STRUCTURE

CD19 is a type I glycoprotein that belongs to Ig superfamily.^1-2 The extracellular region of CD19 contains three different domains. Two of which, the first and the third, are type C2 Ig-like domains.^1-2 CD19 displays a single transmembrane region and a large cytoplasmic tail. ^1-2 This tail contains many sites that can be phosphorylated and are therefore involved in CD19 signalling.²

1. Tedder TF, Isaacs CM. Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol. 1989;143:712-7.

2. Tedder TF. CD19: a promising B cell target for rheumatoid arthritis. Nat Rev Rheumatol. 2009;5:572-7.

LIGANDS

Extracellular

No bona fide ligand for CD19 has been reported. CD19 is associated in cis with CD81, CD21, CD82, and CD225 forming the BCR co-receptor complex. ^1-4 Other cis ligands are CD9, IGHM and CD38.^3-5

Intracellular

At an intracellular level, CD19 can interact with lyn⁶, PIK3R3 ⁴, PIK3R1^4-7, BTK⁷, ARID3A⁷, Sos⁸, Grb2⁸, Vav⁸, PLC-γ2⁸, fyn and lck.¹

1. Tedder TF, Zhou LJ, Engel P. The CD19/CD21 signal transduction complex of B lymphocytes. Immunol Today. 1994;15:437-42.

2. 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.

3. Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E. CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. J Biol Chem. 1998;273:30537-43.

4. Orchard S, Ammari M, Aranda B, Breuza L, Briganti L, Broackes-Carter F, Campbell NH, Chavali G, Chen C, del-Toro N, Duesbury M, Dumousseau M, Galeota E, Hinz U, Iannuccelli M, Jagannathan S, Jimenez R, Khadake J, Lagreid A, Licata L, Lovering RC, Meldal B, Melidoni AN, Milagros M, Peluso D, Perfetto L, Porras P, Raghunath A, Ricard-Blum S, Roechert B, Stutz A, Tognolli M, van Roey K, Cesareni G, Hermjakob H. The MIntAct project--IntAct as a common curation platform for 11 molecular interaction databases. Nucleic Acids Res. 2014;42:D358-63.

5. Deaglio S, Capobianco A, Bergui L, Dürig J, Morabito F, Dührsen U, Malavasi F. CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells. Blood. 2003;102:2146-55.

6. Roifman CM, Ke S. CD19 is a substrate of the antigen receptor-associated protein tyrosine kinase in human B cells. Biochem Biophys Res Commun. 1993;194:222-5.

7. Licata L, Briganti L, Peluso D, Perfetto L, Iannuccelli M, Galeota E, Sacco F, Palma A, Nardozza AP, Santonico E, Castagnoli L, Cesareni G. MINT, the molecular interaction database: 2012 update. Nucleic Acids Res. 2012;40:D857-61.

8. Brooks SR, Li X, Volanakis EJ, Carter RH. Systematic analysis of the role of CD19 cytoplasmic tyrosines in enhancement of activation in Daudi human B cells: clustering of phospholipase C and Vav and of Grb2 and Sos with different CD19 tyrosines. J Immunol. 2000;164:3123-31.

CD19 is a panmarker of the B-cell lineage. Its expression starts in pro-B cells and remains through development and maturation although its level varies. Apart from its expression in B cells, CD19 is also present on a subset of plasma cells.^1-2

1. Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1:36.

2. Robillard N, Wuillème S, Moreau P, Béné MC. Immunophenotype of normal and myelomatous plasma-cell subsets. Front Immunol. 2014;5:137.

3. Nagasawa T. Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol. 2006;6:107-16.

CD19 is part of a complex that modulates the signal transduction of the BCR by different mechanisms.^1-2 For instance, CD19 regulates calcium flux and MAP kinase activation and Src PTK activation.¹ Through these mechanisms, CD19 plays a role in B cell development, activation and differentiation.^3-4 Therefore, it is essential for developing an adequate immune response.

1. Li X, Ding Y, Zi M, Sun L, Zhang W, Chen S, Xu Y. CD19, from bench to bedside. Immunol Lett. 2017;183:86-95.

2. Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1:36.

3. Rickert RC, Rajewsky K, Roes J. Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature. 1995 27;376:352-5.

4. Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity. 1995;3:39-50.

Cell Marker

CD19 can be used as a marker of B cells. Consequently, it is used for the diagnosis of B-cell hematologic malignancies.¹

1. 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.

Therapeutic

Blinatumomab is a bispecific antibody targeting CD19 and CD23 which has been approved by the FDA for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL). In particular, it is indicated for those patients with ALL with minimal residual disease and for those with refractory or relapsed ALL. Blinatumomab has shown its efficacy nearly doubling the survival of patients in a phase III clinical trial. ¹ Apart from that, anti-CD19 antibodies have been studied in other hematologic malignancies and autoimmune diseases.²

In addition, two CAR-T cell therapies targeting CD19 are being used in oncology. First, there is Kymriah, which is indicated for young patients with refractory or relapsed B-cell precursor ALL. The other CAR-T cell therapy is Yescarta and it is indicated for the treatment of relapsed or refractory B-cell lymphoma.^3-4

1. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376:836-847.

2. Naddafi F, Davami F. Anti-CD19 Monoclonal Antibodies: a New Approach to Lymphoma Therapy. Int J Mol Cell Med. 2015;4:143-51.

3. U.S. Food and Drug Administration [internet]. 20/02/2018. Yescarta. Available from: https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm581222.htm.

4. U.S. Food and Drug Administration [internet]. 05/07/2018. Kimriah. Available from: https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm.