CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency.

Abstract

Common variable immunodeficiency (CVI) is characterized by hypogammaglobulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma cells. We hypothesized that T-cell dysfunction resulting in abnormal contactmediated B-cell activation may play a prominent role in the failure of CVI B cells to produce specific antibody. We have previously shown that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evaluated, indicating that CVI B cells respond to signals delivered via CD40. Here we report that CD40 ligand (gp39) mRNA expression by activated lymphocytes from CVI patients (n = 31) as a group was significantly depressed (P < 0.0001) compared with normal controls (n = 32). gp39 mRNA expression by activated lymphocytes from 13 CVI patients fell below the normal control range. T-cell surface expression of functional gp39 protein was correspondingly low in those patients with gp39 mRNA levels below normal control range and normal in patients with gp39 mRNA levels within normal control range. In CVI patients as a group, gp39 mRNA levels correlated with IL-2 mRNA levels (P < 0.002, r = 0.6) and production (P < 0.001, r = 0.7) but not with gene expression or production of other lymphokines evaluated, suggesting an as-yet-undetermined association between gp39 and IL-2 gene regulation. Of the 13 patients whose activated T cells exhibited gp39 mRNA expression below the normal control range, 2 had normal T-cell-derived lymphokine production, whereas the remaining 11 exhibited broader T-cell dysfunction, resulting in IL-2 deficiency, and in some patients deficient production of other lymphokines as well, reflecting a heterogeneity in the underlying mechanisms leading to depressed gp39 expression in these patients. The observation that both gene and surface expression of gp39 by activated T cells is depressed in a subgroup of CVI patients suggests that inefficient signaling via CD40 may be responsible, in part, for failure of B-cell differentiation in these patients. (5, 6). An intrinsic B-cell defect (3,7,8), excessive T-suppressor activity (9-11), or defective T/B-cell interaction (12-15) has been postulated as responsible for the failure of CVI B-cell differentiation.The finding that CVI B cells could proliferate and produce immunoglobulin if appropriately stimulated in vitro (13,16) suggests that T-cell dysfunction resulting in depressed or absent contact-mediated B-cell activation may be of importance for the failure of CVI B cells to differentiate into immunoglobulin-producing plasma cells. It has been shown in both murine and human systems that signals delivered via the B-cell surface antigen CD40 play an important role in B-cell proliferation, differentiation, and isotype switching (17-19). Anti-CD40 monoclonal antibody (mAb) in synergy with interleukin (IL) 4 induces B-cell proliferation (20,21) and IgE secretion (21-25) and in synergy with IL-10 induces B cel...

Gene expression analysis of peripheral T cells in a subgroup of common variable immunodeficiency shows predominance of CCR7– effector-memory T cells

“…Table 2). (a) Genes that were underexpressed (IL-11Ra, integrin a6, CCR7) and (b) genes that were overexpressed (IFN-g, Previous reports on T cell function in CVID have indicated reduced IL-2 secretion and reduced expression of CD40L in some CVID patients [33,34]. Interestingly, both have been reported to be reduced in CCR7 -T cells [21,32].…”

Lymphomas of mucosal‐associated lymphoid tissue in common variable immunodeficiency

“…This immune de®ciency was ®rst recognized about 45 years ago [6] but the fundamental genetic defect(s) remain unknown. While the central immune de®ciency is impaired secretion of immunoglobulin and lack of antibody production [7À9], T cell defects are also present in many, including decreased lymphocyte proliferation to mitogens and antigens [10,11], lack of antigen-primed T cells post vaccination [12,13], expansion of the CD45RO + (memory) T cells at the expense of the CD45RA + (naive) T cell population [14], de®cient expression of CD40 ligand on activated T cells [15], a tendency to accelerated T cell apoptosis, and various cytokine abnormalities [16À22]. The lack of immunoglobulin and functional antibody results in frequent sinopulmonary infections, but lymphadenopathy, splenomegaly, and granulomatous and autoimmune disease appear in signi®cant number of patients [1À5].…”

IL‐4 Synergizes with IL‐10 and Anti‐CD40 MoAbs to Induce B‐Cell Differentiation in Patients with Common Variable Immunodeficiency

“…However, it has also been shown that T cells from all patients with CVI support normal Ig synthesis by B cells derived from healthy donors, suggesting expression of functional CD40L on patients' T cells and intrinsic defects in patients' B cells [17]. Whether defective CD40L expression is the underlying cause of impaired Ig production in patients with CVI is of importance, because it has been suggested that soluble CD40L may have therapeutic potential when treating patients with defective expression of CD40L [16]. It has also been reported that production of cytokines, such as IL-2, IL-4, IL-10 and IFN-g, is impaired in patients with CVI [18][19][20][21], whereas expression of the IL-6 gene is elevated [22,23].…”