Background-Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells.

Common variable immune deficiency (CVID) is a primary immune deficiency characterized by low levels of serum immune globulins, lack of Ab, and reduced numbers of CD27+ memory B cells. Although T, B, and dendritic cell defects have been described, for the great majority, genetic causes have not been identified. In these experiments, we investigated B cell and plasmacytoid dendritic cell activation induced via TLR9, an intracellular recognition receptor that detects DNA-containing CpG motifs from viruses and bacteria. CpG-DNA activates normal B cells by the constitutively expressed TLR9, resulting in cytokine secretion, IgG class switch, immune globulin production, and potentially, the preservation of long-lived memory B cells. We found that CpG-DNA did not up-regulate expression of CD86 on CVID B cells, even when costimulated by the BCR, or induce production of IL-6 or IL-10 as it does for normal B cells. TLR9, found intracytoplasmically and on the surface of oligodeoxynucleotide-activated normal B cells, was deficient in CVID B cells, as was TLR9 mRNA. TLR9 B cell defects were not related to proportions of CD27+ memory B cells. CpG-activated CVID plasmacytoid dendritic cells did not produce IFN-α in normal amounts, even though these cells contained abundant intracytoplasmic TLR9. No mutations or polymorphisms of TLR9 were found. These data show that there are broad TLR9 activation defects in CVID which would prevent CpG-DNA-initiated innate immune responses; these defects may lead to impaired responses of plasmacytoid dendritic cells and loss of B cell function.

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A localized Th2 milieu has been observed in the intestine of subjects with food allergic disorders; however, the role of T cells in the pathophysiology of these disorders remains poorly understood. Our aim was to examine sites of T cell activation in response to food challenge, identify potential factors responsible for T cell recruitment to the gut, and determine the role of T cells in disease. BALB/c mice were systemically sensitized to ovalbumin (OVA) and repeatedly fed with OVA to induce allergic diarrhea. Local cytokine and chemokine expressions were assessed by quantitative PCR, and cytokine secretion levels in the mesenteric lymph node (MLN) were determined by ELISA. Homing molecule expression was determined by flow cytometry, and the role of CD4(+) T cells in promoting disease was tested by adoptive transfer. Mice developed diarrhea associated with changes in epithelial ion transport, mast cell infiltration, intestinal IgE secretion, and local upregulation of Th2 cytokines and the Th2 chemokines CCL1, CCL17, and CCL22 in the small intestine. T cell activation occurred in the MLN before symptom onset, and a single feed of OVA induced T cell proliferation, alpha(4)beta(7) upregulation, and CD62L downregulation. Cells from the MLN, including purified CD4(+) T cells, were able to transfer allergic diarrhea to naive mice. A gut-homing phenotype induced in the MLN and selective upregulation of Th2 chemoattractants are likely important factors in the gastrointestinal recruitment of pathological Th2-skewed CD4(+) T cells in food allergy.

Common variable immunodeficiency (CVID) is characterized by low levels of immune globulins and lack of antibody. Mutations in transmembrane activator and calcium-modulating cyclophilin ligand (TACI), are found in 8-10%, associated with autoimmunity and splenomegaly. Some patients with mutations had increased serum levels of TACI. Because of this, and the prevalence of autoimmunity, splenomegaly, and lymphadenopathy, we quantitated levels of TACI ligands, a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF) and TACI in serum of 77 patients. CVID subjects had markedly increased serum levels of BAFF (p<0.0001), APRIL (p<0.0001), and TACI (p=0.001) but there was no relationship between levels and autoimmunity, lymphadenopathy, splenomegaly, B cell numbers, or mutations in TACI. Peripheral blood mononuclear cells of CVID subjects had increased levels of BAFF mRNA. We conclude that increased constitutive production and/or underlying immuno-regulatory or inflammatory conditions lead to enhanced release of ligands; however, the biological result remains unclear.