CD21-

Synonyms: Cluster of differentiation 21, complement receptor type 2, complement C3d receptor and EBV receptor

by Assia Bassarova

Background

CD21(complement receptor 2 / CR2) is 145-kDa type I transmembrane glycoprotein. It belongs to a family of complement proteins, known as regulators of complement activation. The human CD21 gene is located at chromosome 1q32 that is tightly linked to the genes for CD35, CD55 and C4-binding protein. CD21 binds and recognizes a variety of ligands, such as the Epstein-Barr virus, the IgE receptor CD23, IFNα, and the complement C3 degradation products C3d, iC3b, and C3d,g. CD21 profoundly modulates B cell functions.

CD21 facilitates cellular recognition of the C3 cleavage products C3d and C3d. Complement plays a modulatory role in a variety of B cell functions, including activation and differentiation, antigen internalization and presentation, and immunoglobulin class switching.

Naive B cells require two activation signals to become optimally activated, begin proliferating and generating antigen specific antibodies. The first activation signal is propagated through the stimulation of the B-cell receptor (BCR) and its co-receptor complex composed of complement receptor 2 (CR2, CD21)/CD19/CD81. Co-engagement of the BCR and of CD21 by C3d-opsoninized antigen enhances B cell activation and is also key to the generation of B cell memory.

The B cell uptake of complement C3d-coated antigen plays an important role in formation and maintenance of germinal centers and the subsequent differentiation of memory and effector B cells. B cells are observed to transfer complement-coated antigen to follicular dendritic cells (DCs) via the CR2 receptor; these store the antigen, periodically transferring it back to the B cells to maintain the germinal centers and extend the humoral response.

Staining in normal cells/tissues: CD21 is expressed at higher levels on mature B lymphocytes and FDC in germinal centers. Expression at lower density has been observed with thymocytes and peripheral blood T cells. On epithelial cells, however, CD21 is thought to play a critical role in the natural history of EBV infection.

Staining in tumors: CD21 is used both as an immunohistochemical marker, specific for follicular dendritic cell tumor, but also as a marker highlighting FDC network in different reactive and neoplastic processes in the lymph nodes.

  • (+) Follicular dendritic cell tumors, small cell B cell lymphomas (especially chronic lymphocytic leukemia/small cell lymphocytic lymphoma, mantle cell lymphoma and MZL), hyaline vascular variant of Castleman’s disease, splenic littoral cell angiomas
  • (+/-)  Follicular dendritic cell network in follicular lymphoma, MZL, AITL, nodular lymphocyte-predominant Hodgkin lymphoma
  • -(+) Precursor T-ALL and precursor B-ALL
  •  [-] Dendritic cell neurofibroma with pseudorosettes, histiocytic sarcoma, inflammatory fibroid polyps of GI tract, inflammatory myofibroblastic tumor, splenic hamartomas

Staining pattern: distinct membranous.

Control tissue: Normal tonsil or appendix in which virtually all FDC in the germinal center are strongly stained. CD21 expression is absent or weak on germinal centre B-cells, moderate on the mantle zone B-cells and strong on the marginal zone B-cells (Fig. 1)

Application:

  • Diagnosis of follicular dendritic cell sarcomas
  • Assessment of follicular dendritic cell meshwork structure in follicular lymphoma (preserved FDC network in the background) and DLBCL (small rests of FDC network if present at all)
  • Assessment of follicular dendritic cell meshwork structures AITL and perifollicular variant of PTCL, NOS
  • Differentiate invasive Quilty lesions from acute cellular graft rejection

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