Alternative titles; symbols
HGNC Approved Gene Symbol: CD19
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:28,931,971-28,939,342 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Immunodeficiency, common variable, 3 | 613493 | Autosomal recessive | 3 |
CD19 is a cell surface molecule expressed only by B lymphocytes and follicular dendritic cells of the hematopoietic system. It is the earliest of the B-lineage-restricted antigens to be expressed and is present on most pre-B cells and most non-T-cell acute lymphocytic leukemia cells and B-cell type chronic lymphocytic leukemia cells (Tedder and Isaacs, 1989).
Tedder and Isaacs (1989) isolated cDNA clones that encode CD19 from a human tonsil cDNA library and determined the amino acid sequence. The amino acid sequence showed no significant homology with other known proteins, but the putative extracellular region contained 2 Ig-like domains, indicating that CD19 is a new member of the Ig superfamily. The CD19 molecule has a molecular mass of about 95,000 Da.
Ord et al. (1994) assigned the CD19 gene to 16p11.2 by in situ hybridization and by PCR analysis of a panel of human/hamster somatic cell hybrid DNAs. The mouse gene was mapped to bands F3-F4 of chromosome 7 by in situ hybridization. Segregation analysis in interspecific backcross progeny showed linkage to loci previously mapped to the same region of mouse chromosome 7 in a region of conserved synteny with human chromosome 16.
Carter and Fearon (1992) described the role of CD19 in helping the B cell resolve its dilemma, the conflict between broad specificity and sensitivity. The former is met by low-affinity antigen receptors, which precludes achieving the latter with high-affinity receptors. Coligation of CD19 with the antigen receptor of B lymphocytes decreases the threshold for antigen receptor-dependent stimulation by 2 orders of magnitude. Thus, B lymphocytes proliferate when approximately 100 antigen receptors per cell, 0.03% of the total, are ligated with CD19.
Fujimoto et al. (2000) noted that CD19, which contains a 240-amino acid cytoplasmic tail with 9 conserved tyr (Y) residues, intersects with multiple intracellular signaling pathways. LYN (165120), the predominant Src kinase in B cells, is critical in B-cell antigen receptor (BCR, e.g., IgM; 147020) signaling and regulation. Using cells from transgenic mice, the authors demonstrated that following BCR and/or CD19 ligation, LYN phosphorylates CD19 at Y513, then binds to CD19 via its SH2 domain and phosphorylates Y482 through what Fujimoto et al. (2000) called 'processive phosphorylation.' Phosphorylated CD19-Y482 then recruits another LYN molecule, leading to LYN phosphorylation and/or autophosphorylation. CD19 phosphorylation induces conformational changes that permit phosphorylation of CD19-Y391. This molecule then recruits VAV (164875), which is in turn phosphorylated by LYN. In vivo, CD19 deficiency impaired, and CD19 overexpression enhanced, LYN kinase activity. CD19 thus functions as a specialized adaptor protein for the amplification of Src family kinases that is crucial for intrinsic and antigen receptor-induced signal transduction.
Sato et al. (2000) subtly increased CD19 cell surface expression in mice using transgenic techniques and found that these changes induced autoantibody production. They found a similar increase in CD19 expression on B cells in patients with systemic sclerosis (see 181750), whereas CD20 (MS4A1; 112210), CD22 (107266), and CD40 (109535) expression was unchanged. Sato et al. (2000) proposed that modest changes in expression of regulatory molecules, such as CD19, may shift the balance between tolerance and immunity to autoimmunity.
Using flow cytometric analysis, van Zelm et al. (2014) found reduced numbers of all memory B-cell subsets except CD27 (TNFRSF7; 186711)-negative/IgA-positive B cells in both CD19-deficient patients and CD40L (CD40LG; 300386)-deficient patients compared with controls. Analysis of transcripts after class switching demonstrated that patient transcripts had fewer somatic mutations and reduced usage of IgG2 and IgA2 subclasses. There was also a deficiency in selection strength of mutations for antigen binding in patients compared with controls, whereas selection to maintain superantigen binding was normal. Selection against the autoreactive properties of immunoglobulins was impaired in patients. Somatic hypermutation analysis revealed decreased AICDA (605257) and UNG (191525) activity in CD40L deficiency, but increased UNG activity and decreased mismatch repair in CD19 deficiency. Van Zelm et al. (2014) concluded that both the B-cell antigen receptor and CD40 signaling pathways are required for selection of immunoglobulin reactivity, but that they differentially mediate DNA repair pathways during somatic hypermutation and thereby together shape the mature B-cell repertoire.
Varano et al. (2017) studied the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compared them with observations in human Burkitt lymphoma (113970). Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumor cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumor cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase-3-beta (GSK3-beta; 605004) activity to support MYC-controlled gene expression. BCR- tumor cells exhibit increased GSK3-beta activity and are rescued from their competitive growth disadvantage by GSK3-beta inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3-beta activity after constitutive activation of the MAPK (see 176948) pathway, commonly through RAS (see 190020) mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumor cells, which usually represent a minority of the tumor bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumor cells.
Van Zelm et al. (2006) evaluated 4 patients from 2 unrelated families who had increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of mature B cells in blood, consistent with common variable immunodeficiency (CVID3; 613493). They found that all 4 patients had homozygous mutations in the CD19 gene. Levels of CD19 were undetectable in 1 patient and substantially reduced in the other 3. Levels of CD21 (CR2; 120650) were decreased, whereas levels of CD81 (186845) and CD225 (IFITM1; 604456) were normal, in all 4 patients. The composition of the precursor B-cell compartment in bone marrow and the total numbers of B cells in blood were normal. However, the number of CD27-positive memory B cells and CD5-positive (153340) B cells were decreased. Secondary follicles in lymphoid tissues were small to normal in size and had a normal cellular composition. The few B cells that showed molecular signs of switching from one immunoglobulin class to another contained V(H)-C(alpha) and V(H)-C(gamma) transcripts with somatic mutations. The response of the patients' B cells to in vitro stimulation through the B-cell receptor was impaired, and in all 4 patients, the antibody response to rabies vaccination was poor. Van Zelm et al. (2006) concluded that mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective. On the basis of the crucial role of CD19 in signaling by the B-cell receptor on antigen recognition, van Zelm et al. (2006) thought it likely that defects in other members of the CD19 complex (CD21, CD81, and CD225) also lead to antibody deficiency in humans.
In a 6-year-old Moroccan boy, born of consanguineous parents with CVID3, absence of CD19 on his B cells, and defective B-cell signaling, van Zelm et al. (2011) identified a homozygous missense mutation in the CD19 gene (W52C; 107265.0004). The substitution occurred at a conserved residue in the D1 extracellular immunoglobulin superfamily constant domain. This residue was present in all variable domains in immunoglobulin and T-cell receptors, and was not mutated in 117 Ig class-switched transcripts of B cells. The findings indicated that the W52 residue is critical for proper folding and stability of the immunoglobulin superfamily domain.
In 2 unrelated patients with CVID3, Vince et al. (2011) identified 2 different homozygous truncating mutations in the CD19 gene (107265.0005 and 107265.0006).
Hasegawa et al. (2001) generated mice deficient in both Cd19 and Lyn. Cd19 deficiency suppressed the hyperresponsive phenotype of Lyn -/- B cells and autoimmunity characterized by serum autoantibodies and immune complex-mediated glomerulonephritis in Lyn -/- mice. Cd19/Lyn -/- mice had additional reduction of primitive, predominantly IgM-secreting B1 lymphocytes. Cd19 deficiency inhibited activation of Src family protein tyrosine kinase-dependent signaling pathways and delayed enhanced intracellular calcium responses following B-cell antigen receptor ligation in Lyn -/- B cells. Hasegawa et al. (2001) concluded that Cd19 expression is required for the development of autoimmunity in Lyn -/- mice.
By selective inactivation of Pten (601728) in mouse B lymphocytes and immunohistochemical analysis, Anzelon et al. (2003) detected a selective expansion of marginal zone (MZ) B and B1 cells. Pten-deficient B cells were hyperproliferative in response to mitogenic stimuli and had a lower threshold for activation through the B lymphocyte antigen receptor. Inactivation of Pten rescued germinal center, MZ B, and B1 cell formation in Cd19 -/- mice, which exhibit reduced activation of PI3K (see PIK3CG; 601232). Anzelon et al. (2003) concluded that intracellular phosphatidylinositol-3,4,5-trisphosphate has a central role in the regulation of differentiation of peripheral B-cell subsets.
Using immunohistochemistry and flow cytometric analysis, You et al. (2009) demonstrated that Signr1 (see CD209; 604672)-positive MZ macrophages were absent and Cd11c (ITGAX; 151510)-positive MZ dendritic cells were abnormally distributed in Cd19 -/- mice. Adoptively transferred normal mouse B cells could reconstitute MZ B cells in Cd19 -/- mice and restore MZ macrophage and dendritic cell distribution. In contrast, Cd19 -/- B cells failed to enter the MZ of normal mice. You et al. (2009) concluded that MZ B cells are required for MZ macrophage differentiation and MZ dendritic cell localization, but that MZ B-cell deficiency in Cd19 -/- mice is due to a defect of intrinsic B-cell signaling.
Saito et al. (2002) found that B cells of 'tight-skin' (Tsk/+) mice (see 134797), a model for human systemic sclerosis, had decreased IgM expression, enhanced serum IgG production, spontaneous autoantibody production, and enhanced Cd19 tyrosine phosphorylation, Vav phosphorylation, and Lyn kinase activity. Tsk/+ mice deficient in Cd19 expression showed decreased skin fibrosis, upregulated surface IgM expression, abrogation of hypergammaglobulinemia and autoantibody production, and inhibition of Il6 (147620) production. Saito et al. (2002) concluded that chronic B-cell activation resulting from augmented Cd19 signaling in Tsk/+ mice leads to skin sclerosis and autoimmunity, possibly through overproduction of Il6.
By constructing knockin mice expressing mutant Cr2 (CD21; 120650) that bound C3d (186790) ligands but did not signal through Cd19, Barrington et al. (2009) showed that uncoupling of Cr and Cd19 significantly diminished survival of germinal center B cells and secondary antibody titers. However, B-cell memory was less impaired than it was in mice with complete B-cell Cr deficiency. Barrington et al. (2009) concluded that the interaction of CR and CD19 is important for T-dependent humoral immunity and that CR may have a role in B-cell memory independent of CD19.
In a Turkish girl, born of consanguineous parents, who had common variable immunodeficiency-3 (CVID3; 613493), van Zelm et al. (2006) identified homozygosity for an insertion of an adenine in exon 6 of the CD19 gene. This insertion caused a frameshift, resulting in a premature stop codon at the intracellular amino acid 328. The patient had a history of recurrent bronchiolitis and bronchopneumonia starting at 1 year of age and meningitis starting at 8 years of age. A diagnosis of postinfectious glomerulonephritis was made at the age of 10 years, at which time she was found to have hypogammaglobulinemia.
In 3 sibs, offspring of unrelated parents of Colombian descent, examined at ages 35, 33, and 49 years of age, respectively, for common variable immunodeficiency-3 (CVID3; 613493), van Zelm et al. (2006) identified homozygosity for a dinucleotide deletion of guanine and adenine in exon 11 of the CD19 gene, resulting in a premature stop codon at the intracellular amino acid 465. The parents and several members of the family were heterozygous for the mutation but had no clinical features of immunodeficiency. All 3 sibs had had otitis media, sinusitis, and pharyngitis during childhood. In addition, 1 had had 4 bouts of pneumonia between the ages of 18 and 35 years; he had received diagnoses of bacterial conjunctivitis and chronic gastritis (Helicobacter pylori infection). The study showed that the disruption of CD19 signaling results in a primary antibody deficiency, mainly characterized by a poor antigen-specific response. Normal levels of CD19 transcripts were found in B cells from all patients.
In a Japanese boy with common variable immunodeficiency-3 (CVID3; 613493), Kanegane et al. (2007) identified compound heterozygous genetic alterations resulting in disruption of the CD19 gene. One allele, inherited from the unaffected mother, carried a heterozygous G-to-T transversion in intron 6, resulting in the skipping of exon 6, a frameshift, and premature termination. The other allele carried a 68.5-kb deletion including the ATP2A1 (108730), CD19, and NFATC2IP (614525) genes. Paternal DNA was not available to determine whether the large deletion was inherited or occurred de novo.
In a 6-year-old Moroccan boy, born of consanguineous parents, with common variable immunodeficiency-3 (CVID3; 613493), van Zelm et al. (2011) identified a homozygous c.156G-C transversion (c.156G-C, NM_001770.5) in exon 2 of the CD19 gene, resulting in a trp52-to-cys (W52C) substitution at a conserved residue in the D1 extracellular immunoglobulin superfamily constant domain. Each unaffected parent was heterozygous for the mutation. Flow cytometry showed absence of CD19 expression on the patient's B cells; heterozygous carriers had decreased CD19 expression compared to controls. Western blot analysis of patient cells showed decreased amounts of intracellular protein compared to controls, and the mutant protein was smaller, suggesting abnormal processing and immature glycosylation. Patient B cells showed defective antibody production in response to vaccination, as well as delayed calcium influx from the endoplasmic reticulum to the cytoplasm upon stimulation, consistent with a signaling defect. The few remaining memory B cells from the patient showed greatly reduced somatic hypermutation compared to controls. Expression of wildtype CD19 in patient cells restored the expression of CD19 on the surface of B cells. The findings indicated that the W52 residue is critical for proper folding and stability of the immunoglobulin superfamily domain.
In a 11-year-old girl of Kurdish descent (patient A) with common variable immunodeficiency-3 (CVID3; 613493), Vince et al. (2011) identified a homozygous 1-bp deletion (c.1464delC) in the CD19 gene, resulting in a frameshift and premature termination (Pro488ProfsTer15) in the intracytoplasmic domain. The patient's unaffected parents and sibling were heterozygous for the mutation.
In a 31-year-old woman (Patient B), born of consanguineous Moroccan parents, with common variable immunodeficiency-3 (CVID3; 613493), Vince et al. (2011) identified a homozygous complex insertion in the CD19 gene (c.1653_1671+9del28bpins23bp) that was predicted to disrupt the wildtype stop codon (Gly551GlyfsTer25) and affect the intracytoplasmic domain. The patient had a somewhat unusual phenotype in that she had protective levels of antibodies to vaccinations, had selective IgG1 deficiency, normal levels of IgD-CD27+ switched memory B cells. She had clinical evidence of immunodeficiency, but the major complication was progressive IgA nephropathy and glomerulonephritis resulting in end-stage renal disease.
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Barrington, R. A., Schneider, T. J., Pitcher, L. A., Mempel, T. R., Ma, M., Barteneva, N. S., Carroll, M. C. Uncoupling CD21 and CD19 of the B-cell coreceptor. Proc. Nat. Acad. Sci. 106: 14490-14495, 2009. [PubMed: 19706534] [Full Text: https://doi.org/10.1073/pnas.0903477106]
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Hasegawa, M., Fujimoto, M., Poe, J. C., Steeber, D. A., Lowell, C. A., Tedder, T. F. A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficient mice. J. Immun. 167: 2469-2478, 2001. [PubMed: 11509585] [Full Text: https://doi.org/10.4049/jimmunol.167.5.2469]
Kanegane, H., Agematsu, K., Futatani, T., Sira, M. M., Suga, K., Sekiguchi, T., van Zelm, M. C., Miyawaki, T. Novel mutations in a Japanese patient with CD19 deficiency. Genes Immunity 8: 663-670, 2007. [PubMed: 17882224] [Full Text: https://doi.org/10.1038/sj.gene.6364431]
Ord, D. C., Edelhoff, S., Dushkin, H., Zhou, L.-J., Beier, D. R., Disteche, C., Tedder, T. F. CD19 maps to a region of conservation between human chromosome 16 and mouse chromosome 7. Immunogenetics 39: 322-328, 1994. [PubMed: 7513297] [Full Text: https://doi.org/10.1007/BF00189228]
Saito, E., Fujimoto, M., Hasegawa, M., Komura, K., Hamaguchi, Y., Kaburagi, Y., Nagaoka, T., Takehara, K., Tedder, T. F., Sato, S. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J. Clin. Invest. 109: 1453-1462, 2002. [PubMed: 12045259] [Full Text: https://doi.org/10.1172/JCI15078]
Sato, S., Hasegawa, M., Fujimoto, M., Tedder, T. F., Takehara, K. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J. Immun. 165: 6635-6643, 2000. [PubMed: 11086109] [Full Text: https://doi.org/10.4049/jimmunol.165.11.6635]
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van Zelm, M. C., Bartol, S. J. W., Driessen, G. J., Mascart, F., Reisli, I., Franco, J. L., Wolska-Kusnierz, B., Kanegane, H., Boon, L., van Dongen, J. J. M., van der Burg, M. Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J. Allergy Clin. Immun. 134: 135-144, 2014. [PubMed: 24418477] [Full Text: https://doi.org/10.1016/j.jaci.2013.11.015]
van Zelm, M. C., Reisli, I., van der Burg, M., Castano, D., van Noesel, C. J. M., van Tol, M. J. D., Woellner, C., Grimbacher, B., Patino, P. J., van Dongen, J. J. M., Franco, J. L. An antibody-deficiency syndrome due to mutations in the CD19 gene. New Eng. J. Med. 354: 1901-1912, 2006. [PubMed: 16672701] [Full Text: https://doi.org/10.1056/NEJMoa051568]
van Zelm, M. C., Smet, J., van der Burg, M., Ferster, A., Le, P. Q., Schandene, L., van Dongen, J. J. M., Mascart, F. Antibody deficiency due to a missense mutation in CD19 demonstrates the importance of the conserved tryptophan 41 in immunoglobulin superfamily domain formation. Hum. Molec. Genet. 20: 1854-1863, 2011. [PubMed: 21330302] [Full Text: https://doi.org/10.1093/hmg/ddr068]
Varano, G., Raffel, S., Sormani, M., Zanardi, F., Lonardi, S., Zasada, C., Perucho, L., Patrocelli, V., Haake, A., Lee, A. K., Bugatti, M., Paul, U., and 9 others. The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3-beta inhibition. Nature 546: 302-306, 2017. [PubMed: 28562582] [Full Text: https://doi.org/10.1038/nature22353]
Vince, N., Boutboul, D., Mouillot, G., Just, N., Peralta, M., Casanova, J.-L., Conley, M. E., Bories, J.-C., Oskenhendler, E., Malphettes, M., Fieschi, C., DEFI Study Group. Defects in the CD19 complex predispose to glomerulonephritis, as well as IgG1 subclass deficiency. J. Allergy Clin. Immun. 127: 538-541e1-5, 2011. Note: Electronic Article. [PubMed: 21159371] [Full Text: https://doi.org/10.1016/j.jaci.2010.10.019]
You, Y., Zhao, H., Wang, Y., Carter, R. H. Cutting edge: primary and secondary effects of CD19 deficiency on cells of the marginal zone. J. Immun. 182: 7343-7347, 2009. [PubMed: 19494255] [Full Text: https://doi.org/10.4049/jimmunol.0804295]