FHR3 Blocks C3d-Mediated Coactivation of Human B Cells

The autoimmune renal disease deficient for complement factor H–related (CFHR) genes and autoantibody-positive form of hemolytic uremic syndrome is characterized by the presence of autoantibodies specific for the central complement regulator, factor H, combined with a homozygous deficiency, mostly in CFHR3 and CFHR1. Because FHR3 and FHR1 bind to C3d and inactivated C3b, which are ligands for complement receptor type 2 (CR2/CD21), the aim of the current study was to examine whether FHR3-C3d or FHR1-C3d complexes modulate B cell activation. Laser-scanning microscopy and automated image-based analysis showed that FHR3, but not FHR1 or factor H, blocked B cell activation by the BCR coreceptor complex (CD19/CD21/CD81). FHR3 bound to C3d, thereby inhibiting the interaction between C3d and CD21 and preventing colocalization of the coreceptor complex with the BCR. FHR3 neutralized the adjuvant effect of C3d on B cells, as shown by inhibited intracellular CD19 and Akt phosphorylation in Raji cells, as well as Ca2+ release in peripheral B cells. In cases of CFHR3/CFHR1 deficiency, the FHR3 binding sites on C3d are occupied by factor H, which lacks B cell–inhibitory functions. These data provide evidence that FHR3, which is absent in patients with the autoimmune form of hemolytic uremic syndrome, is involved in B cell regulation.

[1]  A. Goldman,et al.  The Major Autoantibody Epitope on Factor H in Atypical Hemolytic Uremic Syndrome Is Structurally Different from Its Homologous Site in Factor H-related Protein 1, Supporting a Novel Model for Induction of Autoimmunity in This Disease* , 2015, The Journal of Biological Chemistry.

[2]  P. Zipfel,et al.  New insights into disease-specific absence of complement factor H related protein C in mouse models of spontaneous autoimmune diseases. , 2014, Molecular immunology.

[3]  V. Holers.  Complement and its receptors: new insights into human disease. , 2014, Annual review of immunology.

[4]  C. Skerka,et al.  Complement factor H related proteins (CFHRs). , 2013, Molecular immunology.

[5]  P. Barlow,et al.  Functional anatomy of complement factor H. , 2013, Biochemistry.

[6]  L. Rostaing,et al.  Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. , 2013, Clinical journal of the American Society of Nephrology : CJASN.

[7]  A. Goldman,et al.  Microbes Bind Complement Inhibitor Factor H via a Common Site , 2013, PLoS pathogens.

[8]  E. Goicoechea de Jorge,et al.  Dimerization of complement factor H-related proteins modulates complement activation in vivo , 2013, Proceedings of the National Academy of Sciences.

[9]  P. Sánchez-Corral,et al.  Factor H and CFHR1 polymorphisms associated with atypical Haemolytic Uraemic Syndrome (aHUS) are differently expressed in Tunisian and in Caucasian populations , 2012, International journal of immunogenetics.

[10]  D. Svergun,et al.  Structural Analysis of the C-Terminal Region (Modules 18–20) of Complement Regulator Factor H (FH) , 2012, PloS one.

[11]  R. Cantor,et al.  Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility , 2011, PLoS genetics.

[12]  Loreto Gesualdo,et al.  Genome-wide association study identifies susceptibility loci for IgA nephropathy , 2011, Nature Genetics.

[13]  A. Goldman,et al.  Dual interaction of factor H with C3d and glycosaminoglycans in host–nonhost discrimination by complement , 2011, Proceedings of the National Academy of Sciences.

[14]  C. Keilhauer,et al.  An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). , 2010, Human molecular genetics.

[15]  John D Lambris,et al.  Complement: a key system for immune surveillance and homeostasis , 2010, Nature Immunology.

[16]  D. Fearon,et al.  Pillars Article: CD19: Lowering the threshold for antigen receptor stimulation of B lymphocytes. Science, 1992. 256: 105-107. , 2010, Journal of immunology.

[17]  C. Sautès-Fridman,et al.  Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. , 2010, Kidney international.

[18]  P. Barlow,et al.  Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. , 2010, Blood.

[19]  U. Schlötzer-Schrehardt,et al.  Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. , 2009, Blood.

[20]  P. Zipfel,et al.  Complement regulators and inhibitory proteins , 2009, Nature Reviews Immunology.

[21]  Francesco Saverio Tedesco,et al.  Complement in human diseases: Lessons from complement deficiencies. , 2009, Molecular immunology.

[22]  D. Ricklin,et al.  Cutting Edge: Members of the Staphylococcus aureus Extracellular Fibrinogen-Binding Protein Family Inhibit the Interaction of C3d with Complement Receptor 21 , 2008, The Journal of Immunology.

[23]  J. Richter,et al.  The Staphylococcus aureus Protein Sbi Acts as a Complement Inhibitor and Forms a Tripartite Complex with Host Complement Factor H and C3b , 2008, PLoS pathogens.

[24]  P. Zipfel,et al.  Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. , 2008, Blood.

[25]  M. Oppermann,et al.  Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. , 2007, Blood.

[26]  J. Goodship,et al.  Deletion of Complement Factor H–Related Genes CFHR1 and CFHR3 Is Associated with Atypical Hemolytic Uremic Syndrome , 2007, PLoS genetics.

[27]  E. Bergmann-Leitner,et al.  Complement 3d: from molecular adjuvant to target of immune escape mechanisms. , 2006, Clinical Immunology.

[28]  N. Orr,et al.  A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration , 2006, Nature Genetics.

[29]  W. Fridman,et al.  Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. , 2005, Journal of the American Society of Nephrology : JASN.

[30]  S. Pierce,et al.  The Role of the CD19/CD21 Complex in B Cell Processing and Presentation of Complement-Tagged Antigens , 2001, The Journal of Immunology.

[31]  N. Brot,et al.  C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response , 2000, The Journal of experimental medicine.

[32]  S. Meri,et al.  Functional properties of complement factor H‐related proteins FHR‐3 and FHR‐4: binding to the C3d region of C3b and differential regulation by heparin , 1999, FEBS letters.

[33]  M. Dierich,et al.  Characterization of C3dg binding to a recess formed between short consensus repeats 1 and 2 of complement receptor type 2 (CR2; CD21). , 1998, Journal of immunology.

[34]  I. Melchers,et al.  Human B and T lymphocytes have similar amounts of CD21 mRNA, but differ in surface expression of the CD21 glycoprotein. , 1998, International immunology.

[35]  M. Cooper,et al.  The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  E. Kremmer,et al.  Regulation of the B cell response to T-dependent antigens by classical pathway complement. , 1996, Journal of immunology.

[37]  R. Karr,et al.  Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Ahearn,et al.  Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. , 1996, Immunity.

[39]  V. Vetvicka,et al.  Natural antibody and complement-mediated antigen processing and presentation by B lymphocytes. , 1994, Journal of immunology.

[40]  P. Zipfel,et al.  A novel short consensus repeat-containing molecule is related to human complement factor H. , 1993, The Journal of biological chemistry.

[41]  P. Zipfel,et al.  Two additional human serum proteins structurally related to complement factor H. Evidence for a family of factor H-related genes. , 1992, Journal of immunology.

[42]  D. Fearon,et al.  Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. , 2000, Annual review of immunology.

[43]  N. Brot,et al.  C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response: Implications for Systemic Autoimmunity , 2000 .