN transgenic mice were on a mixed 129:B6 genetic background.
Ig transfer and clearance
For maternal Ig transfer, a female FcRn+/- mouse was mated to a male FcRn-/- mouse. At 17 days of gestation, the pregnant female was injected i.v. with 500 µg IgG1 anti-trinitrophenyl (TNP) (mAb 1B7.11) tracer Ab. Sera from her 3-day-old pups were assayed for anti-TNP Ab activity by ELISA, and their liver DNA was used to determine their FcRn genotypes. Ig clearance in adult mice was determined as described (16). Briefly, 100 µg of mouse IgG1 anti-TNP, mouse IgA anti-TNP (mAb 2F.11.15), purified human IgG (GammaGuard; Baxter Healthcare, Deerfield, IL), or directly biotinylated mouse IgG1, IgG2a, IgG2b, and IgG3 (Sigma-Aldrich) tracer was injected into mice i.p., and sera prepared from retro-orbital plexus blood were assayed by ELISA. -phase Ig tracer clearance was based on the amount of Ig retained normalized to that present 24 h after injection.
Serum Ig concentrations and flow cytometry
Total serum Ig and specific mouse isotypes were quantified as described (16, 22). Total Ig and isotype quantification was based on duplicate serum dilutions in which at least two dilutions hit the exponential curve of serially diluted Ig standards: Ig (Calbiochem, San Diego, CA), IgG1 (BD PharMingen, San Diego, CA), IgG2a (PharMingen), IgG2b (Southern Biotechnology, Birmingham, AL), IgG3 (Southern Biotechnology), IgM (BD PharMingen), and IgA (Southern Biotechnology). Data are expressed as equivalents of Ig compared with the Ab standards. For flow cytometry, splenocytes or bone marrow cells were isolated and incubated with propidium iodide and specific conjugated Abs at 4°C for 50 min in staining buffer (1x PBS with 0.1% BSA and 0.1% sodium azide), washed twice, and then analyzed with live cell gating using a FACSCalibur equipped with CellQuest software (BD Biosciences). Conjugated mAbs, CD4 CY3+, CD8a PE, CD45R/B220 APC, CD45R/B220 Cy5, CD19 FITC, and CD138 APC, were obtained from BD Pharmingen.
Quantitative PCR analysis and 5' RACE
Tissues were collected into RNALater (Ambion, Austin, TX), and total RNA was purified using the RNAqueous 4-PCR kit (Ambion) and DNase treated. Synthesis of cDNA from 5–10 µl total RNA was conducted using the Retroscript kit (Ambion). For FcRn expression analysis, PCR primers MuFcRn.5F, 5'-CCTCAAGACCCTGGAGAAGATATTAA-3'; MuFcRn.5R, 5'-CCGTGGGCACTGAGGAATTA-3'; and a TaqMan probe MuFcRn.5P, 5'-6FAM-CTGCTGGGCTGTGAACTGGCCTC-TAMRA-3', were used to amplify and detect a 94-bp cDNA fragment spanning FcRn exons 3 and 4. Reactions (in triplicate) containing the equivalent of 0.5 µl cDNA in the presence of TaqMan PCR Master Mix were run in duplex with the TaqMan 18S Ribosomal RNA Control (Applied Biosystems, Foster City, CA), and the ABI Prism 7700 was used for real-time detection. Mean Ct were calculated; the FcRn expression levels were determined via the ddCt method (Applied Biosystems User Bulletin 2); and expression levels are represented relative to skeletal muscle. The ImmunoQuantArray customized gene expression platform, including the list of genes analyzed and the Global Pattern Recognition (GPR) expression analytical algorithm, has been described4 (http://www.jax.org/research/roop/). The 5' RACE of liver cDNA was performed using Ambion 5' mRNA oligonucleotide adaptors and exon 5 FcRn outer and inner exon 4/5 junction reverse primers. No fragments were detected after 38 amplification cycles using the outer oligonucleotide primers, and only fragments with sizes inconsistent with the expected normal FcRn transcript size were detected with FcRn-/- mice cDNAs after the 38-cycle amplification using the nested primers. These fragments were cloned, sequenced, and proved to be from transcripts unrelated to FcRn.
Specific Ab responses after immunization and ELISPOT
Mice were immunized and challenged with 100 µg DNP-keyhole limpet hemocyanin (KLH) (Calbiochem, San Diego, CA), and sera from retro-orbital plexus blood were assayed for anti-DNP activity, as described (16). For ELISPOT, MultiScreen-HA plates (Millipore, Bedford, MA) were coated with 10 µg/ml of either DNP-KLH, goat anti-mouse IgG, or 100 µg/ml BSA in ELISA coating buffer at 4°C overnight. The plates were then washed three times with PBS and blocked with DMEM medium containing 5% FBS for 1 h at room temperature. Serial dilutions (starting at 1 x 106 cells/well) of spleen and bone marrow cells were added to the wells. The plates were incubated at 37°C with 5% CO2 overnight and washed three times with PBS-Tween; Goat anti-mouse
-alkaline phosphatase (0.5 µg/ml; Southern Biotechnology) was then added to each well. After a 1-h incubation at 37°C, the plates were washed three times with PBS-Tween, followed by PBS and chromogen substrate 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium (Sigma-Aldrich). The plates were then incubated in the presence of chromogen substrate at room temperature for 1 h, and the reaction was terminated by a water wash. Data are reported as the number of spots enumerated in the Ab-coated wells minus those obtained with the corresponding BSA-coated plates.
Costimulator blockade
B6-FcRn-/- and B6 wt control mice were injected i.p. on day -3 with PBS or 20 µg purified CTLA-4 Ig (27) and 20 µg anti-CD40 ligand (CD40L) IgG1 (28) in PBS (kindly provided by B. Soper, The Jackson Laboratory), grafted 1 day later with allogeneic 129/J tail skin, and injected with 12 µg purified CTLA-4 Ig and 12 µg anti-CD40L IgG1 3 days later. Graft survival was scored according to the method of Bailey and Usama (29), and analyzed by Kaplin-Meier Analysis (StatView; Abacus Concepts, Berkeley, CA).
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Results |
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To address the role of FcRn in vivo, we used gene targeting to produce mice with a defective FcRn gene. Homologous recombination resulted in the insertion of a neomycin-resistance cassette and the deletion of a 1588-nt fragment that encompassed the promotor and extended through most of exon 2 to the ApaI site (Fig. 1, A and B). Quantitative PCR of cDNA from livers indicated that FcRn-/- mice produced a minimal signal (Fig. 1C), and extensive 5' RACE analysis failed to detect any FcRn-specific transcript (Fig. 1D and data not shown). Western blot analysis of neonatal intestine extracts probed with an anti-FcRn antiserum failed to reveal any hybridized product (Fig. 1E).
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2m-deficient mice, which are prone to perinatal lethality (D. Roopenian, unpublished data), FcRn-/- mice showed no evidence of a failure to thrive. Adult FcRn-/- and wt mice were indistinguishable based on weight and overt health. Histological analysis of liver, lungs, kidneys, and lymphoid organs of adult FcRn-/- mice was normal (data not shown). FcRn is the receptor required for perinatal IgG transport
To determine directly whether FcRn is responsible for perinatal transfer of maternal IgG, a female FcRn+/- mouse was mated to a male FcRn-/- mouse. In this way, the mother would be FcRn sufficient, while her progeny would be either FcRn-/- or wt. To track maternal IgG transmission, the pregnant female was injected i.v. at 17 days of gestation with anti-TNP IgG1. Her pups were then nursed on the same FcRn+/- mother. Her 3-day-old pups were genotyped for FcRn, and their sera were assayed for anti-TNP Ab activity by ELISA. Anti-TNP IgG1 was evident in sera from wt FcRn+/- neonates, but lowered a minimum of 190-fold in the FcRn-/- littermates (Fig. 2A). Although human neonates acquire their maternal IgG by transplacental routes, neonatal mice acquire most maternal IgG by transintestinal transport (30). Our results suggest that this FcRn-null allele functionally ablated perinatal IgG transport. However, they do not distinguish between the maternofetal vs transintestinal routes.
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To determine whether FcRn is responsible for the extended t1/2 of IgG, adult FcRn-/- and FcRn-/+, as well as 2m-deficient mice, were injected with tracer anti-TNP IgG1 and IgA Abs, and serial blood samples were tested for the amount of tracer remaining. In FcRn wt mice, the t1/2 of the IgG1 tracer (9 days) was predictably greater in comparison with the IgA tracer (1.4 days) (Fig. 2B). In contrast, the IgG1 t1/2 was considerably shortened in both FcRn-/- (1.4 days) and 2m-/- mice (1.0 days). The small difference in FcRn-/- vs 2m-/- t1/2 was significant (p = 0.004 at day 5), and was observed in multiple experiments. FcRn protected all mouse IgG isotypes, because FcRn-/- and 2m-/- mice demonstrated rapid clearance of biotinylated mouse IgG1, IgG2a, IgG2b, and IgG3 in comparison with wt mice (Fig. 2C). Moreover, human IgG was cleared rapidly in FcRn-/- mice, but it was protected in FcRn-/- mice onto which a human FcRn transgene had been crossed (Fig. 2D). These results indicated that both mouse and human FcRn play an important role in extending the t1/2 of IgG.
To determine the effects of FcRn deficiency on maintaining homeostatic Ab levels, serum Ig concentrations were determined in FcRn-/- and wt mice on an isogenic 129/J background. FcRn-/- mice had reduced concentrations of all IgG isotypes compared with their wt sex-matched counterparts, but IgM and IgA concentrations did not differ significantly from wt controls (Fig. 3). These results indicated that FcRn plays an important role in IgG homeostasis.
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To determine whether an FcRn deficiency affects the normal immunological status, FcRn-deficient and wt mice were subjected to a battery of phenotypic tests. We first tested whether an FcRn deficiency affects the transcriptional profile of immunologically important genes. RNA samples isolated from spleens and lungs of three replicate 129 mice isogenic for FcRn-/- and three 129-FcRn wt controls were analyzed using an ImmunoQuantArray, a quantitative PCR-based method that allows one to measure simultaneously the expression of 95 genes selected because they play significant roles in immune homeostasis and function.4 Of the genes surveyed, only FcRn showed a significant difference by the global pattern recognition analytical algorithm (Table I). Thus, FcRn deficiency leads to negligible alterations of the transcriptional immunological phenotype.
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To determine the consequences of an FcRn deficiency on a specific humoral immune response, FcRn-/- and wt C57BL/6 (B6) and 129 background mice were immunized and then challenged 3 wk later with DNP-KLH, and their serum anti-DNP-specific Ig titers were determined. FcRn deficiency on B6 background mice reduced substantially the specific anti-DNP response regardless of IgG Ig isotype (Fig. 4A). This decrease was not a consequence of numbers of plasma cells because TNP-KLH-immunized FcRn-/- and wt mice showed similar numbers of anti-IgG- and anti-TNP-secreting cells by ELISPOT analysis (Table III). On the 129/J background mice, the anti-TNP response was heightened overall, and an FcRn deficiency resulted in a reduction of all anti-DNP IgG isotypes, but it was more episodic compared with B6 background mice (Fig. 4B). Moreover, following immunization, the titers of anti-TNP IgG Abs in 129-FcRn wt mice dropped at an unexpectedly rapid rate given functional FcRn-mediated protection. A more sustained lowering in FcRn-/- mice was observed in total IgG concentrations (Fig. 4C, lower right panel). FcRn protection is known to be saturable at high serum IgG concentrations (half-maximal concentration 5 mg/ml) (31). Immunization of 129 background mice may have induced sufficient hypergammaglobulinemia to exceed the FcRn saturation capacity, thus resulting in an attenuation of FcRn-mediated protection. Taken together, the data suggest that FcRn plays an important role in controlling the concentrations of serum IgG Abs in response to specific antigenic stimuli provided that the concentrations do not exceed the FcRn saturation threshold.
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It is well established that the covalent addition of an IgG-derived Fc moiety prolongs drug t1/2 (3). However, whether this extension is solely dependent on FcRn as compared with other FcR is less clear. To determine directly whether FcRn is the molecule responsible for enhancing the pharmacological efficacy of IgG-coupled therapeutics, we addressed whether mice lacking FcRn were refractory to the immunosuppressive effects of a costimulatory blockade including CTLA-4 Ig and anti-CD40L (both of which possess IgG Fc moieties). B6-FcRn-/- and wt controls were treated with a cocktail of CTLA-4 Ig and anti-CD40L IgG1, and grafted with allogeneic 129/J tail skin (Fig. 5). The rate of allograft rejection by FcRn-deficient mice was retarded considerably compared with that of FcRn wt controls, and similar to that observed in mice that received PBS rather than the costimulatory blockade. These results indicated that FcRn is the FcR responsible for the enhanced pharmacological efficacy of IgG-Fc-conjugated drugs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2m-deficient mice (15). Moreover, FcRn-deficient mice very nearly matched the IgG homeostasis phenotype first observed in 2m-deficient mice (16, 17, 18, 32). However, in multiple experiments, these mice do show a slightly increased IgG serum t1/2 compared with 2m-deficient mice. We were unable to detect any FcRn transcription by 5' RACE or translated product by Western blot analysis (Fig. 1E), arguing against a leaky mutation. It is thus possible that other 2m-dependent proteins act weakly to stabilize IgG. Nevertheless, the results prove unequivocally that FcRn is a critical receptor for both perinatal IgG transport and for extending the t1/2 of IgG Abs in adults.
Until now, the only in vivo model to assess the function of FcRn was using mice deficient in the 2m common L chain. It has therefore been difficult to dissociate the biology imposed by FcRn from that of many other 2m-dependent class I molecules. The FcRn H chain-deficient mice reported in this work make it possible to understand the role of FcRn in vivo. The absence of FcRn did not lead to significant aberrations in the induction of T or B cell responses. However, it diminished the ability to retain normal concentrations of serum IgG. Moreover, the serum concentrations of IgG Abs available after immunization were considerably diminished, while the number of IgG Ab-secreting plasma cells was unchanged. Although we cannot formally exclude the possibility that an FcRn deficiency decreases the amount of IgG secreted by each plasma cell, it is far more likely that the diminished IgG levels are a consequence of excessive IgG clearance. In any case, FcRn plays a pivotal role in maximizing the IgG Abs available for humoral effector mechanisms of immunity. Thus, situations in which 2m-deficient mice are unable to clear viruses efficiently (reviewed in Ref. 12) and are less able to engender protective immunity after immunization (33) could at least in part be explained by their concurrent deficiency in FcRn-mediated protection. A similar explanation can be extended for findings that a 2m deficiency ameliorates humoral pathology associated with systemic lupus erythematosus-like autoimmune diseases and bullous pemphigoid (16, 22, 23, 26, 34, 35). Thus, therapeutics designed to specifically block FcRn could prevent Ab-mediated effector mechanisms normally leading to autoimmune disorders.
This ability of FcRn to conserve IgG has important implications for pharmacological design. Although it is well established that therapeutic IgG Abs and proteins designed to include the Fc region of IgG show improved serum persistence, our studies are the first to show the critical involvement of FcRn to achieve therapeutic efficacy of such molecules. Previous work has shown that the serum persistence of mouse IgG molecules can be shortened or extended by altering hinge region amino acids thought to affect FcRn interaction sites, suggesting that engineering to enhance the FcRn-Fc interaction could lead to more efficacious drugs (reviewed in Ref. 36). Because mouse and human FcRn show differing isotype and species affinity (37) (D. Roopenian, unpublished data), mice deficient in mouse FcRn and transgenic for human FcRn are especially suited for such therapeutic development.
FcRn is a remarkable example of the functional plasticity of class I family proteins. Through minimal structural changes, FcRn has acquired a specialized Fc-binding function (38), resulting in IgG transport and stabilization. The role of IgG Abs in infectious and autoimmune diseases is unresolved. Models in which B cells are depleted, ablated, or developmentally compromised do not directly address this issue because B cells are important for cognate Ag presentation functions as well as acting as precursors for plasma cells. The discrete IgG-lowering phenotype of FcRn-deficient mice should be useful in addressing this central issue.
Note added in proof. We have recently found that FcRn extends the T1/2 of albumin (39).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Derry Roopenian, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609. E-mail address: dcr{at}jax.org
3 Abbreviations used in this paper: FcRn, neonatal FcR; 2m, 2-microglobulin; CD40L, CD40 ligand; KLH, keyhole limpet hemocyanin; TNP, trinitrophenyl; GpR, Global Pattern Recognition; wt, wild type.
4 S. Akilesh, D. J. Shaffer, D. C. Roopenian. Customized molecular phenotyping by quantitative gene expression and pattern recognition analysis. Submitted for publication.
Received for publication October 30, 2002. Accepted for publication January 23, 2003.
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2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. USA 93:5512.2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc. Natl. Acad. Sci. USA 89:6070.2-microglobulin gene. J. Virol. 67:332.2 microglobulin dependence of lupus-like autoimmune syndrome of MRL-lpr mice. J. Immunol. 176:4933.
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2-microglobulin-deficient mice are resistant to bullous pemphigoid. J. Exp. Med. 186:777.Related articles in The JI:
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H. Crowley, J. Alroy, T. J. Sproule, D. Roopenian, and B. T. Huber The MHC class I-related FcRn ameliorates murine Lyme arthritis Int. Immunol., March 1, 2006; 18(3): 409 - 414. [Abstract] [Full Text] [PDF]
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 K. M. Chung, G. E. Nybakken, B. S. Thompson, M. J. Engle, A. Marri, D. H. Fremont, and M. S. Diamond Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc {gamma} Receptor-Dependent and -Independent Mechanisms J. Virol., February 1, 2006; 80(3): 1340 - 1351. [Abstract] [Full Text] [PDF]
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 J. Kim, C. L. Bronson, W. L. Hayton, M. D. Radmacher, D. C. Roopenian, J. M. Robinson, and C. L. Anderson Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces Am J Physiol Gastrointest Liver Physiol, February 1, 2006; 290(2): G352 - G360. [Abstract] [Full Text] [PDF]
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