To the Editor:

B-cell chronic lymphocytic leukemia (B-CLL) is a malignancy characterized by the accumulation of long-lived CD5+cells1 in which cytokines might be involved in the proliferation and survival of malignant B cells.2-6 

In particular, interleukin-4 (IL-4) prevents B-CLL cell clones from entering spontaneous apoptosis by increasing the expression of bcl-25 and protects B-CLL cells against anti-APO1–induced apoptosis.6 Only one report has analyzed the intracellular expression of IL-4 in T cells of patients with B-CLL.7 We examined the expression of IL-4 and IL-4 receptor (IL-4R) in unstimulated leukemic B cells and T cells from 10 patients with untreated stage A B-CLL and compared them with 10 normal controls using flow cytometric analyses.

We found that the proportion of CD19+ cells expressing cytoplasmic IL-4 was significantly higher in B-CLL patients than in controls (P < .002; Table1). The proportion of CD3+cells expressing cytoplasmic IL-4 was significantly higher in B-CLL patients than in controls (P < .02). Although the proportion of CD19+ cells expressing IL-4R was similar, the proportion of CD3+ cells expressing the IL-4R in B-CLL patients was significantly higher than in normal controls (P < .02). IL-4 could not be detected in the supernatant after the in vitro culture of the cells from both patients and controls. After stimulation with the mitogen PWM, six of the seven control samples and none of the patient cells had detectable supernatant IL-4 (P < .03; Table2).

Table 1.

Comparison of Cytoplasmic IL-4 and IL-4R Expression in B-CLL Patients Versus Controls

Patient No. CD19/IL-4 Unst-150CD3/IL-4 Unst-150CD19/IL-4R-150CD3/IL-4R-150Controls CD19/IL-4 Unst-150CD3/IL-4 Unst-150CD19/IL-4R-150CD3/IL-4R-150
1  30.00 21.57  97.13  2.67  1  5.14  2.17  52.97  1.06 
2  21.57  26.09  42.91  3.74  2  4.71  2.96 61.47  0.83  
3  28.78  13.52  28.22  0.58  5.35  1.82  82.53  0.63  
4  18.30  11.17 11.22  1.52  4  10.13  1.67  74.76  2.48  
53.80  5.35  70.50  6.75  5  9.89  4.18  64.85 0.78  
6  21.64  2.62  56.26  3.22  6  1.45 3.83  88.37  3.29  
7  14.81  7.23  69.97  3.47 7  6.76  3.36  69.13  1.33  
8  6.36  2.62 83.41  6.08  8  8.16  0.41  69.63  1.76  
17.39  3.17  20.50  5.16  9  11.93  0.96 82.16  3.70  
10  11.29  2.19  96.87  7.80  10 8.32  0.93  41.55  0.98 
Patient No. CD19/IL-4 Unst-150CD3/IL-4 Unst-150CD19/IL-4R-150CD3/IL-4R-150Controls CD19/IL-4 Unst-150CD3/IL-4 Unst-150CD19/IL-4R-150CD3/IL-4R-150
1  30.00 21.57  97.13  2.67  1  5.14  2.17  52.97  1.06 
2  21.57  26.09  42.91  3.74  2  4.71  2.96 61.47  0.83  
3  28.78  13.52  28.22  0.58  5.35  1.82  82.53  0.63  
4  18.30  11.17 11.22  1.52  4  10.13  1.67  74.76  2.48  
53.80  5.35  70.50  6.75  5  9.89  4.18  64.85 0.78  
6  21.64  2.62  56.26  3.22  6  1.45 3.83  88.37  3.29  
7  14.81  7.23  69.97  3.47 7  6.76  3.36  69.13  1.33  
8  6.36  2.62 83.41  6.08  8  8.16  0.41  69.63  1.76  
17.39  3.17  20.50  5.16  9  11.93  0.96 82.16  3.70  
10  11.29  2.19  96.87  7.80  10 8.32  0.93  41.55  0.98 

Abbreviation: unst, unstimulated.

F0-150

The data are presented as a percentage of CD19 and CD3+cells expressing cytoplasmic IL-4 and surface IL-4R. The proportion of CD3+ cells expressing IL-4R in B-CLL patients was significantly higher in patients than in controls (P < .01). The proportion of CD19 and CD3+cells expressing cytoplasmic IL-4 was also significantly higher in B-CLL patients than in controls (P < .03 andP < .01, respectively).

Table 2.

IL-4 Secretion by Lymphocytes From B-CLL Patients and Normal Controls

Patient No. Spon (pg/mL) PWM (pg/mL)Controls Spon (pg/mL) PWM (pg/mL)
1  ND ND  1  ND  0.23  
2  ND  ND  2  ND  3.27 
3  ND  ND  3  ND  1.02  
4  ND  ND  ND  0.15  
5  ND  ND  5  ND  2.37  
6  ND ND  6  ND  4.78  
7  ND  ND  7  ND ND 
Patient No. Spon (pg/mL) PWM (pg/mL)Controls Spon (pg/mL) PWM (pg/mL)
1  ND ND  1  ND  0.23  
2  ND  ND  2  ND  3.27 
3  ND  ND  3  ND  1.02  
4  ND  ND  ND  0.15  
5  ND  ND  5  ND  2.37  
6  ND ND  6  ND  4.78  
7  ND  ND  7  ND ND 

IL-4 secretion by lymphocytes from normal controls was significantly increased compared with that from the patients (P < .01).

Abbreviations: Spon, spontaneous secretion; PHA, phytohemagglutinin-stimulated secretion; PWM, pokeweed mitogen-stimulated secretion; ND, not detected.

The demonstration that T cells from B-CLL patients display a greater percentage of IL-4R expression from normal individuals is novel. It is unclear whether the T cells from B-CLL patients express both the IL-4R together with IL-4 or this aberrant expression occurs on different T-cell populations in these patients. It is intriguing that no increase in IL-4R expression could be found on malignant B-CLL cells despite the expression of cytoplasmic IL-4. It is possible that the IL-4 from the B-CLL B cells is released and taken up rapidly by the T cells, and this leads to the aberrant expression of the IL-4R. Alternatively, the interaction between the malignant B cells and T cells may occur in a microenvironment in which local concentrations of IL-4 may be high, but these are not reflected in the blood. The disproportionate relationship between IL-4 and its receptor in the normal T-cell compartment compared with the malignant B-cell compartment in B-CLL is presumably important in the pathogenesis of B-CLL and merits further investigation.

1
Boumsell
 
L
Bernard
 
A
Lepage
 
V
Degos
 
L
Lemerle
 
J
Dausset
 
J
Some chronic lymphocytic leukaemia cells bearing surface immunoglobulins share determinants with T cells.
Eur J Immunol
8
1978
900
2
Cordingley
 
F
Hoffbrand
 
A
Heslop
 
H
Turner
 
M
Bianchi
 
M
Reittie
 
J
Vyakarman
 
A
Meager
 
A
Brenner
 
M
Tumour necrosis factor as an autocrine tumour growth factor for chronic B-cell malignancies.
Lancet
1
1988
969
3
Nerl
 
C
Janssen
 
O
Kabelitz
 
D
B cell maturation in chronic B cell lymphocytic leukaemia. III. Effect of recombinant cytokines on leukaemic B cell proliferation.
Leukaemia
2
1988
50S
4
Touw
 
I
Dorssers
 
L
Lovemberg
 
B
The proliferative response of B cell chronic lymphocytic leukaemia to interleukin 2: Functional characterisation of the interleukin 2 membrane receptors.
Blood
69
1987
1667
5
Dancescu
 
M
Rubio-Trujillo
 
M
Biron
 
G
Delespesse
 
G
Sarfati
 
M
Interleukin-4 protects chronic lymphocytic leukaemic B cells from death by apoptosisa and upregulates Bcl-2 expression.
J Exp Med
176
1992
1319
6
Mainou-Fowler
 
T
Craig
 
V
Copplestone
 
A
Hamon
 
M
Prentice
 
A
Effect of anti-APO-1 on spontaneous apoptosis of B cells in chronic lymphocytic leukaemia: The role of bcl-2 and interleukin-4.
Leuk Lymphoma
19
1995
301
7
Mu
 
X
Kay
 
N
Gosland
 
M
Jennings
 
D
Analisis of blood T-cell cytokine expression in B-chronic lymphocitic leukaemia: Evidence for increased levels of cytoplasmic IL-4 in resting and activated CD8 T cell.
Br J Haematol
96
1997
733
Sign in via your Institution