Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

CD19 Deficiency Due to Genetic Defects in the CD19 and CD81 Genes

  • Menno C. van ZelmEmail author
  • Ismail Reisli
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_24-1

Definition

An immunodeficiency defined by deleterious mutations and/or deletions in CD19 or CD81 encoding CD19 and CD81 B cell surface proteins.

Prevalence

To date, 10 patients have been identified with CD19 deficiency due to mutations in CD19 and 1 patient due to a deleterious mutation in CD81.

Physiology of CD19 and the Complex Members CD21, CD81, and CD225

B-cell lineage commitment from hematopoietic stem cells is a stepwise process and critically depends on several transcription factors, including E2A, EBF, and Pax5 (Lin and Grosschedl 1995; Urbanek et al. 1994; Zhuang et al. 1994). In addition to functioning as B-cell commitment factor, Pax5 directly regulates CD19 gene expression (Kozmik et al. 1992). As a result, CD19 membrane expression – first described in 1983 (Nadler et al. 1983) – is a direct marker of committed B cells and is reflective of the expression of Pax5 (Fig. 1). CD19 is expressed prior to surface immunoglobulin (Ig) and two previously characterized markers that are now known as CD20 (Stashenko et al. 1980) and CD21 (Nadler et al. 1981) (Fig. 1).
Fig. 1

CD19 complex function and gene expression levels in B-cell precursors. (a) Upon antigen recognition, the BCR induces a signaling cascade. The CD19 complex acts to lower the threshold for activation through recruitment of phosphoinositide 3-kinase (PI3K). Together, these signals induce nuclear translocation of at least three transcription factors (NF-kB, ERK, and NFAT) and stimulate protein translation. (bd) Gene expression levels of CD19-complex members (b), other B-cell markers (c), and transcription factors (d). Data are derived from purified B-cell precursors using Affymetrix HG-U133A/B Gene Chips and data were normalized into zero mean and unit standard deviation (z-score) (van Zelm et al. 2005)

The CD19 gene encodes a single transmembrane protein with an N-terminal extracellular domain containing 2 Ig-like domains and a C-terminal intracellular tail with conserved tyrosine residues necessary for intracellular signaling (Stamenkovic and Seed 1988; Tedder and Isaacs 1989) (Fig. 1). CD19 was found to directly bind to CD21 (complement receptor 2; CR2) (Matsumoto et al. 1991), which binds to complement fragment C3d and is the receptor for Epstein-Barr virus (EBV) (Moore et al. 1987; Tedder et al. 1984; Weis et al. 1987). Two other components of the same complex were found to be CD81 (TAPA-1) and CD225 (encoded by the IFITM1 gene) (Bradbury et al. 1992). CD81 and CD225 had been identified before (Chen et al. 1984; Oren et al. 1990) and were found to bind each other (Takahashi et al. 1990). The proteins are not lineage-restricted and bind each other independent of CD19 or CD21. Conversely, CD19 expression does require the presence of CD81 (Maecker and Levy 1997; Miyazaki et al. 1997; Tsitsikov et al. 1997), and in turn CD19 directly binds CD21 (Matsumoto et al. 1991). The complex of CD19/CD21/CD81/CD225 is fully formed on immature and mature B cells (Fig. 1) and functions to augment signaling through surface immunoglobulins (B-cell antigen receptor; BCR) (Bradbury et al. 1992; Matsumoto et al. 1993).

Clinical Presentation

All 11 patients presented during childhood, predominantly with recurrent upper and/or lower respiratory infections (Table 1). In several cases, bacterial septicemia, meningitis, and conjunctivitis have been observed, as well as gastrointestinal problems. The severity of infections is highly variable between patients, and the benign disease course in four patients was likely the cause of delayed diagnosis in adulthood, 18–44 years after onset of infections (patients B1–3 and F1).
Table 1

Epidemiological, genetic, and clinical characteristics of all CD19 deficiency cases with genetic defects in CD19 and CD81 that have been reported to date

Patient

Descent

Gene

Gender

Age at onset

Age at diagnosis

Presenting manifestations

Clinical manifestations before diagnosis

Clinical manifestations at diagnosis

Treatment

Outcome

Reference

A1

Turkish

CD19

F

1

10

LRI

Recurrent LRI and meningitis

COPD, postinfectious GN

IVIG, NSAID

Mild SLE, good

(Artac et al. 2010; van Zelm et al. 2006)

A2

  

M

0.5

12

Recurrent URI/LRI

Recurrent LRI and otitis

Recurrent URI/LRI

IVIG

Good

 

B1

Colombian

CD19

M

7

35

URI

Recurrent LRI, chronic sinusitis

LRI, bacterial conjunctivitis, gastritis

IVIG, sinus surgery

Good

(van Zelm et al. 2006)

B2

  

F

6

33

URI

LRI, herpes zoster, chronic sinusitis

Recurrent bacterial conjunctivitis/dacryocystitis, diarrhea

IVIG, sinus surgery

Good

 

B3

  

F

5

49

URI

Recurrent LRI, recurrent skin abscesses, chronic sinusitis

LRI, recurrent bacterial conjunctivitis, chronic diarrhea

IVIG, sinus surgery

Good

 

C1

Japanese

CD19

M

5

8a

Pyelonephritis, bronchitis, gastritis, thrombocytopenia

NR

Pyelonephritis, bronchitis, gastritis, thrombocytopenia

IVIGs

Good

(Kanegane et al. 2007)

D1

Moroccan

CD19

M

NR

6

URI/LRI

Recurrent URI/LRI, S. pneumoniae septicemia

Recurrent URI/LRI

IVIG, SCIG

Good

(van Zelm et al. 2011)

E1

Kurdish

CD19

F

5

11

URI, giardiasis

Recurrent URI

Pneumococcal meningitis

NR

Good

(Vince et al. 2011)

F1

Moroccan

CD19

F

13

31

Failure to thrive, microscopic hematuria, proteinuria

Chronic sinusitis, pneumococcal pneumonia

IgA nephropathy, nephrotic syndrome

Sinus surgery

Nephrotic syndrome/ESRD

(Vince et al. 2011)

G1

French

CD19

M

3mo

11b

RSV bronchiolitis, asthma mimicking symptoms

Asthma resembling symptoms

Recurrent URI/LRI

Bronchiectasis, lobar atelectasis, COPD

IVIG, lobectomy

Chronic lung disease

(Skendros et al. 2014)

H1

Moroccan

CD81

F

2

6c

NR

IgA nephropathy, Henoch-Schönlein purpura

Thrombocytopenia, hypogammaglobulinemia

IVIG, immune suppression

Nephrotic syndrome /ESRD

(van Zelm et al. 2010)

Table adapted from Skendros et al. 2014.

COPD chronic obstructive pulmonary disease, ESRD end-stage renal disease, F female, GN glomerulonephritis, IVIGs intravenous immunoglobulins, LRI lower respiratory infection, M male, NR non-reported, RSV respiratory syncytial virus, SCIGs subcutaneous immunoglobulins, URI upper respiratory infection

aDiagnosis of CVID and IVIG therapy at age of 5 year, genetic diagnosis of CD19 deficiency at age of 8 year

bDiagnosis of hypogammaglobulinemia and IVIG therapy at age of 7 year, genetic diagnosis of CD19 deficiency at age of 11 year

cDiagnosis of IgA nephropathy and Henoch-Schönlein purpura at age 3.5 year, genetic diagnosis of CD19 deficiency and start IVIG at age of 6 year

In addition to bacterial infections, several patients experienced complications due to viral infections (herpes zoster, RSV) or parasites (giardiasis). Noninfectious complications are rare and include one patient with mild systemic lupus erythematosus (SLE). Further, two patients, one with CD19 and one with CD81 gene defects, suffered from IgA nephropathy, and 4/11 patients had specific auto antibodies and defective selection against autoreactivity in IgG and IgA transcripts (van Zelm et al. 2014), however, currently without specific organ disease.

Genetics

In total, 11 patients from 8 families have been described with a CD19 deficiency (Table 1). Ten patients have biallelic genetic defects in CD19 (Fig. 2), and all but one were homozygous. Although not all parents from patients with homozygous defects were confirmed to be relatives, taking into account the rarity of the mutant alleles, CD19 deficiency is most likely to be found in children from consanguineous parents. Remarkably, the heterozygous splice site mutation c.947-1G>T from Japanese patient C1 was also found in homozygous state in French patient G1. Considering the different genetic backgrounds, it is likely that these events occurred independently and that to date eight unique genetic lesions in CD19 have been described. These concerned four small insertions and/or deletions, one large deletion, and two splice site mutations that all resulted in complete absence of truncated CD19 proteins. In only one case, a missense mutation concerning a conserved tryptophan resulted in the complete absence of membrane CD19 (van Zelm et al. 2011). The complete absence of CD19 membrane expression resulted in reduced CD21 expression levels but did not affect CD81 or CD225 expression (Fig. 3).
Fig. 2

Overview genetic defects in CD19-deficient patients. (a) Schematic depiction of the human CD19 and CD81 genes with the positions of the identified genetic defects. (b) Overview of mutant alleles in 11 patients from 8 unrelated families

Fig. 3

Expression of CD19-complex members on B cells. (a) Dot plots showing CD19 and CD81 expression on B cells from a healthy control, patient D1 with a CD19 gene defect and patient H1 with a CD81 gene defect. (b) CD21 and CD225 expression levels on B cells from the same individuals as in a

The 11th patient (H1) did not carry mutations in her CD19 alleles (Fig. 2). Instead, a homozygous splice site mutation was identified in the CD81 gene that disrupted membrane expression of both CD19 and CD81 (Fig. 3) (van Zelm et al. 2010). CD21 was only slightly reduced and CD225 normally expressed on the patient’s B cells. Using in vitro complementation experiments, it was demonstrated that the defective CD81 expression resulted in absence of CD19 on the patient’s B cells. These results confirmed and extended previous observations of the dependence of CD19 membrane expression in CD81 (Maecker and Levy 1997; Miyazaki et al. 1997; Tsitsikov et al. 1997).

Immunological Phenotype

Until that time, genetic defects underlying predominantly antibody deficiencies (PAD) had only been identified in patients with agammaglobulinemia and a complete lack of B cells and in patients with a defect in germinal center responses and Ig class switch recombination (Conley et al. 2009). CD19-deficient patients differed from both groups in regards to the presence of B cells in blood and normal architecture of germinal centers in lymphoid tissue despite hypogammaglobulinemia (Artac et al. 2010; Kanegane et al. 2007; Skendros et al. 2014; van Zelm et al. 2006, 2010, 2011; Vince et al. 2011).

Immunologically, all patients show typical features of antibody deficiency with low IgG in combination with reduced serum IgA and/or IgM levels (Tables 2 and 3), and impaired responses to vaccinations (Tables 2 and 3). Only patient F1 was specifically deficient in IgG1 with normal to high levels of other IgG subclasses, IgM and IgA, and normal responses to previous vaccinations (Table 3). Thus, with the exception of patient F1, CD19-deficient patients fit the criteria of common variable immunodeficiency (CVID) (Bousfiha et al. 2015; Conley et al. 1999).
Table 2

Immunological characteristics of pediatric CD19-deficient patients

 

A1

A2

C1

D1

E1

G1

H1

Normal values

Gender

F

M

M

M

F

M

F

 

Age (year)

10

12

8

6

11

11

4

 

Blood cells (cells/μl)

Lymphocytes

4480

1900

ND

1630

2745

ND

2195

2906 ± 1,081a

 CD3+ T cells

3270

1700

1775

1107

2141

ND

1385

2000 ± 766

 CD4+ T cells

1792

669

1064

637

1125

ND

956

1247 ± 601

 CD8+ T cells

1478

1031

781

353

796

ND

345

547 ± 184

 CD20+ B cells

806

60

538

321

300

ND

426

453 ± 265

 CD16/CD56+ NK cells

313

100

ND

156

184

ND

292

266 ± 170

B-cell subsets (% of CD20)

 Transitional

ND

8

ND

3

0

5

1

6 ± 3

 Naive mature

91

87

67.5

90

89

91

90

66 ± 9

 CD27 + IgM + IgD+ memory

3

2

5.4

3

8

2

4

7 ± 3

 CD27 + IgD- memory

2

1

7.6

3

2

1

3

11 ± 5

Ig serum levels (g/L)

 IgG

3.25

0.91

2.49

3.00

2.30

4.4

2.40

5.04–14.64

  IgG1

ND

ND

ND

ND

0.66

1.7

ND

2.92–8.16

  IgG2

ND

ND

ND

ND

1.44

3.4

ND

0.83–5.13

  IgG3

ND

ND

ND

ND

36

0.4

ND

0.08–1.11

  IgG4

ND

ND

ND

ND

<0.01

0.002

ND

0.01–1.21

 IgA

2.92

0.01

0.10

0.50

1.25

Normal

0.71

0.27–1.95

 IgM

0.25

0.59

0.18

0.40

0.35

0.4

0.35

0.24–2.10

 IgE (IU/ml)

37

ND

9

ND

ND

ND

ND

0–100

Isohemagglutinins

Absent

ND

ND

Low

ND

ND

ND

 

Vaccination responses

Impaired

Impaired

Impaired

Impaired

Impaired

Impaired

Impaired

 

Autoantibodies

SS-A, ANA

ND

ND

ND

ND

Anti-platelet

 

M male, F female. Only positive tests for autoantibodies are indicated. Bold font indicates subnormal values; underlined supranormal. ND not determined

aMean ± SD from (van Zelm et al. 2011)

Table 3

Immunological characteristics of adult CD19-deficient patients

 

B1

B2

B3

F1

Normal values

Gender

M

F

F

F

 

Age (year)

35

33

49

31

 

Blood cells (cells/μl)

Lymphocytes

2182

2508

2059

1440

1000–2800

 CD3+ T cells

1520

1855

1384

1152

700–2100

 CD4+ T cells

713

1070

620

590

300–1400

 CD8+ T cells

720

692

696

533

200–900

 CD19+ B cells

286

521

268

61

100–500

 CD16/CD56+ NK cells

277

348

288

23

90–600

B-cell subsets (% of CD20)

    

 Transitional

ND

ND

ND

0

2 (1–3)a

 Naive mature

92

96

92

59

67 (54–76)a

 CD27 + IgM + IgD+ memory

5

1

3

22

15 (11–23)a

 CD27 + IgD- memory

1

0

2

12

15 (10–20)a

Ig serum levels (g/L)

 IgG

2.04

1.98

2.56

4.93

7.51–15.6

  IgG1

ND

ND

ND

1.70

4.9–11.4

  IgG2

ND

ND

ND

3.06

1.5–6.4

  IgG3

ND

ND

ND

2.11

0.2–1.1

  IgG4

ND

ND

ND

2

0.08–1.4

 IgA

0.18

0.07

0.19

3.50

0.82–4.53

 IgM

0.47

0.30

0.60

1.35

0.46–3.04

 IgE (IU/ml)

ND

ND

ND

ND

0–100

Isohemagglutinins

Low

Low

Low

Present

 

Vaccination responses

Impaired

Impaired

Impaired

Normal

 

Autoantibodies

Anti-DNA

ANA

 

M male, F female. Only positive tests for autoantibodies are indicated. Bold font indicates subnormal values; underlined supranormal. ND not determined

aMedian (IQR) from (Mouillot et al. 2010)

Leukocyte and lymphocyte subsets were normally present in all patients, with the exception of low total B cell numbers in one child and one adult with CD19 gene defects. The reduced IgG serum levels were accompanied by low memory B cell numbers, again with the exception of patient F1. Interestingly, most patients showed reduced numbers of transitional B cells. On the other hand, the patients did not display an expansion of CD21low B cells that is frequently found in patients with CVID (Warnatz et al. 2002; Wehr et al. 2008). This was irrespective of the generally lower expression levels of CD21 on patient’s B cells as a result of the absence of CD19 (Fig. 3b) (van Zelm et al. 2006, 2011).

Heterozygous carriers of CD19 or CD81 gene defects have reduced expression of surface CD19 on their B cells (Fig. 3c) (Artac et al. 2010; Reisli et al. 2009; van Zelm et al. 2006, 2010, 2011). In carriers with CD19 gene defects, this is accompanied by reduced CD21 expression levels. Despite these phenotypical changes, extensive analysis of 30 carriers revealed that these were not more susceptible to infections, had normal total serum IgG, IgA and IgM levels, as well as normal responses to vaccinations and circulating memory B cells (Artac et al. 2010).

The impaired antibody responses in CD19-deficient patients seemed to result from defective activation of B cells via their BCRs. B cells from all tested patients showed impaired fluxes of intracellular Ca2+ upon stimulation with anti-IgM (van Zelm et al. 2006, 2010, 2011). CD19 is already expressed in precursor B cells in bone marrow at the stage where the pre-BCR is expressed. Signaling via the pre-BCR is crucial for developmental progression of progenitor B cells. As a result, genetic defects in genes encoding components of this pre-BCR (Igμ, CD79a, CD79b, and λ14.1) and directly downstream signaling molecules (BTK, BLNK, PLCγ2) result in a complete absence of mature B cells and hypogammaglobulinemia (Conley et al. 2009). As CD19-deficient patients do not lack mature B cells, it can be concluded that CD19 does not have a critical role in pre-BCR signaling. However, 2/11 patients presented with low total B cell numbers (Tables 2 and 3). Thus, in line with mouse models (Diamant et al. 2005; Otero and Rickert 2003), it is possible that human progenitor B cell differentiation is less efficient in absence of CD19.

Importantly, in vitro stimulation of B cells was dependent on CD19 even in the absence of complement, suggesting that the CD19-complex can be recruited to the BCR in absence of crosslinking via C3d and CD21. Indeed, CD21 is not required for B-cell activation via the BCR with large amounts of antigen (Thiel et al. 2012; Wentink et al. 2015). Only with limiting amounts of IgM, crosslinking the BCR via complement and CD21 to the CD19-complex is needed to induce a Ca2+ flux (Thiel et al. 2012). The potential of CD19 to signal independently of CD21 likely underlies the relatively mild phenotype of CD21-deficient individuals. Their B cells express normal to high levels of CD19 and are capable of mounting specific antibody responses (Thiel et al. 2012; Wentink et al. 2015).

Complement-independent recruitment of the CD19-complex to the BCR is thought to be regulated via the CD81-tetraspanin network (Mattila et al. 2013). Upon antigen binding, the BCR triggers signaling and reorganization of the cytoskeleton (Freeman et al. 2015). This increases BCR mobility and diffusion (Treanor et al. 2010) to allow interactions with CD19 that is immobilized on the membrane by the CD81-tetraspanin network. Specifically, CD19-mediated recruitment of Vav, PLCγ2, and PI3K enhances BCR-induced signaling.

In addition to enhancing BCR signaling, CD19-mediated recruitment has been shown to enhance Toll-like receptor (TLR)9 and BAFFR signaling (Keppler et al. 2015; Morbach et al. 2016). Rather than a co-receptor complex that is recruited, it might be more appropriate to view the CD19-complex as a generic hub used by receptors in and on B cells to induce PI3K signaling.

Diagnosis

Currently, all identified mutations result in absence of membrane CD19 expression. This could be due to selective reporting as absence of CD19 provides the best clue for a CD19 deficiency. The conserved tyrosines in the C-terminal cytoplasmic tail of CD19 are critical for its function (Sato et al. 1997; Wang et al. 2002). Hence, mutations that affect these residues or that result in truncated forms could potentially be expressed, while still lack functional properties. Defective CD19 expression can be readily assessed by routine staining of peripheral blood lymphocytes including antibodies against CD19 for detection of B cells. It is noticed because the percentages of all lymphocyte subpopulations do not add up to 100%. The use of a CD19 antibody in combination with another broadly B-cell reactive antibody such as CD20, CD22, IgM, or IgD is suggested to prevent misdiagnosis of agammaglobulinemia.

Additional surface staining for CD81 and genetic analysis are needed for a final diagnosis and to distinguish between mutations in CD19 and CD81.

Management of CD19 Deficiency

The predominant clinical complications of CD19-deficient patients are recurrent respiratory infections (Table 1). Therefore, immunoglobulin replacement therapy is the treatment of choice. CD19-deficient patients rarely require immunosuppressive therapy. While hematopoietic stem cell transplantation is potentially curative, the prognosis of CD19 deficiency seems to be favorable in the absence of IgA nephropathy, and therefore none of the currently described patients has required this therapy.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Immunology and PathologyCentral Clinical School, Monash UniversityMelbourneAustralia
  2. 2.Department of Respiratory MedicineThe Alfred HospitalMelbourneAustralia
  3. 3.The Jeffrey Modell Diagnostic and Research Centre for Primary ImmunodeficienciesMelbourneAustralia
  4. 4.Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Department of PediatricsNecmettin Erbakan UniversityKonyaTurkey

Section editors and affiliations

  • Klaus Warnatz
    • 1
  • Joris M. van Montfrans
    • 2
  1. 1.Center for Chronic ImmunodeficiencyUniversity Medical Center and University of FreiburgFreiburgGermany
  2. 2.UMC UtrechtUtrechtNetherlands