Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production.

BACKGROUND: Toll-like receptors contribute to the establishment of adaptive immune responses. OBJECTIVE: The reported studies were conducted to examine the effects of the Toll-like receptor (TLR)-7 ligand, resiquimod, on human naive B-cell differentiation. METHODS: Naive human B cells were cultured with resiquimod in the presence or absence of IL-2 and IL-10. Secreted IgM and IgG were measured by ELISA, and IL-6, IL-10, and IFN-alpha were measured by a multiplex protein array. Cell proliferation was assessed by measuring [(3)H]thymidine uptake. mRNA for activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts was measured by means of RT-PCR. RESULTS: Resiquimod induced the production of IgM and, to a lesser extent, IgG by naive human B cells in association with the secretion of IL-6 and IL-10, and a weak proliferative response. IL-2 and IL-10 synergized with resiquimod in markedly augmenting resiquimod-induced IgM and IgG production and proliferation. Resiquimod also stimulated production of IgG by B cells isolated from the blood of a patient with the X-linked hyper-IgM syndrome, with a greater response when these cells were costimulated with IL-2 and IL-10. The stimulated naive B cells from healthy volunteers displayed molecular evidence of immunoglobulin class-switch recombination-namely the appearance of activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts. CONCLUSION: Perturbation of TLR-7 on naive human B cells can lead to the induction of immunoglobulin class switch and IgG production in the absence of B-cell receptor cross-linking and CD40-CD40L interaction. The results are relevant to vaccine development and mechanisms by which microbial infection may lead to autoimmunity.

Progressive multifocal leukoencephalopathy in a patient with common variable immunodeficiency and abnormal CD8+ T-cell subset distribution.

BACKGROUND: Patients with primary hypogammaglobulinemia have been reported to have encephalopathy, but progressive multifocal leukoencephalopathy (PML) due to JC virus reactivation is a rare cause. OBJECTIVE: To provide the clinical details and case discussion of a patient diagnosed as having common variable immunodeficiency (CVID) who has progressive neurodegenerative symptoms and was found to have PML and an abnormal CD8+ T-cell subset distribution. METHODS: A detailed case report providing the patient's immunodeficiency history, diagnostic evaluation, and medical management and a review of related literature. RESULTS: Before his neurodegenerative illness, the patient was found to have hypogammaglobulinemia, poor specific antibody responses, low circulating B-cell levels, and abnormal delayed-type hypersensitivity responses; there was no Bruton tyrosine kinase (BTK) mutation. The PML was diagnosed using brain biopsy and was confirmed using a DNA probe specific for JC virus. Peripheral blood flow cytometry at the time of PML diagnosis revealed an accumulation of naive CD8+ T cells (CD3+CD8+CD45RA+) and a deficiency of memory CD8+ T-cell subsets (CD3+CD8+CD45RA- or CD3+CD8+CD45RO+). Despite aggressive treatment with interleukin 2, interferon-gamma, and intravenous cidofovir, the patient died. CONCLUSIONS: JC virus infection should be considered in the differential diagnosis of the patient with CVID and signs and symptoms of encephalopathy. The role of this patient's abnormal CD8' T-cell subset distribution in the development or control of this rare infection is worthy of consideration and has encouraged us to enumerate naive and memory CD4+ and CD8+ T-cell subsets in patients diagnosed as having CVID, even in the absence of neurodegenerative symptoms.