STRUCTURE

CD21 is a glycoprotein with a large extracellular domain, a transmembrane domain and a short cytoplasmic tail. The extracellular domain is constituted by 15 or 16 short consensus repeat in tandem and it displays the N-terminal region of the protein. The extracytoplasmic portion of the molecule can be cleaved giving rise to a soluble form of CD21. ^1-2

1. Frémeaux-Bacchi V, Kolb JP, Rakotobé S, Kazatchkine MD, Fischer EM. Functional properties of soluble CD21. Immunopharmacology. 1999;42:31-7.

2. Weis JJ, Fearon DT, Klickstein LB, Wong WW, Richards SA, de Bruyn Kops A, Smith JA, Weis JH. Identification of a partial cDNA clone for the C3d/Epstein-Barr virus receptor of human B lymphocytes: homology with the receptor for fragments C3b and C4b of the third and fourth components of complement. Proc Natl Acad Sci U S A. 1986;83:5639-43.4.

LIGANDS

Extracellular

CD23¹, the C3 fragments iC3b, C3d and C3dg^2-4, the gp350/220^2-5 and IFN-alpha.⁶ It forms a complex in cis with CD19, TAPA-1 and Leu-13.^7-8 It also interacts in cis with CD35.⁹ CD21 is also the receptor of EBV⁵.

1. Aubry JP, Pochon S, Graber P, Jansen KU, Bonnefoy JY. CD21 is a ligand for CD23 and regulates IgE production. Nature. 1992;358:505-7.

2. Frémeaux-Bacchi V, Kolb JP, Rakotobé S, Kazatchkine MD, Fischer EM. Functional properties of soluble CD21. Immunopharmacology. 1999;42:31-7.

3. Roozendaal R, Carroll MC. Complement receptors CD21 and CD35 in humoral immunity. Immunol Rev. 2007;219:157-66.

4. van den Elsen JM, Isenman DE. A crystal structure of the complex between human complement receptor 2 and its ligand C3d. Science. 2011;332:608-11.

5. Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci U S A. 1984;81:4510-4.

6. Asokan R, Hua J, Young KA, Gould HJ, Hannan JP, Kraus DM, Szakonyi G, Grundy GJ, Chen XS, Crow MK, Holers VM. Characterization of human complement receptor type 2 (CR2/CD21) as a receptor for IFN-alpha: a potential role in systemic lupus erythematosus.

7. Matsumoto AK, Kopicky-Burd J, Carter RH, Tuveson DA, Tedder TF, Fearon DT. Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19. J Exp Med. 1991;173:55-64.

8. Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF. The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J Immunol. 1992;149:2841-50.

9. Tuveson DA, Ahearn JM, Matsumoto AK, Fearon DT. Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex. J Exp Med. 1991;173:1083-9.

Intracellular associate molecules

The transmembrane domain of CD21 potentially binds to VAP-A and WDR1, whereas the cytoplasmic tail potentially interacts with AP4S1. ATP6AP2 is also a potential binding candidate.¹

1. Tessier J, Cuvillier A, Glaudet F, Khamlichi AA. Internalization and molecular interactions of human CD21 receptor. Mol Immunol. 2007;44:2415-25.

CD21 is expressed on B lymphocytes and lymphoblasts as well as on thymocytes and on a fraction of T cells.^1-3 Other cells that express CR2 are follicular dendritic cells⁴, epithelial cells and astrocytes.^5-6

1. Frémeaux-Bacchi V, Kolb JP, Rakotobé S, Kazatchkine MD, Fischer EM. Functional properties of soluble CD21. Immunopharmacology. 1999;42:31-7.

2. Tsoukas CD, Lambris JD. Expression of CR2/EBV receptors on human thymocytes detected by monoclonal antibodies. Eur J Immunol. 1988;18:1299-302.

3. Fischer E, Delibrias C, Kazatchkine MD. Expression of CR2 (the C3dg/EBV receptor, CD21) on normal human peripheral blood T lymphocytes. J Immunol. 1991;146:865-9.

4. Liu YJ, Xu J, de Bouteiller O, Parham CL, Grouard G, Djossou O, de Saint-Vis B, Lebecque S, Banchereau J, Moore KW. Follicular dendritic cells specifically express the long CR2/CD21 isoform. J Exp Med. 1997;185:165-70.

5. Sixbey JW, Davis DS, Young LS, Hutt-Fletcher L, Tedder TF, Rickinson AB. Human epithelial cell expression of an Epstein-Barr virus receptor. J Gen Virol. 1987;68:805-11.

6. Gasque P, Chan P, Mauger C, Schouft MT, Singhrao S, Dierich MP, Morgan BP, Fontaine M. Identification and characterization of complement C3 receptors on human astrocytes. J Immunol. 1996;156:2247-55.

CD21, along with CD19, is part of a complex that modulates the signal transduction of the BCR, lowering the threshold of activation of B cells. ^1-3 A second function of CD21 consists of the retention of antigens in the membrane of follicular dendritic cells.^4-7 This process is vital as the antigens exposed by follicular dendritic cells should be acquired by B cells during the germinal center reaction. ⁸ What is more, another role of CD21 is the transport of immune complexes to follicular dendritic cells either in the spleen or in the lymph node by marginal zone B cells or naïve B cells.^9-11 Therefore, CD21 is necessary for the generation of an adequate immune response.¹²

1. Carter RH, Fearon DT. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science. 1992;256:105-7.

2. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996;271:348-50.

3. Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF. The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J Immunol. 1992;149:2841-50.

4. Brockman MA, Verschoor A, Zhu J, Carroll MC, Knipe DM. Optimal long-term humoral responses to replication-defective herpes simplex virus require CD21/CD35 complement receptor expression on stromal cells. J Virol. 2006;80:7111-7.

5. Barrington RA, Pozdnyakova O, Zafari MR, Benjamin CD, Carroll MC. B lymphocyte memory: role of stromal cell complement and FcgammaRIIB receptors. J Exp Med. 2002;196:1189-99.

6. Papamichail M, Gutierrez C, Embling P, Johnson P, Holborow EJ, Pepys MB. Complement dependence of localisation of aggregated IgG in germinal centres. Scand J Immunol. 1975;4:343-47.

7. Fang Y, Xu C, Fu YX, Holers VM, Molina H. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J Immunol. 1998;160:5273-9.

8. Oropallo MA, Cerutti A. Germinal center reaction: antigen affinity and presentation explain it all. Trends Immunol. 2014;35:287-9.

9. Cinamon G, Zachariah MA, Lam OM, Foss FW Jr, Cyster JG. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol. 2008;9:54-62.

10. Ferguson AR, Youd ME, Corley RB. Marginal zone B cells transport and deposit IgM-containing immune complexes onto follicular dendritic cells. Int Immunol. 2004;16:1411-22.

11. Phan TG, Grigorova I, Okada T, Cyster JG. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat Immunol. 2007;8:992-1000.

12. Hebell T, Ahearn JM, Fearon DT. Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science. 1991;254:102-5.

Cell marker

CD21 can be used as a marker to differentiate B cell subtypes. ^1-2 Furthermore, CD21 is a useful marker for classifying the B-cell precursor acute lymphoblastic leukemia.³ In addition, CD21 can be used as a marker of prognosis in CLL and DLBCL.^4-5

1. Boldt A, Borte S, Fricke S, Kentouche K, Emmrich F, Borte M, Kahlenberg F, Sack U. Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies. Cytometry B Clin Cytom. 2014;86:191-206.

2. Kaminski DA, Wei C, Qian Y, Rosenberg AF, Sanz I. Advances in human B cell phenotypic profiling. Front Immunol. 2012;3:302.

3. Van Dongen JJ, Lhermitte L, Böttcher S, Almeida J, van der Velden VH, Flores-Montero J, Rawstron A, Asnafi V, Lécrevisse Q, Lucio P, Mejstrikova E, Szczepański T, Kalina T, de Tute R, Brüggemann M, Sedek L, Cullen M, Langerak AW, Mendonça A, Macintyre E, Martin-Ayuso M, Hrusak O, Vidriales MB, Orfao A; EuroFlow Consortium (EU-FP6, LSHB-CT-2006-018708). EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26:1908-75.

4. Nichols EM, Jones R, Watson R, Pepper CJ, Fegan C, Marchbank KJ. A CD21 low phenotype, with no evidence of autoantibodies to complement proteins, is consistent with a poor prognosis in CLL. Oncotarget. 2015;6:32669-80.

5. Otsuka M, Yakushijin Y, Hamada M, Hato T, Yasukawa M, Fujita S. Role of CD21 antigen in diffuse large B-cell lymphoma and its clinical significance. Br J Haematol. 2004;127:416-24.

Therapeutic

To our knowledge, only one antibody targeting CD21, OKB7, has been studied. This antibody has been tested, labeled with iodine, in phase I studies of non-Hodgkin’s lymphoma. Positive antitumor responses were detected in 13 out of 18 patients which suggests that CD21 might be a novel therapeutic approach in non-Hodgkin’s lymphoma.^1-2

On the other hand, a different therapy is the CD21-targeted complement inhibitor which consists of a fusion protein of a complement inhibitor bound to a C3 binding region of CD21.³ Beneficial effects have already been reported using this approach in murine models of atherosclerosis or arthritis.^3-4

1. Czuczman MS, Straus DJ, Divgi CR, Graham M, Garin-Chesa P, Finn R, Myers J, Old LJ, Larson SM, Scheinberg DA. Phase I dose-escalation trial of iodine 131-labeled monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma. J Clin Oncol. 1993;11:2021-9.

2. Scheinberg DA, Straus DJ, Yeh SD, Divgi C, Garin-Chesa P, Graham M, Pentlow K, Coit D, Oettgen HF, Old LJ. A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: effects of tumor burden and antigen expression. J Clin Oncol. 1990;8:792-803.

3. Song H, He C, Knaak C, Guthridge JM, Holers VM, Tomlinson S. Complement receptor 2-mediated targeting of complement inhibitors to sites of complement activation. J Clin Invest. 2003;111:1875-85.

4. Song H, Qiao F, Atkinson C, Holers VM, Tomlinson S. A complement C3 inhibitor specifically targeted to sites of complement activation effectively ameliorates collagen-induced arthritis in DBA/1J mice. J Immunol. 2007;179:7860-7.