Increased survival and reduced renal injury in MRL/lpr mice treated with a human Fcγ receptor II (CD32) peptide

Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease affecting many organs. The deposition in kidney tissue of immune complexes and their interaction with macrophages is thought to trigger the inflammatory response leading to glomerulonephritis. It has been demonstrated that inhibition of this interaction in murine models can alleviate the disease. Six synthetic peptides were derived from the membrane‐proximal extracellular domain (EC2) of human Fcγ receptor II (huFcγRII). Of these, one peptide, huRII6, was shown to be a potent competitive inhibitor of IgG binding to recombinant FcγRII in vitro. To examine the possible therapeutic impact of huRII6 in vivo, this peptide, or a control, was given by subcutaneous injection to female MRL/lpr mice from weeks 7 to 36, resulting in an enhanced survival rate compared with control‐treated animals and a reduction of proteinuria. Histopathological examination of the kidneys showed a reduction in deposition of immune complexes and preservation of structure. Such a functional peptide should prove useful for examining the role of IgG–FcγR interactions in experimental models of disease and may provide for the development of FcR‐targeting drugs to treat autoimmune disorders.

[1]  L. Morel,et al.  Murine Models of Systemic Lupus Erythematosus , 2011, Journal of biomedicine & biotechnology.

[2]  B. Harder,et al.  Recombinant Soluble Human FcγR1A (CD64A) Reduces Inflammation in Murine Collagen-Induced Arthritis1 , 2009, The Journal of Immunology.

[3]  Gaiping Zhang,et al.  Efficient recovery of a functional extracellular domain of bovine IgG2 Fc receptor (boFcgamma2R) from inclusion bodies by a rapid dilution refolding system. , 2008, Journal of immunological methods.

[4]  U. Jacob,et al.  Amelioration of collagen-induced arthritis by human recombinant soluble FcgammaRIIb. , 2008, Clinical immunology.

[5]  T. Witte,et al.  Treatment of lupus-prone NZB/NZW F1 mice with recombinant soluble Fcγ receptor II (CD32) , 2007 .

[6]  Jiyong Zhou,et al.  Identification of the linear epitope for Fc‐binding on the bovine IgG2 Fc receptor (boFcγ2R) using synthetic peptides , 2006, FEBS letters.

[7]  Jiyong Zhou,et al.  Identification of neutralizing epitopes on the VP2 protein of infectious bursal disease virus by phage-displayed heptapeptide library screening and synthetic peptide mapping. , 2005, Viral immunology.

[8]  G. Sármay,et al.  Functional mapping of the FcγRII binding site on human IgG1 by synthetic peptides , 2004 .

[9]  G. Sármay,et al.  Synthesis and receptor binding of IgG1 peptides derived from the IgG Fc region , 2004, Journal of molecular recognition : JMR.

[10]  Dennis R. Burton,et al.  Human antibody–Fc receptor interactions illuminated by crystal structures , 2004, Nature Reviews Immunology.

[11]  Wei Zhang,et al.  Crystal Structure of the Ectodomain of Human FcαRI* , 2003, Journal of Biological Chemistry.

[12]  P. Bjorkman,et al.  Insights into IgA-mediated immune responses from the crystal structures of human FcαRI and its complex with IgA1-Fc , 2003, Nature.

[13]  B. Wines,et al.  Soluble FcγRIIa inhibits rheumatoid factor binding to immune complexes , 2003 .

[14]  P. Heeringa,et al.  Opposite Regulation of Type II and III Receptors for Immunoglobulin G in Mouse Glomerular Mesangial Cells and in the Induction of Anti-glomerular Basement Membrane (GBM) Nephritis* , 2002, The Journal of Biological Chemistry.

[15]  P. Sondermann,et al.  The structure of Fc receptor/Ig complexes: considerations on stoichiometry and potential inhibitors. , 2002, Immunology letters.

[16]  G. Gilkeson,et al.  Use of genetic knockouts to modulate disease expression in a murine model of lupus, MRL/Ipr mice , 2002, Immunologic research.

[17]  J. Kinet,et al.  The analysis of the human high affinity IgE receptor Fc epsilon Ri alpha from multiple crystal forms. , 2001, Journal of molecular biology.

[18]  C. Sautès-Fridman,et al.  The Structure of a Human Type III Fcγ Receptor in Complex with Fc* , 2001, The Journal of Biological Chemistry.

[19]  A G Brooks,et al.  Crystal structure of the extracellular domain of a human Fc gamma RIII. , 2000, Immunity.

[20]  J. Kinet,et al.  Structure of the Fc fragment of human IgE bound to its high-affinity receptor FcεRIα , 2000, Nature.

[21]  Robert Huber,et al.  The 3.2-Å crystal structure of the human IgG1 Fc fragment–FcγRIII complex , 2000, Nature.

[22]  Menotti Ruvo,et al.  Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulin-binding peptide , 2000, Nature Biotechnology.

[23]  W. Chan,et al.  Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Practical Approach Series) , 2019 .

[24]  B. Austen,et al.  Solid‐phase synthesis and cyclization of a large branched peptide from IgG Fc with affinity for FcγRI , 1999 .

[25]  P. Barton,et al.  Crystal structure of the human leukocyte Fc receptor, FcγRIIa. , 1999, Nature Structural Biology.

[26]  U. Jacob,et al.  Crystal structure of the soluble form of the human Fcγ‐receptor IIb: a new member of the immunoglobulin superfamily at 1.7 Å resolution , 1999, The EMBO journal.

[27]  J. Kinet,et al.  Crystal Structure of the Human High-Affinity IgE Receptor , 1998, Cell.

[28]  R. Schmidt,et al.  FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia , 1998 .

[29]  T. Yamazaki,et al.  Resistance of Fc receptor- deficient mice to fatal glomerulonephritis. , 1998, The Journal of clinical investigation.

[30]  J. Ravetch,et al.  Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. , 1998, Science.

[31]  J. Ravetch,et al.  Divergent roles for Fc receptors and complement in vivo. , 1998, Annual review of immunology.

[32]  R. Schmidt,et al.  Impaired IgG-Dependent Anaphylaxis and Arthus Reaction in FcγRIII (CD16) Deficient Mice , 1996 .

[33]  P. Hogarth,et al.  Recombinant soluble FcγRII inhibits immune complex precipitation , 1995 .

[34]  J. Ravetch,et al.  Cytotoxic antibodies trigger inflammation through Fc receptors. , 1995, Immunity.

[35]  J. Ravetch,et al.  Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. , 1994, Science.

[36]  E. Witort,et al.  Identification of the IgG binding site of the human low affinity receptor for IgG Fc gamma RII. Enhancement and ablation of binding by site-directed mutagenesis. , 1994, The Journal of biological chemistry.

[37]  J. Ravetch,et al.  FcR γ chain deletion results in pleiotrophic effector cell defects , 1994, Cell.

[38]  P. Hogarth,et al.  Recombinant soluble human Fc gamma RII: production, characterization, and inhibition of the Arthus reaction , 1993, The Journal of experimental medicine.

[39]  M. Mannik.  Pathophysiology of circulating immune complexes. , 1982, Arthritis and rheumatism.

[40]  B. Hahn,et al.  Restricted subpopulations of DNA antibodies in kidneys of mice with systemic lupus. Comparison of antibodies in serum and renal eluates. , 1980, Arthritis and rheumatism.

[41]  A. Theofilopoulos,et al.  Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains , 1978, The Journal of experimental medicine.