Deficiencies in Humoral Immunity

Humoral immunity has been studied extensively in CLL patients, ever since decreased immu-noglobulin concentrations, associated with increased risk of infection, were discovered in these patients. Complement deficiencies have also been identified in CLL patients and may also increase susceptibility to infectious complications. Deficiencies in complement components have been reported to enhance the risk of acquiring infection in CLL patients with hypogamma-globulinemia.

2.2.1. Immunoglobulin Deficiencies

The most prominent and earliest of the immune defects identified in CLL was hypogamma-globulinemia (hypo GG) (15). Although decreased IgG concentration has received the most attention, deficiencies in both serum IgA and IgM concentrations occur more frequently (16). Decreased duration of survival in CLL has been related to low concentrations of IgA and IgG, but not IgM (17). Decreased concentrations of IgA in patients with CLL has been associated with frequent respiratory infections, as it has in patients with primary IgA deficiency. However, associations between low concentrations of IgA and IgM and infection is less apparent than with IgG (1). Also, the role of deficiencies in secretory immunoglobulins (present on mucosal surfaces) has not been determined but is probably important. Decreased concentrations of secretory IgM have been detected in CLL patients (1).

As their disease progress, most CLL patients develop severe, persistent hypo GG. The frequency of hypo GG is related to the stage and duration of disease (18). Once it is present, it has not reversed even when a complete remission has been achieved with conventional chemotherapy, although recent experience suggests that it may reverse following successful therapy with fludarabine. Elevated serum p2-microglobulin concentrations correlate with rapid development of hypo GG (19). Normal B-lymphocytes secrete immunoglobulins, and the low levels of immunoglobulins in CLL are attributed to decreased production by B-lymphocytes. It is unclear whether this is owing to deficiencies in the number or the function of B-lymphocytes. In vitro studies showed that leukemic B-lymphocytes failed to produce immunoglobulins in the presence of normal T-lymphocytes, but also, leukemic T-lymphocytes suppressed the secretion of immunoglobulins by normal B-lymphocytes (20). This finding suggests that abnormal function of both B- and T-cells may be responsible for hypo IgG. Other studies have suggested that hypo IgG is caused by dilution of normal B-lymphocytes by the accumulation of the clonal neoplastic B-lymphocyte population and not by abnormal T-lymphocyte activity (21).

Most patients are deficient in at least one IgG subclass, even some with early-stage disease (22). The most significant deficiencies are in IgG3 and IgG4 (23). IgG3 is a major component of the humoral response to herpes simplex, which is a common cause of viral infection in CLL patients. IgG4 is an important humoral response to parasitic infections. It has been suggested that selective deficiencies in these two IgG subclasses could be caused by abnormal cytokine production by altered T-cells.

Most studies examining the frequency and severity of infection related to serum IgG concentrations have not included homogenous populations, but rather patients with varying stages and durations of disease who have received various or no therapies. In general, patients with hypo GG have two to three times more infections than those with normal concentrations, and these infections are more likely to be serious. Shaw et al. (24) found that 61% of patients with hypo GG had major infections compared with 33% without hypo GG. In one large study, 50% of patients with serum IgG concentrations of greater than 7g/L had no infections during the study period compared with only 13% with IgG concentrations less than 4g/L (25). In the former group, 36% of patients had a severe infection, with a mortality rate of 38%, compared with 74% frequency of severe infection in the latter group, with a mortality rate of 65%.

The ability to produce specific antibodies to antigenic stimuli may be of more prognostic significance than deficient concentrations of immunoglobulins (26). Deficient antibody responses to antigenic stimuli are a well-known consequence of antitumor chemotherapy, but they may also be present in CLL patients prior to any therapy. Even CLL patients with normal IgG concentrations may have poor specific antibody responses. Deficiencies in antibody response may be owing to impaired antibody production or defects in antigen presentation. Poor secondary antibody responses have been found following diphtheria, typhoid, mumps, and influenza immunizations in untreated CLL patients (24). Also, deficiencies in antibody responses to Escherichia coli and S. pneumoniae have been associated with recurrent infections. When CLL patients with no infection were compared with those with recurrent or chronic infections, no patients in the latter group had an antibody response to typhoid-paratyphoid AB vaccination, but less than 40% in the former group had an antibody response (27). None of the patients with hypo GG responded to the vaccination, but some with normal concentrations also failed to respond.

2.2.2. Deficiencies in Complement Components

Sera from as many as 55% of CLL patients have decreased properdin activity, and a defect in properdin-dependent bacteriophage neutralization has been described (28). Decreased concentrations of at least one complement component have been found in nearly 70% of CLL patients at the time of diagnosis, and the concentrations remained relatively constant for a median of nearly 1 yr thereafter (28). Deficiencies in complement components correlate with the stage of disease, and most patients also have hypo GG.

In one study, some patients had deficiencies in only the early classical pathway (C1-C4), the late classical pathway (C5-C9), or the alternative pathway, whereas some had deficiencies in all three (28). In some studies, the most frequently detected deficiency was component C1 (29). Low concentrations of C1 and C4 have been associated with increased risk of infection, although this has not been confirmed by all studies. Sera from patients with deficiencies in these components have severely impaired bactericidal activity in vitro. Poor opsinization of Staphylococcus aureus, Haemophilus influenzae, and especially S. pneumoniae has been associated with defective activation of complement (30).

Decreased concentrations of C3b have been found in CLL patients receiving adrenal corticosteroids, although this deficiency may be disease-related. Deficient binding of C3b to S. pneumoniae, S. aureus, and E. coli was found in over 50% of patients with CLL, and all of these patients had abnormal binding to at least one of these bacteria (30). Sera from infected CLL patients bound less C3b than that from noninfected patients. Although it seems apparent that complement deficiencies occur in CLL patients, it must be recognized that most of the data have been derived from small numbers of patients.

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