Malignant BCells CD5CD19

The malignant B-CLL B-cell has been well characterized by surface immunophenotype. This latter feature gives us a potential clue as to its origin and functional capacity. In addition to the common B-cell antigens CD19, CD20, and CD21, these malignant cells have been demonstrated to express CD5 and variable amounts of surface-bound immunoglobulin (sIg). In normal hosts, CD5+ B-cells occur at the edge of germinal centers in the mantle zone of lymphoid follicles (14) and are found in cord blood. This latter marker on the malignant B-CLL clone may provide insight into the level of arrest in development of the monoclonal CLL B-cell. The faint expression of sIgs on the B-CLL B-cells is also common to normal B-cells at the edge of germinal centers. The sIgs in B-CLL are usually IgM and/or IgD, and rarely IgG or IgA (15). The sIgs often have reactivity for multiple self-antigens (polyreactive autoantibodies) with low avidity and frequently behave like rheumatoid factor (9). Up to 25% of patients with B-CLL have associated autoimmune phenomena, including autoimmune hemolytic anemia and autoimmune thrombocytopenia (10). Interestingly, the offending autoantibodies are of the IgG type and do not appear to be a direct product of the B-CLL B-cells. Thus, there is a discrepancy between the B-CLL-associated cell-

bound, low-affinity IgM antibodies and the circulating, cytopenia-inducing IgG autoantibodies. To date it is not clear whether the CLL B-cell sIg plays a role in the induction of the IgG autoantibodies.

Investigations into the nature of modulation of B-cell surface receptors and other molecules on the monoclonal B-cell have provided insight into the etiology of some aspects of the cellular immune dysfunction seen with B-CLL. Recent studies have identified the presence of CD95 ligand (CD95L) on the cell surface of B-CLL cells. CD95 (Fas) is a known death receptor protein expressed on the surface of cells, and its interaction with CD95L results in apoptosis of the CD95-expressing cell. Panayiotidis et al. (16) demonstrated decreased levels of CD95 on the leukemic B-cells in CLL patients. However, subsequent work demonstrated increased Fas ligand (CD95L) on the surface of the monoclonal CLL B-cell (17). The exact nature of CD95-CD95L interaction on CLL B-cells needs to be more fully delineated, since this is an important death pathway. Recent work by Sampalo et al. (8). detected the spontaneous inhibition of autologous bone marrow cell production of Ig by normal B-cells via a mechanism involving B-CLL B-cells. Cocultivation of CD5+-depleted bone marrow cells with autologous B-CLL B-cells resulted in decreased Ig production by the bone marrow cells, and this effect increased when the leukemic B-cells were stimulated with phorbol myristate acetate (PMA). The bone marrow plasma cells were demonstrated to express CD95, whereas the monoclonal CLL B-cells were found to express CD95L. Most importantly, increased apoptosis was detected when the bone marrow plasma cells were incubated with the monoclonal CLL B-cells. This CD95-CD95L interaction could result in increased apoptosis of the normal Ig-producing B-cells and suggests a unique cellular mechanism for the hypogammaglobulinemia noted in B-CLL patients. Additional work has also demonstrated the increased expression of CD95 on both CD4+ and CD8+ T-cells in B-CLL (17). The implications of this work with regard to its effect on the cellular immune system in B-CLL will be discussed in more detail below.

CD23 is a protein expressed on the surface of most of B-CLL B-cells. The protein is a low-affinity receptor for IgE and is an adhesion molecule expressed on activated mature B-cells. CD23 expression appears to be upregulated when immature B-cells are exposed to IL-4 (18). Proteolysis of CD23 results in increased concentrations of soluble CD23. Indeed, most patients with B-CLL have been noted to have increased levels of soluble CD23. Furthermore, the plasma level of CD23 correlates with disease activity (19,20). Interestingly, soluble CD23 can induce cell growth and differentiation of B- and T-cells as well as myeloid cell lines (21,22). CD21 is the natural ligand for CD23 (23), and their interaction is involved in cell adhesion, B-cell activation, and proliferation. Since these two molecules are coexpressed on B-CLL B-cell membranes, their interaction may promote growth or cellular viability of the leukemic cells.

The monoclonal CLL B-cell appears to be an ineffective APC. Normal activated B-cells are effective APCs, which interact with T-cells to elicit an immune response. The inability of CLL B-cells to act as effective APCs can be explained in part by their diminished expression of membrane CD80 (B7-1) and CD86 (B7-2), costimulatory molecules required for T-cell activation (24). Activation of the T-cell requires at least two receptor-receptor ligand interactions. First, the antigen/ major histocompatibility complex must bind to the T-cell receptor (TCR). In addition, the CD80/ CD86 complex must bind to CD28 on the T-cell surface to elicit activation of the T-cell (25). Stimulation of the TCR without CD28 interaction with CD80/CD86 results in T-cell anergy (26).

CLL B-cells, as well as normal B-lymphocytes, express CD40 on their cell surface. CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, interacts with CD40 ligand (CD154), which is transiently expressed on activated T-cells, leading to B-cell activation with

Fig. 2. Membrane profile of the B-cell and the T-helper cell with respect to expression of the critical activation or receptor/receptor ligand interactions that are probably involved in the efficient and complete activation of the the T-cell. Since the CLL B-cell is often deficient in several of these important receptors (reviewed in text and briefly in Fig. 3) the T-cell may not be properly activated in patients with B-CLL. ICAM, intercellular adhesion molecule; LFA-1, leukocyte function-associated antigen-1.

Fig. 2. Membrane profile of the B-cell and the T-helper cell with respect to expression of the critical activation or receptor/receptor ligand interactions that are probably involved in the efficient and complete activation of the the T-cell. Since the CLL B-cell is often deficient in several of these important receptors (reviewed in text and briefly in Fig. 3) the T-cell may not be properly activated in patients with B-CLL. ICAM, intercellular adhesion molecule; LFA-1, leukocyte function-associated antigen-1.

upregulation of various molecules, including CD80 (27). Incubation of CLL B-cells with activated T-cells similarly resulted in upregulation of CD80 in the leukemic cells (28,29) Kato et al. (30) noted that the CD4+ T-cells of patients with CLL failed to express surface CD154 after CD3 ligation despite adequate levels of mRNA for CD154. These investigators determined that CLL B-cells could also block the induction of CD154 in normal T-cells by a CD40-directed mechanism.

Thus, a negative complex feedback mechanism appears to exist in B-CLL, in which the decreased APC ability of the leukemic B-cell pool results in T-cell anergy, whereas the absence of activated T-cells results in deficient B-cell activation. Figure 2 illustrates the spectrum of membrane antigens on B-cells known to be crucial to efficient and vigorous T-cell helper activation. A novel strategy to break this "immunodeficiency" cycle has involved the introduction of transgenic CD154 expression in CLL B-cells. This generates CD154 on the membrane of CLL B-cells, resulting in a more efficient leukemic APC and subsequent induction of cytolytic T-cell activity (30). This approach for the transformation of leukemic CLL B-cells into effective APCs is currently undergoing clinical trials.

An additional set of T-cell costimulatory molecules, CD27 and CD70, appear to be regulated in a matter similar to CD40/CD154 (31). CD27 expressed on the surface of B-cells appears to interact with CD70 on the surface of T-cells. This interaction, in concert with TCR activation, results in T-cell proliferation. Ranheim et al. (31) demonstrated the coexpression of CD70 and CD27 on the surface of leukemic B-cells, and soluble CD27 was also detectable. A CD40-dependent downmodulation of CD27 with reciprocal upregulation of CD70 was noted in the B-CLL B-cells. The latter work has suggested that the CD27-CD70 interactions on CLL B-cells may be an important and distinct costimulatory signal for T-cell proliferation. The possible role of soluble CD27 in disturbing this costimulation exists in B-CLL since there are increased levels of soluble CD27 in B-CLL. Finally, there are complex and contrary changes for CD70 on CLL B-cells in relation to the cytokine(s) present in the microenvironment. Thus, the complex interplay between various surface molecules necessary for efficient T-cell activation may not occur because of membrane abnormalities present on CLL B-cells. Some of the contributing factors that probably impact on T-cell function in B-CLL are illustrated in Fig. 3. This defective B/T-cell interaction probably has implications for the cellular immune arm of the B-CLL patient. Table 2 summarizes the aberrant expression of surface molecules on B-CLL cells and their role in immune dysfunction.

Fig. 3. Multiple causes of T-cell immunodeficiency in B-CLL. Both B-cell secreted cytokines and defective membrane receptor profiles of B-cells can lead to significant T-cell dysfunction including decreased CD40 ligand and ultimately T-cell functional defects that include poor proliferative response to mitogens and defective helper and cytotoxic function. IL, interleukin; TGF, transforming growth factor.

Fig. 3. Multiple causes of T-cell immunodeficiency in B-CLL. Both B-cell secreted cytokines and defective membrane receptor profiles of B-cells can lead to significant T-cell dysfunction including decreased CD40 ligand and ultimately T-cell functional defects that include poor proliferative response to mitogens and defective helper and cytotoxic function. IL, interleukin; TGF, transforming growth factor.

Table 2

Aberrant Expression of Surface Molecules on B-CLL Cells and Their Role in Immune Dysfunction

Surface molecule

Effect on immune cells

Increased CD95 ligand

Increased CD5 Increased CD23

(cell-bound and soluble) Increased CD21 Decreased CD80

Decreased CD86 Increased soluble CD27

Increased interleukin-4 receptor

Apoptosis of CD95-expressing cells: possible role in development of hypogammaglobulinemia owing to interaction with CD95+ B-cells, resultant decrease in CD95+ T-cells Unknown function Induction of B-cell proliferation

Receptor for CD23, coexpression may promote leukemic cell growth Coexpression with CD86 and interaction with T-cell required for

T-cell activation See CD80 above

May have role in interrupting normal CD27/CD70 interaction necessary for T-cell activation Decreased apoptosis

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