Exploiting the neonatal crystallizable fragment receptor to treat kidney disease

The neonatal crystallizable fragment receptor (FcRn) was initially discovered as the receptor that allowed passive immunity in newborns by transporting maternal IgG through the placenta and enterocytes. Since its initial discovery, FcRn has been found to exist throughout all stages of life and in many different cell types. Beyond passive immunity, FcRn is necessary for intrinsic albumin and IgG recycling and is important for antigen processing and presentation. Given its multiple important roles, FcRn has been used in many disease treatments including a new class of agents that were developed to inhibit FcRn for the treatment of a variety of autoimmune diseases. Certain cell populations within the kidney also express high levels of this receptor. Specifically, podocytes, proximal tubule epithelial cells, and vascular endothelial cells have been found to use FcRn. In this review, we summarize what is known about FcRn and its function within the kidney. We also discuss how FcRn has been used for therapeutic benefits, including how newer FcRn inhibiting agents are being used to treat autoimmune diseases. Lastly, we will discuss which kidney diseases may respond to FcRn inhibitors and how further work studying FcRn within the kidney may lead to therapies for kidney diseases. The neonatal crystallizable fragment receptor (FcRn) was initially discovered as the receptor that allowed passive immunity in newborns by transporting maternal IgG through the placenta and enterocytes. Since its initial discovery, FcRn has been found to exist throughout all stages of life and in many different cell types. Beyond passive immunity, FcRn is necessary for intrinsic albumin and IgG recycling and is important for antigen processing and presentation. Given its multiple important roles, FcRn has been used in many disease treatments including a new class of agents that were developed to inhibit FcRn for the treatment of a variety of autoimmune diseases. Certain cell populations within the kidney also express high levels of this receptor. Specifically, podocytes, proximal tubule epithelial cells, and vascular endothelial cells have been found to use FcRn. In this review, we summarize what is known about FcRn and its function within the kidney. We also discuss how FcRn has been used for therapeutic benefits, including how newer FcRn inhibiting agents are being used to treat autoimmune diseases. Lastly, we will discuss which kidney diseases may respond to FcRn inhibitors and how further work studying FcRn within the kidney may lead to therapies for kidney diseases. The neonatal crystallizable fragment receptor (FcRn) is now known to not only be the receptor needed for passive transfer of immunity across the placenta but also has been found to be essential for recycling or transcytosis of albumin and monomeric IgG in a variety of cells. Thus, FcRn is the molecule responsible for the long half-lives of these serum proteins. FcRn is also required in trafficking immune complexes (ICs) to the lysosome for proteolytic degradation of ICs and antigen presentation on major histocompatibility complex II (MHCII), thereby playing a key role in adaptive immunity. The multifaceted functions of FcRn are now being used to create therapeutics for autoimmune diseases in which circulating antibodies play a pathogenic role. In this review, we will describe the structure and function of FcRn. We will focus on this receptor's role in the kidney and describe how modulation of FcRn is being used to create therapies with the potential to treat kidney diseases. The existence of the FcRn was first proposed by Brambell1Brambell F.W. The transmission of immunity from mother to young and the catabolism of immunoglobulins.Lancet. 1966; 2: 1087-1093Abstract PubMed Google Scholar in 1966 as the molecule responsible for the passive transfer of immunity between the mother and fetus. The actual receptor was eventually purified from the rat's intestine by Simister and Mostov2Simister N.E. Mostov K.E. An Fc receptor structurally related to MHC class I antigens.Nature. 1989; 337: 184-187Crossref PubMed Scopus (638) Google Scholar in 1989. The human FcRn heavy chain gene (Fcγ receptor and transporter gene, FCGRT) is located on chromosome 19. The original sequencing of FCGRT found that the gene contained 7 exons and 6 introns, with exons 2 to 5 encoding the signal sequence and extracellular α1-α2-α3 domains, exon 6 encoding the transmembrane domain, and exon 7 encoding the cytoplasmic tail.3Mikulska J.E. Pablo L. Canel J. Simister N.E. Cloning and analysis of the gene encoding the human neonatal Fc receptor.Eur J Immunogenet. 2000; 27: 231-240Crossref PubMed Scopus (32) Google Scholar Subsequent sequence data from the Human Genome Project contain 10 exons instead of the 7 originally proposed.4International Human Genome Sequencing ConsortiumFinishing the euchromatic sequence of the human genome.Nature. 2004; 431: 931-945Crossref PubMed Scopus (3689) Google Scholar FCGRT orthologues exist in most species with high interspecies conservation at the amino acid level. The FcRn heavy chain, which has significant homology to MHC class I molecules, associates noncovalently with ß2-microglobulin to form a heterodimer.2Simister N.E. Mostov K.E. An Fc receptor structurally related to MHC class I antigens.Nature. 1989; 337: 184-187Crossref PubMed Scopus (638) Google Scholar Unlike the MHC class I molecule, the peptide binding groove in the FcRn protein is occluded and is thus unable to present antigen.5Burmeister W.P. Gastinel L.N. Simister N.E. et al.Crystal structure at 2.2 A resolution of the MHC-related neonatal Fc receptor.Nature. 1994; 372: 336-343Crossref PubMed Scopus (287) Google Scholar,6Raghavan M. Gastinel L.N. Bjorkman P.J. The class I major histocompatibility complex related Fc receptor shows pH-dependent stability differences correlating with immunoglobulin binding and release.Biochemistry. 1993; 32: 8654-8660Crossref PubMed Scopus (91) Google Scholar The cytoplasmic tail of the FcRn heavy chain contains several conserved sorting motifs that are necessary for correct trafficking of the receptor.7Wu Z. Simister N.E. Tryptophan- and dileucine-based endocytosis signals in the neonatal Fc receptor.J Biol Chem. 2001; 276: 5240-5247Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar A dileucine (L322/L323) and tryptophan motif (W311) have been shown to play a role in endocytosis of FcRn,7Wu Z. Simister N.E. Tryptophan- and dileucine-based endocytosis signals in the neonatal Fc receptor.J Biol Chem. 2001; 276: 5240-5247Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar but these experiments were in a cell line that does not endogenously express FcRn. Another conserved motif within the cytoplasmic tail of the receptor is a calmodulin-binding domain. Mutation of residues in this domain decreased the half-life of FcRn and decreased IgG transcytosis in Madin-Darby canine kidney cells, which also lacks endogenous FcRn expression, suggesting a possible role for calcium/calmodulin regulation of FcRn trafficking. Although other Fcγ receptors have high genetic variability, FCGRT is monomorphic, with variability arising from the variable number of tandem repeat (VNTR) polymorphisms labeled VNTR1 to VNTR5 that lead to variable expression levels of FcRn at the mRNA and protein levels.8Gouilleux-Gruart V. Chapel H. Chevret S. et al.Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.Clin Exp Immunol. 2013; 171: 186-194Crossref PubMed Scopus (52) Google Scholar,9Sachs U.J. Socher I. Braeunlich C.G. et al.A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor alpha-chain promoter.Immunology. 2006; 119: 83-89Crossref PubMed Scopus (86) Google Scholar More recently, 2 additional VNTRs, designated as VNTR6 and VNTR8, have been discovered in a subset of patients with ovarian cancer.10O'Shannessy D.J. Bendas K. Schweizer C. et al.Correlation of FCGRT genomic structure with serum immunoglobulin, albumin and farletuzumab pharmacokinetics in patients with first relapsed ovarian cancer.Genomics. 2017; 109: 251-257Crossref PubMed Scopus (10) Google Scholar Despite its name, the FcRn is expressed at all life stages and is found in epithelial, endothelial, immune cells, keratinocytes, and hepatocytes. It is found in multiple organs including the kidney, intestinal tract, placenta, liver, and hematopoietic system.11Pyzik M. Kozicky L.K. Gandhi A.K. Blumberg R.S. The therapeutic age of the neonatal Fc receptor.Nat Rev Immunol. 2023; 23: 415-432Crossref PubMed Scopus (16) Google Scholar FcRn is predominantly found intracellularly but can be present at the cell surface, particularly in antigen-presenting cells such as monocytes and dendritic cells.12Gan Z. Ram S. Ober R.J. Ward E.S. Using multifocal plane microscopy to reveal novel trafficking processes in the recycling pathway.J Cell Sci. 2013; 126: 1176-1188Crossref PubMed Scopus (36) Google Scholar,13Rath T. Kuo T.T. Baker K. et al.The immunologic functions of the neonatal Fc receptor for IgG.J Clin Immunol. 2013; 33: S9-S17Crossref PubMed Scopus (113) Google Scholar Within the kidney, FcRn is expressed in macrophages, monocytes, dendritic cells, proximal tubular cells (PCT), peritubular capillary endothelial cells, glomerular endothelial cells, and podocytes (Figure 1).14Akilesh S. Huber T.B. Wu H. et al.Podocytes use FcRn to clear IgG from the glomerular basement membrane.Proc Natl Acad Sci U S A. 2008; 105: 967-972Crossref PubMed Scopus (223) Google Scholar, 15Haymann J.-P. Levraud J.-P. Bouet S. et al.Characterization and localization of the neonatal Fc receptor in adult human kidney.J Am Soc Nephrol. 2000; 11: 632-639Crossref PubMed Google Scholar, 16Sarav M. Wang Y. Hack B.K. et al.Renal FcRn reclaims albumin but facilitates elimination of IgG.J Am Soc Nephrol. 2009; 20: 1941-1952Crossref PubMed Scopus (112) Google Scholar, 17Kidney Precision Medicine Project (KPMP)KPMP datasets for "an atlas of healthy and injured cell states and niches in the human kidney".2022Google Scholar, 18Kobayashi N. Suzuki Y. Tsuge T. et al.FcRn-mediated transcytosis of immunoglobulin G in human renal proximal tubular epithelial cells.Am J Physiol Renal Physiol. 2002; 282: F358-F365Crossref PubMed Scopus (109) Google Scholar Whole tissue single-cell RNA sequencing of samples from patients with chronic kidney disease found increasing populations of dendritic cells expressing FcRn.17Kidney Precision Medicine Project (KPMP)KPMP datasets for "an atlas of healthy and injured cell states and niches in the human kidney".2022Google Scholar Interestingly, in the samples of patients with acute kidney injury, populations of descending thin limb cells and phagocytes were noted to express FcRn but were not noted in healthy individuals.17Kidney Precision Medicine Project (KPMP)KPMP datasets for "an atlas of healthy and injured cell states and niches in the human kidney".2022Google Scholar Of note, no significant FcRn expressions in podocytes were reported in the single-cell RNA sequencing data.17Kidney Precision Medicine Project (KPMP)KPMP datasets for "an atlas of healthy and injured cell states and niches in the human kidney".2022Google Scholar However, many other sources have found FcRn expression in podocytes.14Akilesh S. Huber T.B. Wu H. et al.Podocytes use FcRn to clear IgG from the glomerular basement membrane.Proc Natl Acad Sci U S A. 2008; 105: 967-972Crossref PubMed Scopus (223) Google Scholar,15Haymann J.-P. Levraud J.-P. Bouet S. et al.Characterization and localization of the neonatal Fc receptor in adult human kidney.J Am Soc Nephrol. 2000; 11: 632-639Crossref PubMed Google Scholar,19Dylewski J. Dobrinskikh E. Lewis L. et al.Differential trafficking of albumin and IgG facilitated by the neonatal Fc receptor in podocytes in vitro and in vivo.PLoS One. 2019; 14e0209732Crossref PubMed Scopus (15) Google Scholar,20Ichinose K. Ushigusa T. Nishino A. et al.Lupus nephritis IgG induction of calcium/calmodulin-dependent protein kinase IV expression in podocytes and alteration of their function.Arthritis Rheumatol. 2016; 68: 944-952Crossref PubMed Scopus (46) Google Scholar Similarly, the PCT has been reported to express FcRn,15Haymann J.-P. Levraud J.-P. Bouet S. et al.Characterization and localization of the neonatal Fc receptor in adult human kidney.J Am Soc Nephrol. 2000; 11: 632-639Crossref PubMed Google Scholar,16Sarav M. Wang Y. Hack B.K. et al.Renal FcRn reclaims albumin but facilitates elimination of IgG.J Am Soc Nephrol. 2009; 20: 1941-1952Crossref PubMed Scopus (112) Google Scholar,18Kobayashi N. Suzuki Y. Tsuge T. et al.FcRn-mediated transcytosis of immunoglobulin G in human renal proximal tubular epithelial cells.Am J Physiol Renal Physiol. 2002; 282: F358-F365Crossref PubMed Scopus (109) Google Scholar whereas single-cell RNA sequencing data have demonstrated only low levels of expression.17Kidney Precision Medicine Project (KPMP)KPMP datasets for "an atlas of healthy and injured cell states and niches in the human kidney".2022Google Scholar,21Wu H. Uchimura K. Donnelly E.L. et al.Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics.Cell Stem Cell. 2018; 23: 869-881.e868Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar These discrepancies have resulted in some controversy about whether and to what extent these cell types use FcRn. However, these differences may reflect the inherent limitations and difficulty of correlating data using different methods, particularly at the quantitative level. Initially, the primary role for FcRn was believed to be the transporter of IgG across the placenta from the mother to fetus as well as the diversion of monomeric IgG and albumin from the degradative pathway and toward the recycling or transcytotic pathway. This diverting pathway accounted for the long half-lives of these proteins compared with other serum proteins. Subsequent work has shown that FcRn also plays an important role in the trafficking of ICs and in antigen presentation, indicating a key function for this receptor in the immune system. Below, we describe the general mechanisms of FcRn handling of albumin, IgG, and ICs and will then focus specifically on what is known about the role of FcRn in the kidney. FcRn binds to the Fc portion of IgG at acidic pH (5.0–6.5) and with rare exceptions (mouse IgG2b and some human IgG3 allotypes) does not bind at neutral pH.22Raghavan M. Bonagura V.R. Morrison S.L. Bjorkman P.J. Analysis of the pH dependence of the neonatal Fc receptor/immunoglobulin G interaction using antibody and receptor variants.Biochemistry. 1995; 34: 14649-14657Crossref PubMed Scopus (283) Google Scholar,23Rodewald R. pH-dependent binding of immunoglobulins to intestinal cells of the neonatal rat.J Cell Biol. 1976; 71: 666-669Crossref PubMed Scopus (218) Google Scholar At pH approximately 6, residues within the Fc portion of IgG become protonated, allowing for interaction with Glu115 and Asp130 in FcRn.24Medesan C. Matesoi D. Radu C. et al.Delineation of the amino acid residues involved in transcytosis and catabolism of mouse IgG1.J Immunol. 1997; 158: 2211-2217Crossref PubMed Google Scholar, 25Martin W.L. West Jr., A.P. Gan L. Bjorkman P.J. Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding.Mol Cell. 2001; 7: 867-877Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 26Kim J.K. Tsen M.F. Ghetie V. Ward E.S. Identifying amino acid residues that influence plasma clearance of murine IgG1 fragments by site-directed mutagenesis.Eur J Immunol. 1994; 24: 542-548Crossref PubMed Scopus (122) Google Scholar As the pH level rises, the protonation of the binding residues within the Fc portion is lost, leading to disassociation of FcRn and IgG. This mechanism allows for FcRn binding to monomeric IgG in the late endosome/early lysosome and disassociation of the FcRn/IgG complex at the neutral pH of the cell surface, thereby allowing for recycling or transcytosis of monomeric IgG (Figure 2). In endothelial cells, FcRn binding of IgG results in recycling of IgG back to the plasma, whereas in polarized epithelial beds such as intestinal cells, FcRn allows for IgG transcytosis from the basal to apical membrane or vice versa.27Ward E.S. Zhou J. Ghetie V. Ober R.J. Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans.Int Immunol. 2003; 15: 187-195Crossref PubMed Scopus (170) Google Scholar,28Dickinson B.L. Badizadegan K. Wu Z. et al.Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line.J Clin Invest. 1999; 104: 903-911Crossref PubMed Scopus (370) Google Scholar The transcytotic pathway requires the presence of the motor protein myosin Vb, the small GTPase Rab25, and the calcium-dependent kinase calmodulin.29Tzaban S. Massol R.H. Yen E. et al.The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity.J Cell Biol. 2009; 185: 673-684Crossref PubMed Scopus (145) Google Scholar,30Dickinson B.L. Claypool S.M. D'Angelo J.A. et al.Ca2+-dependent calmodulin binding to FcRn affects immunoglobulin G transport in the transcytotic pathway.Mol Biol Cell. 2008; 19: 414-423Crossref PubMed Scopus (46) Google Scholar FcRn is saturable; consequently, when the levels of IgG exceed the binding capability of FcRn, the excess IgG is trafficked to the lysosome and degradation.27Ward E.S. Zhou J. Ghetie V. Ober R.J. Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans.Int Immunol. 2003; 15: 187-195Crossref PubMed Scopus (170) Google Scholar X-ray crystallography has revealed that FcRn binds to monomeric IgG with a 2:1 stoichiometry. Recent work has also found that the fragment antigen binding arms of IgG are also able to bind FcRn although the precise details of these interactions remain elusive.31Schoch A. Kettenberger H. Mundigl O. et al.Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics.Proc Natl Acad Sci U S A. 2015; 112: 5997-6002Crossref PubMed Scopus (141) Google Scholar,32Wang W. Lu P. Fang Y. et al.Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences.Drug Metab Dispos. 2011; 39: 1469-1477Crossref PubMed Scopus (143) Google Scholar FcRn's function has also been studied in vivo, particularly in knockout (KO) mice. Global FcRn KO mice were found to have significantly decreased serum IgG levels compared with wild-type (approximately 0.5 mg/ml in KO compared with 1.5 mg/ml in wild-type), with no decrement in IgA or IgM levels.33Roopenian D.C. Christianson G.J. Sproule T.J. et al.The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs.J Immunol. 2003; 170: 3528-3533Crossref PubMed Scopus (380) Google Scholar The half-life of IgG was also found to be significantly reduced from 9 days in the wild-type to approximately 1.4 days in the global FcRn KOs. Additional studies using bone marrow chimera mice showed that the half-life of IgG was 5.2 days in wild-type animals with wild-type bone marrow compared with 1.3 days in FcRn KOs with KO bone marrow. However, FcRn KO mice with wild-type bone marrow had their IgG half-life extended to 2.3 days.34Akilesh S. Christianson G.J. Roopenian D.C. Shaw A.S. Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism.J Immunol. 2007; 179: 4580-4588Crossref PubMed Scopus (222) Google Scholar Further work using a mouse line with conditional deletion of FcRn in both endothelial and hematopoietic cells found that the half-life of IgG1 in the conditional KO mice was significantly reduced compared with wild-type (8.2 hours vs. 217.8 hours, respectively), whereas the half-life of IgA was not affected.35Montoyo H.P. Vaccaro C. Hafner M. et al.Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice.Proc Natl Acad Sci U S A. 2009; 106: 2788-2793Crossref PubMed Scopus (169) Google Scholar Serum IgG levels were also almost 4-fold lower, and albumin levels were 2-fold lower in the conditional KO mice compared with wild-type.35Montoyo H.P. Vaccaro C. Hafner M. et al.Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice.Proc Natl Acad Sci U S A. 2009; 106: 2788-2793Crossref PubMed Scopus (169) Google Scholar These studies indicate that endothelial and hematopoietic cells are the major sites of IgG and albumin reclamation by FcRn. There are no documented cases of FcRn KO or deficiency in humans. The only known disease to directly affect FcRn is familial hypercatabolic hypoproteinemia, in which a mutation in ß2-microglobulin prevents expression of ß2-microglobulin and FcRn, resulting in significant hypoalbuminemia, low serum IgG levels, and severely reduced half-lives of both these serum proteins.36Waldmann T.A. Terry W.D. Familial hypercatabolic hypoproteinemia. A disorder of endogenous catabolism of albumin and immunoglobulin.J Clin Invest. 1990; 86: 2093-2098Crossref PubMed Scopus (85) Google Scholar Cultured cell lines have been used to determine the cellular compartments in which FcRn binds to monomeric IgG and how transcytosis or recycling of IgG occurs. Early studies found that in endothelial cells, FcRn appeared to be in early endosomes (EEA1 and Rab5+ compartments) and recycling endosomes (Rab4 and Rab11a+ compartments) although spatial resolution of these imaging studies was not optimal.37Ober R.J. Martinez C. Lai X. et al.Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level.Proc Natl Acad Sci U S A. 2004; 101: 11076-11081Crossref PubMed Scopus (225) Google Scholar, 38Ward E.S. Martinez C. Vaccaro C. et al.From sorting endosomes to exocytosis: association of Rab4 and Rab11 GTPases with the Fc receptor, FcRn, during recycling.Mol Biol Cell. 2005; 16: 2028-2038Crossref PubMed Scopus (158) Google Scholar, 39Ober R.J. Martinez C. Vaccaro C. et al.Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn1.J Immunol. 2004; 172: 2021-2029Crossref PubMed Scopus (261) Google Scholar IgG is thought to enter the cell via pinocytosis and to bind FcRn in sorting endosomes (EEA1-, Rab5-, Rab4-, and Rab11a-positive compartments) with an acidic pH of approximately 6. Subsequently, the FcRn/IgG complex separates from sorting endosomes to Rab4+ and Rab11a+ recycling endosomes. Ultimately, IgG that bounds to FcRn within recycling endosomes is delivered to the cell surface, where fusion of these vesicles results in IgG release from the cell.37Ober R.J. Martinez C. Lai X. et al.Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level.Proc Natl Acad Sci U S A. 2004; 101: 11076-11081Crossref PubMed Scopus (225) Google Scholar Albumin, which has a long half-life of 21 to 28 days, is the serum protein found at highest concentration in humans.40Chaudhury C. Mehnaz S. Robinson J.M. et al.The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan.J Exp Med. 2003; 197: 315-322Crossref PubMed Scopus (488) Google Scholar Albumin is a carrier for multiple ions and compounds such as fatty acids and bilirubin and plays a key role in regulating oncotic pressure. As with IgG, FcRn in endothelial cells diverts albumin from the degradative pathway, allowing for albumin recycling back to the serum (Figure 2).35Montoyo H.P. Vaccaro C. Hafner M. et al.Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice.Proc Natl Acad Sci U S A. 2009; 106: 2788-2793Crossref PubMed Scopus (169) Google Scholar,40Chaudhury C. Mehnaz S. Robinson J.M. et al.The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan.J Exp Med. 2003; 197: 315-322Crossref PubMed Scopus (488) Google Scholar FcRn binds albumin at acidic pH in a 1:1 ratio, and binding is significantly decreased (approximately 200-fold lower) at neutral pH.41Chaudhury C. Brooks C.L. Carter D.C. et al.Albumin binding to FcRn: distinct from the FcRn-IgG interaction.Biochemistry. 2006; 45: 4983-4990Crossref PubMed Scopus (233) Google Scholar The site of albumin binding on FcRn is separate from that of IgG, and thus, FcRn can bind albumin and IgG at the same time.41Chaudhury C. Brooks C.L. Carter D.C. et al.Albumin binding to FcRn: distinct from the FcRn-IgG interaction.Biochemistry. 2006; 45: 4983-4990Crossref PubMed Scopus (233) Google Scholar Studies of albumin trafficking in endothelial cell lines have shown that after uptake, albumin is found in early endosomal compartments, and that albumin engineered to have impaired binding to FcRn is preferentially directed to the lysosome. Albumin with increased affinity for FcRn is preferentially recycled and appears in the cell culture media.38Ward E.S. Martinez C. Vaccaro C. et al.From sorting endosomes to exocytosis: association of Rab4 and Rab11 GTPases with the Fc receptor, FcRn, during recycling.Mol Biol Cell. 2005; 16: 2028-2038Crossref PubMed Scopus (158) Google Scholar,42Schmidt E.G.W. Hvam M.L. Antunes F. et al.Direct demonstration of a neonatal Fc receptor (FcRn)-driven endosomal sorting pathway for cellular recycling of albumin.J Biol Chem. 2017; 292: 13312-13322Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar FcRn sorts monomeric IgG and ICs differently. As noted above, monomeric IgG is salvaged from lysosomal degradation and recycled or transcytosed. In contrast, ICs are directed by FcRn to the lysosome (Figure 3).43Weflen A.W. Baier N. Tang Q.J. et al.Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules.Mol Biol Cell. 2013; 24: 2398-2405Crossref PubMed Scopus (71) Google Scholar This differential trafficking is believed to result from the exclusion of FcRn-ICs from recycling compartments due to the size of these complexes. FcRn-mediated trafficking of ICs to the lysosome allows for proteolytic digestion of the antigen and presentation on MHC molecules. A seminal study by Qiao et al.44Qiao S.W. Kobayashi K. Johansen F.E. et al.Dependence of antibody-mediated presentation of antigen on FcRn.Proc Natl Acad Sci U S A. 2008; 105: 9337-9342Crossref PubMed Scopus (213) Google Scholar definitively showed that in antigen-presenting cells, FcRn is required for IC trafficking to the lysosome for proteolytic degradation of antigen and presentation on MHC class II molecules. This study also showed that FcRn significantly increases the efficiency of antigen presentation by antigen-presenting cells to CD4+ T cells. Subsequent work also found that FcRn is needed for efficient cross-presentation of antigen by CD8−CD11b+ but not CD8+CD11b− dendritic cells to CD8+ T cells.45Baker K. Qiao S.W. Kuo T.T. et al.Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cells.Proc Natl Acad Sci U S A. 2011; 108: 9927-9932Crossref PubMed Scopus (170) Google Scholar The differential requirement for FcRn in antigen cross-presentation in these 2 dendritic cell subsets is likely due to the fact that CD8+CD11b− dendritic cells have endocytic compartments with a neutral pH, which significantly diminishes the binding of ICs to FcRn. Direct evidence for the importance of FcRn-mediated antigen presentation in diseases comes from rodent studies, showing that FcRn confers protection in an intestinal Citrobacter rodentium infectious colitis model in which CD4+ T-cell activation is required to clear the pathogen,46Yoshida M. Kobayashi K. Kuo T.T. et al.Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria.J Clin Invest. 2006; 116: 2142-2151Crossref PubMed Scopus (196) Google Scholar and in mouse, Clostridiodes difficile infection and Lyme disease models.47Amadou Amani S. Lang G.A. Ballard J.D. Lang M.L. The murine neonatal Fc receptor is required for transport of immunization-induced C. difficile-specific IgG to the gut and protection against disease but does not affect disease susceptibility.Infect Immun. 2021; 89e0027421Crossref Scopus (3) Google Scholar,48Crowley H. Alroy J. Sproule T.J. et al.The MHC class I-related FcRn ameliorates murine Lyme arthritis.Int Immunol. 2006; 18: 409-414Crossref PubMed Scopus (5) Google Scholar FcRn has not been specifically studied in renal endothelial cells but has been examined in podocytes and the PCT. Using global FcRn KO mice, Akilesh et al.14Akilesh S. Huber T.B. Wu H. et al.Podocytes use FcRn to clear IgG from the glomerular basement membrane.Proc Natl Acad Sci U S A. 2008; 105: 967-972Crossref PubMed Scopus (223) Google Scholar found that the lack of FcRn leads to IgG accumulation in the glomerulus, which is readily apparent by 6 months of age. Within the glomerulus, IgG accumulated primarily within the mesangium in the KO mice with no IgG deposition seen in the wild type. Podocyte-specific KO of FcRn also results in mesangial accumulation of IgG, but not albumin, in the KO animals by 6 months of age, with worsening accumulation of IgG and mesangial expansion as the mice age.19Dylewski J. Dobrinskikh E. Lewis L. et al.Differential trafficking of albumin and IgG facilitated by the neonatal Fc receptor in podocytes in vitro and in vivo.PLoS One. 2019; 14e0209732Crossref PubMed Scopus (15) Google Scholar Consistent with the known role for FcRn in trafficking of ICs to the lysosome in antigen-presenting cells, the KO of FcRn in cultured podocytes decreased the trafficking of ICs to the lysosome.