Overview Of The Immune Deficits In Bcll

The Revised Authoritative Guide To Vaccine Legal Exemptions

Vaccines Have Serious Side Effects

Get Instant Access

To set the stage for a description of the immune deficits in B-CLL, we provide a brief, relevant review of the normal immune system. An intact immune system will include both humoral and cellular components. The humoral component is comprised of circulating antibodies (i.e., IgA, IgG, IgM) that have reactivity to specific antigens and are important in the host defense against infectious microbes. A polyclonal population of B-lymphocytes residing primarily in the lymph nodes, spleen, and gastrointestinal tract produces these antibodies. These antibodies react with antigens, including those on the surface of the infectious microbe (particularly with encapsulated bacteria), allowing the innate cellular immune system to recognize and destroy the infectious agent. Antibodies can also trigger the cellular release (i.e., by mast cells, monocytes) of inflammatory mediators (i.e., cytokines, chemokines) that are important in recruiting additional immune cells to participate and compete for the host response.

The cellular components of the immune system involve numerous cell types, including T-lymphocytes, natural killer (NK) cells, and dendritic cells (DCs). Those of potential clinical importance in B-CLL are briefly discussed here. T-lymphocytes have memory and specificity to particular infectious agents (viral and bacterial), whereas NK cells are capable of spontaneous and nonspecific killing of viral infected cells and tumor cells. NK function is often referred to as innate immunity. T-lymphocytes can be divided into two functionally distinct groups, CD4+ (Th) helper and CD8+ cytolytic/suppressor cells (Ts). Both subsets can be divided on the basis of cytokine secretion profiles. Thus, T1 T-cells (Th1, Ts1) secrete predominantly interleukin-2 (IL-2) and/ or interferon-y vs IL-4, IL-5, and IL-10 for the T2 cells (Th2, Ts2 type cells). It is important for host defense to have a complete T-cell repertoire of both CD4+ and CD8+ subsets. An important aspect of activated CD4+ helper T-cells includes the release of an array of cytokines (i.e., IL-2, interferon-y) with many disparate functions, including activation of B- and T-lymphocytes. This stimulation is critical in initiating and amplifying the proliferation and differentiation of these cells. An important role for activated CD8+ cytolytic T-lymphocytes is to react with the target cell and induce cell lysis. This latter activity is particularly important in the destruction of intracellular infectious agents, including viruses and intracellular bacteria. In addition, these cells can release cytokines such as interferon and tumor necrosis factor.

In the normal immune response, T-cell activation is mediated by interactions between antigen-presenting cells (APCs) like B-cells and dendritic cells (DC). These interactions involve a pathway of highly regulated events critical for specific activation and control of both B- and T-cells (Fig. 1). T-cells that encounter antigen in conjunction with APCs have cell-cell contact via at least the leukocyte function associated antigen-1 (LFA-1; CD11a) and intercellular adhesion

Fig. 1. Immune cell compartments known to be abnormal in B-CLL. Only the most well-characterized defects are listed here. Thus, both the polyclonal and malignant B-cells are deficient and at least contribute to the hypogammaglobulinemia often seen in this disease. The natural killer (NK) cells are consistently abnormal and may represent a significant defect in innate immunity for these patients. Finally, T-cells in this disease have many complex defects that in total give many B-CLL patients considerable difficulty both in resisting infections and in generating an effective antitumor impact. LGL, large granular lymphocyte.

Fig. 1. Immune cell compartments known to be abnormal in B-CLL. Only the most well-characterized defects are listed here. Thus, both the polyclonal and malignant B-cells are deficient and at least contribute to the hypogammaglobulinemia often seen in this disease. The natural killer (NK) cells are consistently abnormal and may represent a significant defect in innate immunity for these patients. Finally, T-cells in this disease have many complex defects that in total give many B-CLL patients considerable difficulty both in resisting infections and in generating an effective antitumor impact. LGL, large granular lymphocyte.

molecule-1 (ICAM-1; CD54) interaction. At that time cell binding is still nonspecific and of low affinity. The LFA-1/ICAM-1 interaction is a major contributor to adhesion between T-cells and other lymphoid cells. The binding of LFA-1 (CD11a)/ICAM-1 (CD54) allows the cells to be brought into close proximity for antigen recognition to take place via the T-cell receptor (TCR)/ CD3 complex. T-cell response (T-cell activation) is enhanced via interactions between HLA antigens and the TCR, a process that is upregulated by the CD3 complex and strengthened by CD4 (MHC class II) or CD8 (MHC class I) binding. TCR/CD3 complex signals lead to the initiation of key T-cell immune responses, including cytokine production and surface marker upregulation. The T-cell surface marker CD28 interacts with the CD80/CD86 receptors on the B-cells, and increased expression of CD154 on the T-cell leads to binding with its B-cell surface ligand, CD40. Production of IL-2 occurs, and receptors for this cytokine (CD25/IL-2R) are expressed some 2 d post activation, facilitating recruitment of other T-cells with continued activation and clonal expansion. It is believed that expression of CTLA-4 (CD152) sends a negative "off" signal to the T-cell, which serves to control the immune response via cessation of T-cell proliferation or by inducing apoptosis.

B-CLL is notable in that a significant proportion of patients develop infectious complications, which are associated with impaired immune responses. Because of the frequent bacterial infections seen early on in the disease course of B-CLL and the viral/fungal infections seen later on or with therapy in B-CLL, investigations into the underlying causes have been undertaken. Early studies identified defects in both the humoral and cellular immune responses. Hypogamma-globulinemia detected by serum protein electrophoresis has been noted to occur in up to 70% of these patients (3), and significant declines in certain antibody classes have been demonstrated to correlate with disease severity (4). It is likely that up to 50% of patients with B-CLL sustain infectious complications during the course of their disease. Patients with hypogamma-globulinemia have more frequent infections with encapsulated bacteria, including Streptococcus pneumoniae and Hemophilus influenza (5,6). Not only is the overall level of circulating antibodies reduced in B-CLL, but antibody responses to individual vaccination appears to decline with

Table 1

B-CLL Immune Cell Dysfunction and Associated Clinical Complications

Affected cell type Associated defect

B-cell Hypogammaglobulinemia—increased bacterial infections

Decreased vaccination response T-cell Increased viral and intracellular bacterial infections

Natural killer cell Possible association with increased autoimmune phenomena and/or second malignancies

Dendritic cell ? Unknown, possible dysfunction progressive disease (7). Recent in vitro data suggest that the B-CLL cells inhibit spontaneous immunoglobulin production by bone marrow cells, suggesting an etiology for the hypogammaglobulinemia (8). In addition, the monoclonal B-CLL B-cells often produce antibodies, which are reactive with self antigens (9). These antibodies may contribute to immune abnormalities seen with this disorder (10).

Components of the cellular immune system are also known to be impaired/altered in patients with B-CLL. Figure 1 summarizes the different immune cell subsets known to be abnormal in patients with B-CLL. Most prominently, blood T-cell dysfunction has been well documented with B-CLL patients. The blood CD4/CD8 ratio, with a relative decrease in helper phenotype, has been reported in patients with B-CLL (11,12). A clinical manifestation of this defect in T-lymphocyte function may include the decreased responsiveness or anergy noted on skin recall antigen tests to common antigens. NK cells in B-CLL have a significant deficit in their ability to be activated and to lyse appropriate cellular targets (13). Less information is available for DCs/APCs, although some recent information suggests that these cells are also defective in B-CLL (reviewed below in Subheading 3.5.). These in vitro immune defects and their potential relationship to clinical and/or immune defects seen in vivo in B-CLL are listed in Table 1.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment