Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency

Abstract

The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

B-cell tumor development in Tet2-deficient mice

“…22 A representative analysis is shown in Figure 1E. The abnormal B-cell population showed oligo/monoclonality ( Figure 1E, bottom panel), markedly different in comparison with the polyclonality observed in lanes corresponding to wild-type B-cell populations ( Figure 1E, top panel).…”

“…22 PCR products were run on a 3130xl sequencer (Applied Biosystems), and data were analyzed using Peakscanner software (Applied Biosystems). PCR fragments were sequenced using the same VH family primer used for amplification.…”

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease–associated dysgammaglobulinemia

“…33 Whereas physiologic concentrations of BAFF contribute to purging of autoreactive B cells in the periphery, exogenous administration or overexpression of BAFF is known to rescue autoreactive B cells resulting in production of antichromatin and anti-DNA antibodies. [42][43][44][45] Indeed, BAFF antagonists are seriously considered for treatment of SLE. 46 Highest BAFF/B-cell ratios were observed in our cGVHD patient cohort with hypogammaglobulinemia, resulting from significantly increased BAFF levels and low CD19 ϩ B-cell numbers.…”

B cell–intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice

“…10 For immunization with a Streptococcus pneumoniae whole-cell vaccine (PnWCV), 100 g of unencapsulated PnWCV was administered subcutaneously twice 2 weeks apart as described. 11 Seven days after the boosting immunization, animals were bled, and serum IgG Abs specific for the vaccine were measured by ELISA as described.…”