Lack of specific antibody response in common variable immunodeficiency (CVID) associated with failure in production of antigen-specific memory T cells

Abstract

SUMMARYSeveral T cell defects have been described in the antibody deficiency disease, CVID, but there have been few data on the generation of responses of specific T cell populations to primary neoantigens. We have now used immunization with the neoantigens, keyhole limpet haemocyanin (KLH) and DNP-Ficoll, to evaluate immune responses in CVID patients and normal donors. B and T cell responses were examined 2 and 4 weeks post-immunization. Sera were examined for IgM and IgG anti-KLH responses by ELISA and for anti-DNP-Ficoll activity by haemagglutination. The frequency of KLH-responsive T cells was measured by DNA synthesis in a limiting dilution culture system. Low density cells enriched for dendritic cells were pulsed with KLH and cultured with different numbers of autologous T cells. T cells from normal donors and from patients showed a low frequency of antigen-specific precursor T cells (Յ1:200 000). After KLH immunization the frequency increased in normal donors (1:60 000 and 1:30 000 at 2 and 4 weeks, respectively), while in CVID patients it did not change from the preimmunization level. The defect may extend to a dysfunction of antigen-specific cells, rather than being solely due to the reduced numbers of cells, since mean responses of 'positive' wells were also reduced. The serum-specific antibody response paralleled the T cell data, in that all normal donors but none of the CVID patients generated IgG KLH-specific antibodies. CVID patients did produce IgM antibodies against the T-independent DNP-Ficoll, but at a lower level than normal controls. These data show that both T and B cells from CVID patients have defective responses to specific antigen, implicating both lineages in the antibody deficiency.

Fine-Scale Mapping at IGAD1 and Genome-Wide Genetic Linkage Analysis Implicate HLA-DQ/DR as a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency

“…Altered signaling via pMHC/TCR can result in differential phosphorylation patterns in downstream kinases, such as ZAP-70, which shows defective activation and recruitment in CVID (52)(53)(54). Ab deficiency in IgAD/CVID may develop as a result of impaired T cell activation and insufficient T cell help to B cells, consistent with IgA being the most T cell-dependent isotype and with the impairment of T cell-dependent processes in germinal centers observed in some CVID patients, such as affinity maturation (62) and memory formation (63). Although functional defects may be secondary to thymic pMHCII/TCR interactions, transgenic models of self-tolerance point to complex mechanisms involving peripheral and central selection coupled with a dysregulation of many immune effector genes, rather than processes mediated purely by thymic deletion (64).…”

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].…”

Long term recovery of IgG and IgM production during HIV infection in a patient with common variable immunodeficiency (CVID)

“…4 The observation that the immunodeficiency in CVID can be substantially reversed by HIV infection should encourage research into the mechanism responsible for this phenomenon.…”

“…Other features include granulomatous involvement of various organs and autoimmune disease. 3 The mechanisms underlying CVID are not known but the evidence supports a combination of abnormalities in T cells and monocytes 4 and, in some cases, B cells. 5 A variety of T cell defects have been described, with clear evidence of a failure to generate antigen specific "memory" CD4 + T cells after immunisation.…”

“…5 A variety of T cell defects have been described, with clear evidence of a failure to generate antigen specific "memory" CD4 + T cells after immunisation. 4 The current consensus is that a major subgroup of patients with CVID have a complex polygenic disorder of immune regulation, with one or more genes predisposing to the more common but less severe IgAD. …”