The Pivotal Role of C1qR in Mixed Cryoglobulinemia

  • Domenico Sansonno
  • Loredana Sansonno
  • Franco Dammacco


Non-enveloped HCV core protein, a constitutive antigen component of cryoglobulins in HCV-infected patients, is required for generating cryoglobulin-mediated tissue injury in vivo upon engagement of the globular domain of C1q receptor (gC1qR). gC1qR is proteolytically cleaved from the cell surface, suggesting that the cleavage event is physiologically relevant. Circulating gC1qR may affect numerous aspects of cell biology via intracellular and extracellular pathways. Higher serum levels of gC1qR in mixed cryoglobulinemia indicate that this protein plays a relevant role in the pathogenesis of cryoglobulin-related damage, including immune complex formation and cryoprecipitation.


Mixed Cryoglobulinemia Globular Head Cryoglobulinemic Vasculitis Span Amino Acid Mixed Cryoglobulinemia Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Saadoun D, Rosenzwajg M, Landau D et al (2008) Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 111(11):5334–5341PubMedCrossRefGoogle Scholar
  2. 2.
    Sansonno D, Lauletta G, Nisi L et al (2003) Non-enveloped HCV core protein as constitutive antigen of cold-precipitable immune complexes in type II mixed cryoglobulinaemia. Clin Exp Immunol 133(2):275–282PubMedCrossRefGoogle Scholar
  3. 3.
    Sabile A, Perlemuter G, Bono F et al (1999) Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates. Hepatology 30:1064–1076PubMedCrossRefGoogle Scholar
  4. 4.
    Kurtz JB, Boxall F, Qusir N et al (2001) The diagnostic ­significance of an assay for ‘total’ hepatitis C core antigen. J Virol Methods 96:127–132PubMedCrossRefGoogle Scholar
  5. 5.
    Gorevic PD, Frangione B (1991) Mixed cryoglobulinemia cross-reactive idiotypes. Implications for the relationship of MC to rheumatic and lymphoproliferative diseases. Semin Hematol 28:79–94PubMedGoogle Scholar
  6. 6.
    Lindahl G, Sjobring U, Johnsson E (2000) Human complement regulators: a major target for pathogenic microorganisms. Curr Opin Immunol 12:44–51PubMedCrossRefGoogle Scholar
  7. 7.
    Kittlesen DJ, Chianese-Bullock KA, Yao ZQ et al (2000) Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest 106:1239–1249PubMedCrossRefGoogle Scholar
  8. 8.
    Yao ZQ, Nguyen DT, Hiotellis AI et al (2001) Hepatitis C core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway. J Immunol 167:5264–5272PubMedGoogle Scholar
  9. 9.
    Dammacco F, Sansonno D, Piccoli C et al (2000) The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinaemia, and overt B-cell malignancy. Semin Liver Dis 20:143–145PubMedCrossRefGoogle Scholar
  10. 10.
    Yao Z-Q, Prayter D, Trabue C et al (2008) Differential regulation of SOCS-1 sognalling in B and T lymphocytes by hepatitis C virus core protein. Immunology 2:197–207CrossRefGoogle Scholar
  11. 11.
    Lim BL, Reid KBM, Ghebrehiwet B et al (1996) The binding for globular heads of complement C1q, gC1qR. Functional expression and characterization as a novel vitronectin binding factor. J Biol Chem 271:26739–26744PubMedCrossRefGoogle Scholar
  12. 12.
    Sansonno D, Cornacchiulo V, Iacobelli AR et al (1995) Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinaemia. Hepatology 21:305–312PubMedGoogle Scholar
  13. 13.
    Sansonno D, Gesualdo L, Monno C et al (1997) Hepatitis C virus-related proteins in kidney tissue from hepatitic C virusinfected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology 25:1237–1244PubMedCrossRefGoogle Scholar
  14. 14.
    Ghebrehiwet B, Lim B-L, Kumar L et al (2001) gC1q-R/p33: a member of a new class of multifunctional and multicompartimental cellular proteinsis involved in inflammation and infection. Immunol Rev 180:65–77PubMedCrossRefGoogle Scholar
  15. 15.
    Joseph K, Ghebrehiwet B, Peerschke EI et al (1996) Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular “heads” of C1q (gC1q-R). Proc Natl Acad Sci U S A 93:8552–8557PubMedCrossRefGoogle Scholar
  16. 16.
    Lim BL, Reid KBM, Ghebrehiwet B et al (1996) The binding protein for globular heads of complement C1q, gC1qR. Functional expression and characterization as a novel vitronectin binding factor. J Biol Chem 271:26739–26744CrossRefGoogle Scholar
  17. 17.
    Paul DB, Kuhns MC, McNamara AL et al (1995) Short-term stability of HIV provirus levels in the peripheral blood of HIV-infected individuals. J Med Virol 47:292–297PubMedCrossRefGoogle Scholar
  18. 18.
    Simos G, Georgatos SD (1994) The lamin B receptor-associated protein p34 shares sequence homology and antigenic determinants with the splicing factor 2-associated protein p32 [letter]. FEBS 346:225–228CrossRefGoogle Scholar
  19. 19.
    Krainer AR, Mayeda A, Kozak D et al (1991) Functional expression of cloned human splicing factor SF2: homology to RNA-binding proteins, U1 70 K, and drosophila splicing regulators. Cell 66:383–394PubMedCrossRefGoogle Scholar
  20. 20.
    Seytter T, Lottspeich F, Neupert W et al (1998) Mam33p, an oligomeric, acidic protein in the mitochondrial matrix of Saccharomyces cerevisiae is related to the human complement receptor gC1q-R. Yeast 14(4):303–310PubMedCrossRefGoogle Scholar
  21. 21.
    Sunayama J, Ando Y, Itoh N et al (2004) Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore forming protein p32. Cell Death Differ 11:771–781PubMedCrossRefGoogle Scholar
  22. 22.
    Matthews DA, Russell WC (1998) Adenovirus core protein V interacts with p32 a protein which is associated with both the mitochondria and the nucleus. J Gen Virol 79:1677–1685PubMedGoogle Scholar
  23. 23.
    Luo Y, Yu H, Peterlin BM (1994) Cellular protein modulates effects of human immunodeficiency virus type I Rev. J Virol 68:3850–3856PubMedGoogle Scholar
  24. 24.
    Joseph K, Ghebrehiwet B, Kaplan A-P (2001) Activation of the kininforming cascade on the surface of endothelial cells. Biol Chem 382:71PubMedCrossRefGoogle Scholar
  25. 25.
    Peerschke EI, Ghebrehiwet B (1988) Identification and partial characterization of human platelet C1q binding sites. J Immunol 141(10):3505–3511PubMedGoogle Scholar
  26. 26.
    Jiang J, Zhang Y, Krainer AR et al (1999) Crystal structure of human p32, a doughnut-shaped acidic mitochondrial matrix protein. Proc Natl Acad Sci USA 96(7):3572–3577PubMedCrossRefGoogle Scholar
  27. 27.
    Zlatarova AS, Rouseva M, Roumenina LT et al (2006) Existence of different but overlapping IgG- and IgM-binding sites on the globular domain of human C1q. Biochemistry 45(33):9979–9988PubMedCrossRefGoogle Scholar
  28. 28.
    Gaboriaud C, Jaunhuix J, Gruez A et al (2003) The crystal structure of globular head of complement protein C1q provides a basis for its versatile recognition properties. J Biol Chem 278:46974–46982PubMedCrossRefGoogle Scholar
  29. 29.
    Sansonno D, Dammacco F (2005) Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis 5(4):227–236PubMedCrossRefGoogle Scholar
  30. 30.
    Frank MM (1995) Animal models for complement deficiencies. J Clin Immunol 15(6 Suppl):113S–121SPubMedCrossRefGoogle Scholar
  31. 31.
    Fujita T, Gigli I, Nussenzweig V (1978) Human C4-binding protein II: role in proteolysis of C4b by C3b-inactivator. J Exp Med 148(4):1044–1051PubMedCrossRefGoogle Scholar
  32. 32.
    Okroj M, Heinegård D, Holmdahl R et al (2007) Rheumatoid arthritis and the complement system. Ann Med 39(7):517–530PubMedCrossRefGoogle Scholar
  33. 33.
    Sansonno D, Tucci FA, Ghebrehiwet B et al (2009) Role of the receptor for the globular domain of C1q protein in the pathogenesis of hepatitis C virus-related cryoglobulin vascular damage. J Immunol 183(9):6013–6020PubMedCrossRefGoogle Scholar
  34. 34.
    Waggoner SN, Hall CH, Hahn YS (2007) HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. J Leukoc Biol 82(6):1407–1419PubMedCrossRefGoogle Scholar
  35. 35.
    Peerschke EI, Ghebrehiwet B (1998) Platelet receptors for the complement component C1q: implications for hemostasis and thrombosis. Immunobiology 199(2):239–249PubMedCrossRefGoogle Scholar
  36. 36.
    Nickelet V, Mihatsch NJ (2003) Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant 18(11):2232–2239CrossRefGoogle Scholar
  37. 37.
    Peerschke EI, Ghebrehiwet B (2007) The contribution of gC1qR/p33 in infection and inflammation. Immunobiology 212(4–5):333–342PubMedCrossRefGoogle Scholar
  38. 38.
    Ghebrehiwet B, Cebada Mora C, Tantral L et al (2006) gC1qR/p33 serves as a molecular bridge between the complement and contact activation systems and is an important catalyst in inflammation. Adv Exp Med Biol 586:95–105PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  • Domenico Sansonno
    • 1
  • Loredana Sansonno
    • 2
  • Franco Dammacco
    • 1
  1. 1.Department of Biomedical Sciences and Clinical OncologyUniversity of Bari Medical SchoolBariItaly
  2. 2.Laboratory of Genetics, Department of Biomedical SciencesUniversity of Foggia Medical SchoolFoggiaItaly

Personalised recommendations