• C3bR
• C4bR
• Complement Receptor Type One, CR1
• Immune Adherence Receptor

MAJOR LINKS FOR CD35  

• NCBI LocusLink Record: 1378
• Mendelian Inheritance in Man (OMIM): 120620
• SwissProt annotated protein record: P17927

• Receptor for C3b and C4b bound to immune complexes
• Cofactor for specific proteolytic cleavage of C3b and C4b by plasma serine protease, factor I
• Accelerates the decay of both the classical and alternative pathway C3 and C5 convertases on cells to which it is bound (intrinsic activity) and nearby cells (extrinsic activity)

CELLULAR FUNCTION OF CD35  

• On leukocytes and tissue sources, CD35 mediates adherence of C4b/C3b coated particles in preparation for phagocytosis. Phagocytosis most often requires the cooperation of CD35 with complement receptor type 3 (CR3, CD11b/CD18) and the Fcg receptors
• Primary function of erythrocyte CD35 is mediating the adherence of targets coated with C4b/C3b and their transport to the fixed phagocyte systems of the spleen and liver
• By facilitating C3b and C4b cleavage by factor I and accelerating the decay of the C3 and C5 convertases, CD35 limits complement activation and produces ligands for other complement receptors

DISEASE RELEVANCE OF CD35 AND FUNCTION OF CD35 IN INTACT ANIMAL  

• CD35 plays a major role in the removal and processing of immune complexes and facilitating their localization to lymphoid follicles
• A recombinant soluble form of CD35, consisting of SCRs 1-30 but lacking the transmembrane and cytoplasmic domains, is in clinical trials as a complement inhibitor. This reagent has provided the means to establish a major role for complement in ischemia-reperfusion injury
• A CD35 knockout model in the mouse demonstrates impaired B-cell responses to T-cell-dependent antigens
• The use of monoclonal antibodies to CD35 cross-linked to either autoantigens or antibodies to pathogens is currently being investigated as a means of promoting clearance
• A transient, acquired and disease activity-related reduction in CR1/number erythrocyte occurs in SLE and other syndromes with excessive amounts of complement fixing immune complexes

• Families in which CD35 is a member
  • CD35-->regulators of complement activation gene

MOLECULAR STRUCTURE OF CD35  

• Type 1 single-chain cell surface membrane glycoprotein
• 225kDa form: 1,998 total aa, 1,930 aa extracellular, N-terminus contains 24 potential N-linked glycosylation sites, 25 aa transmembrane domain, and 43 aa cytoplasmic tail
• Extracellular region is composed entirely of tandemly repeated complement control protein (CCP) repeats (also termed short consensus repeats, SCRs) of approximately 65 aa
• Each repeat contains 4 conserved cysteines, linked 1-3 and 2-4, and a tryptophan between cysteines 3 and 4
• High sequence homology (60-100%) between every seventh repeat permits grouping every seven repeats into a unit termed a long homologous repeat (LHR). LHRs are termed A, B, C, and D, corresponding to repeats 1-7, 8-15, 16-21, and 22-28
• SCRs 29 and 30 show reduced homology with the repeats grouped into LHRs
• Molecular mass polymorphism due to the differences in the number of SCRs encoded by different alleles (190kDa, 23 SCRs; 220kDa, 30 SCRs; 250kDa, 37 SCRs; 280kDa, 44 SCRs)
• Functional domains localize to first three SCRs of LHRs A, B, and C

MOLECULAR MASS OF CD35  

POST-TRANSCRIPTIONAL MODIFICATION OF CD35  

• A cDNA clone has been identified which encodes a secreted form comprising the amino-terminal 8.5 SCRs. A protein product of this transcript has not been detected in vivo
• A CD35-like genomic clone has been identified with approximately 90% homology to CD35. It possesses SCRs 1-6 joined to SCR9. There is no stop codon in these exons
• Smaller molecular mass forms of CD35 are expressed, predominantly on erythrocytes, by non-human primates. Some of these smaller forms are bound to the cell surface membrane by a GPI anchor
• Mouse CD35 and CD21 are generated by alternative splicing of a common message onto the CD21 message of 15 SCRs, which appends 6 SCRs from the amino terminus of CR1 producing a hybrid CR2/CR1 protein

POST-TRANSLATIONAL MODIFICATION OF CD35  

• N-linked glycosylation accounts for molecular mass differences of CD35 between erythrocytes and leukocytes
• No O-linked carbohydrate

SUBSTRATES FOR CD35  

• By binding C3b or C4b, CD35's primary ligands, CD35 is thought to induce a conformational change in these ligands making them more susceptible to site-specific cleavage by the plasma serine protease, factor I
• CD35 is a cofactor for the first cleavage reaction, which leads to production of C3bi. It is a necessary cofactor for the cleavage of C3bi to C3c and C3dg

ENZYMES WHICH MODIFY CD35   - No information

LIGANDS FOR CD35 AND MOLECULES ASSOCIATED WITH CD35  

• CD35 is expressed on erythrocytes, neutrophils, monocytes, eosinophils, B-lymphocytes, and 10-15% of T-lymphocytes
• It has also been identified on glomerular podocytes, follicular-dendritic cells, and some astrocytes
• The Knops, McCoy, Swain-Langley, and York blood group antigens are located on CD35
• For most non-primates, including rabbit and guinea pig, CD35 is expressed on platelets rather than erythrocytes
• The immune adherence receptor on mouse and rat platelets remains to be identified
• It does not cross react with antibodies to mouse CR1/CR2

SELECTION OF OTHER CD35-SPECIFIC REFERENCE MAB  

REVIEWS

1. Ahearn JM,Fearon DT Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21). Adv Immunol 1989 46:183 PubMed

2. Hourcade D,Holers VM,Atkinson JP The regulators of complement activation (RCA) gene cluster. Adv Immunol 1989 45:381 PubMed

3. Moore FD Jr Therapeutic regulation of the complement system in acute injury states. Adv Immunol 1994 56:267 PubMed

4. Ross GD,Medof ME Membrane complement receptors specific for bound fragments of C3. Adv Immunol 1985 37:217 PubMed

5. Taylor RP,Ferguson PJ Primate erythrocyte (E) complement receptor (CR1) as an anchor site for bispecific-based therapies to clear pathogens or autoantibodies safely from the circulation. J Hematother 1995 4:357 PubMed

PRIMARY CITATIONS

6. Birmingham DJ,Logar CM,Shen XP,Chen W The baboon erythrocyte complement receptor is a glycophosphatidylinositol-linked protein encoded by a homologue of the human CR1-like genetic element. J Immunol 1996 157:2586 PubMed

7. Changelian PS,Jack RM,Collins LA,Fearon DT PMA induces the ligand-independent internalization of CR1 on human neutrophils. J Immunol 1985 134:1851 PubMed

8. Kalli KR,Hsu PH,Bartow TJ,Ahearn JM,Matsumoto AK,Klickstein LB,Fearon DT Mapping of the C3b-binding site of CR1 and construction of a (CR1)2- F(ab')2 chimeric complement inhibitor. J Exp Med 1991 174:1451 PubMed

9. Krych M,Clemenza L,Howdeshell D,Hauhart R,Hourcade D,Atkinson JP Analysis of the functional domains of complement receptor type 1 (C3b/C4b receptor; CD35) by substitution mutagenesis. J Biol Chem 1994 269:13273 PubMed

10. Mathew JM,Naziruddin B,Duffy B,Krych M,Mohanakumar T Functional analysis of complement receptor 1 using a new monoclonal antibody, KuN241. Hybridoma 1995 14:29 PubMed

11. Molina H,Holers VM,Li B,Fung Y,Mariathasan S,Goellner J,Strauss-Schoenberger J,Karr RW,Chaplin DD Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc Natl Acad Sci U S A 1996 93:3357 PubMed

12. Moulds JM,Nickells MW,Moulds JJ,Brown MC,Atkinson JP The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera. J Exp Med 1991 173:1159 PubMed

13. Nickells MW,Subramanian VB,Clemenza L,Atkinson JP Identification of complement receptor type 1-related proteins on primate erythrocytes. J Immunol 1995 154:2829 PubMed

14. O'Shea JJ,Brown EJ,Seligmann BE,Metcalf JA,Frank MM,Gallin JI Evidence for distinct intracellular pools of receptors for C3b and C3bi in human neutrophils. J Immunol 1985 134:2580 PubMed

15. Reist CJ,Liang HY,Denny D,Martin EN,Scheld WM,Taylor RP Cross-linked bispecific monoclonal antibody heteropolymers facilitate the clearance of human IgM from the circulation of squirrel monkeys. Eur J Immunol 1994 24:2018 PubMed

16. Tausk FA,McCutchan A,Spechko P,Schreiber RD,Gigli I Altered erythrocyte C3b receptor expression, immune complexes, and complement activation in homosexual men in varying risk groups for acquired immune deficiency syndrome. J Clin Invest 1986 78:977 PubMed

WWW RESOURCES

Portions copyright by Garland Press and by the International Workshops on Human Leukocyte Differentiation Antigens; used with permission

Modified 10/14/99   mpr@mail.nih.gov