Immune Defects

The immune system is composed of unique and diverse effector cells and soluble factors (proteins) that must be carefully orchestrated in order to carry out innate and adaptive protective functions. CLL B cells disrupt the immune function of patients with CLL (Table 23.5). The most evident manifestation of immune dysfunction is the increased risk and frequency of infection. Many patients with CLL succumb to infection or ineffectively treated autoimmunity.42-44 The treatments used for CLL, such as purine analogs, further immunosuppress patients and put them at increased risk for opportunistic infections and may exacerbate or unmask autoimmunity.45-47

HUMORAL DEFECTS Immunoglobulin

Hypogammaglobulinemia is a common and progressive immune defect in patients with CLL and is another factor that increases the risk of infection.4448 Furthermore, dysregulated humoral immunity is associated with ineffective production of antigen-specific antibodies.49

Hypogammaglobulinemia is not always present at diagnosis, but frequently develops as the disease progresses. It follows that the incidence increases with duration of disease and with advancing stage.50-52 It is progressive and tends to be irreversible; immunoglob-ulin levels rarely return to normal even in those patients achieving complete remission with treatment. This refractoriness to recovery may be related to prolonged lymphopenia induced by purine analogs.

Immune defects in patients with CLL

Defect T cell

B cell

Neutrophil

Hypogammaglobulinemia

Complement Deficiency

Characteristic

Inverted blood CD4/CD8 ratio Poor T-cell response to mitogens

Defective expression of function-associated surface molecules

Increased CD8+ suppressor cell function

Anergy/hyporesponsive skin testing

Reduced number in blood Reduced immunoglobulin production

Quantitative decrease in neutrophils

Functional defects—chemotaxis, phagocytosis, and chemiluminescence

Overall decreased serum immunoglobulin levels Decreased serum IgG3, IgG4, and IgA

Decreased mucosal IgA and IgM

Decreased C1 and C4 C1 esterase inhibitor deficiency

Hypogammaglobulinemia is directly related to morbidity and mortality in patients with CLL since it increases the risk for infection with encapsulated bacteria, and infection is the cause of death in 30-50% of patients with CLL.52-55 Also, reduced mucosal IgA and IgM are risk factors for developing respiratory tract infections, such as pneumonia. The risk of morbidity and mortality appears to increase when IgG levels fall below 700 mg/dL; reduced serum IgA levels are also correlated with shorter survival.56 It is intriguing that certain isotypes and subclasses tend to be more commonly affected, particularly IgG3 and IgG4.55 57 Some patients have marked hypogammaglobulinemia but do not develop infections, leading to speculation that certain Ig subclasses may be more critical for protection than currently appreciated.

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