BDCA-2

The BDCA-2 protein (BDCA-2 stands for: Blood Dendritic Cell Antigen 2) is encoded by the CLEC4C gene (CLEC4C stands for: C-Type Lectin Domain Family 4 Member C) located on chromosome 12p13.31. BDCA-2 is a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily.

The members of this lectin family share a common protein fold and diverse functions, such as cell adhesion, cell-cell signaling, glycoprotein turnover, and a role in inflammation and immune responses.

The encoded BDCA-2 protein is a type 2 transmembrane protein and plays a role in the function of dendritic plasmacytoid cells. BDCA-2 is a lectin-like cell surface receptor that may play a role in antigen capture by dendritic cells (Dzionek A et al. 2019; Riboldi E et al. 2011).

The BDCA-2 protein specifically recognizes non-sialylated galactose-terminated biantenary glycans containing the trisaccharide epitope Gal (beta1-3/4)GlcNAc(beta1-2)Man (Jégouzo SA et al. 2015). It binds to serum IgG (Jégouzo SA et al. 2015) and efficiently channels the ligand into antigen-processing and peptide-loaded compartments for presentation to T cells.

The BDCA-2 receptor protein can strongly inhibit the induction of IFN-alpha/beta expression in plasmacytoid dendritic cells (Riboldi E et al. 2011). May act as a signaling receptor that activates protein tyrosine kinases and mobilizes intracellular calcium.

The BDCA2 protein is exclusively expressed on plasmacytoid dendritic cells (pDCs), whose uncontrolled production of type I IFN (IFN-I) is crucial for the pathogenesis of SLE and other autoimmune diseases.

Recently, an anti-BDCA2 antibody (litifilimab) has been developed that causes a complete suppression of IFNα production and a broader inhibition of the production of inflammatory cytokines (Li X et al. 2024), which play a central role in the pathogenesis of systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE).

Litifilimab, a humanized monoclonal antibody, binds to BDCA2, which is only found on plasmacytoid dendritic cells (pDCs). Litifilimab is currently being investigated in phase III studies in both SLE and CLE (Cho YM et al. 2024). The consequence of BDCA2 binding is the inhibition of IFN-I as well as IFN-III, cytokine and chemokine production. These results confirmed the importance of pDCs and IFN-I in SLE and CLE.

1. Cho YM, Furie R. The development of litifilimab (BIIB 059) for cutaneous and systemic lupus erythematosus. Immunotherapy. 2024 Jan;16(1):15-20. doi: 10.2217/imt-2023-0086. Epub 2023 Oct 25. PMID: 37877249.

2. Dzionek A et al. (2019) BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med 194:1823-1834.

3. Jégouzo SA et al. (2015) A Novel Mechanism for Binding of Galactose-terminated Glycans by the C-type Carbohydrate Recognition Domain in Blood Dendritic Cell Antigen 2. J Biol Chem 290:16759-1671.
4. Li X et al. (2024) An immunomodulatory antibody-drug conjugate targeting BDCA2 strongly suppresses plasmacytoid dendritic cell function and glucocorticoid responsive genes. Rheumatology (Oxford) 63:242-250.
5. Riboldi E et al. (2011) Human C-type lectin domain family 4, member C (CLEC4C/BDCA-2/CD303) is a receptor for asialo-galactosyl-oligosaccharides. J Biol Chem 286:35329-35333.