Adina Kay Knight

TLR9 Activation Is Defective in Common Variable Immune Deficiency

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.

Toll-like receptor 7 and 9 defects in common variable immunodeficiency.

BACKGROUNDnCommon variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells.nnnOBJECTIVEnBecause Toll-like receptor (TLR) activation of B cells can initiate and potentially sustain normal B cell functions, we examined functional outcomes of TLR7 and TLR9 signaling in CVID B cells.nnnMETHODSnTLR7-mediated, TLR7/8-mediated, and TLR9-mediated cell proliferation, isotype switch, and immunoglobulin production by control and CVID B cells or isolated naive and memory B cell subsets were examined. We quantitated TNF-alpha, IL-6, and IL-12 production in response to TLR1-9 ligands and measured IFN-alpha production by TLR7-stimulated PBMCs and isolated plasmacytoid dendritic cells (pDCs). IFN-beta mRNA expression by TLR3-stimulated fibroblasts was assessed.nnnRESULTSnUnlike CD27(+) B cells of controls, TLR7-activated, TLR7/8-activated, or TLR9-activated CVID B cells or isolated CD27(+) B cells did not proliferate, upregulate CD27, or shed surface IgD. TLR-stimulated CVID B cells failed to upregulate activation-induced cytosine deaminase mRNA or produce IgG and IgA. TLR7-stimulated PBMCs and pDCs produced little or no IFN-alpha. Reconstituting IFN-alpha in TLR7-stimulated CVID B-cell cultures facilitated proliferation, CD27 upregulation, and isotype switch. These TLR defects are restricted because CVID PBMCs stimulated with TLR ligands produced normal amounts of TNF-alpha, IL-6, and IL-12; TLR3-mediated expression of IFN-beta by CVID fibroblasts was normal.nnnCONCLUSIONnDefective TLR7 and TLR9 signaling in CVID B cells and pDCs, coupled with deficient IFN-alpha, impairs CVID B cell functions and prevents TLR-mediated augmentation of humoral immunity in vivo.

A Functional Role for CCR6 on Proallergic T Cells in the Gastrointestinal Tract

BACKGROUND & AIMSnCCL20 is a chemokine that regulates the homeostatic and inflammatory trafficking of leukocytes to the small intestine and regulates the development of the gastrointestinal lymphoid architecture. T cells expressing T helper cell (Th) 2 cytokines are critical for experimental food allergy, and we hypothesized that CCL20 is involved in the localization of these cells to the gut.nnnMETHODSnWe evaluated the role of CCR6 in allergic diarrhea induced by sensitization and oral challenge with ovalbumin (OVA) using CCR6(+/+) and CCR6(-/-) mice.nnnRESULTSnCCR6(-/-) mice were protected from OVA-induced diarrhea but surprisingly were not impaired in mastocytosis or allergen-specific immunoglobulin E. CCR6(-/-) mice were also protected from T cell-mediated diarrhea induced by anti-CD3 antibody. Allergic diarrhea was associated with an increased expression of Th2 cytokines within the intestinal mucosa that was significantly reduced in CCR6(-/-) mice. Inhibition of lymphocyte homing by treatment with FTY720 did not impair allergic diarrhea, indicating that reactivation of T cells could occur locally within the small intestine. Finally, T-cell transfer studies demonstrated that CCR6 was required both on the transferred T cells and in the recipient mouse to manifest allergic disease in the gastrointestinal tract.nnnCONCLUSIONSnThese studies highlight a mast cell- and immunoglobulin E-independent role for CCR6-bearing T cells in the pathogenesis of gastrointestinal allergic disease.

Alcohol-induced rash caused by topical tacrolimus

BACKGROUNDnTopical treatment with tacrolimus may be complicated by ingestion-related flushing caused by consuming small amounts of alcohol, a reaction that can be mistaken for food allergy.nnnOBJECTIVEnTo increase awareness of a drug interaction with alcohol that can mimic food allergy.nnnMETHODSnWe describe 3 patients who used topical tacrolimus, 2 with an atopic history and 1 without, who presented with a flushing reaction after ingesting alcohol.nnnRESULTSnCessation of topical tacrolimus use resolves the alcohol-related skin reaction.nnnCONCLUSIONSnA careful history, including consideration of alcohol use, should be obtained in patients who use topical tacrolimus and present with new skin complaints, because these factors may be evidence of an avoidable drug interaction and not worsening of atopic disease or a food allergy.

CTLA-4 gene exon-1 +49 A/G polymorphism: lack of association with autoimmune disease in patients with common variable immune deficiency.

The presence of the G allele of exon-1 +49 A/G polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene has been described as a risk factor associated with the development of autoimmune diseases. Since Common Variable Immune Deficiency (CVID) is associated with autoimmune manifestations in approximately 25% of patients, we sought to examine the association of the CTLA-4 single nucleotide polymorphism with autoimmunity and other inflammatory complications. Sixteen of 47 CVID (34%) patients had a history of autoimmunity, and 15 (32%) had known granulomatous disease with or without lymphoid hyperplasia. CTLA-4 genotype frequencies were AA 40% (19), AG 45% (21), and GG 15% (7). Allele frequencies were A 63% and G 37%, similar to control populations. There were no significant associations between CTLA-4 exon-1 +49 A/G polymorphism and autoimmune or lymphoid hyperplasia and granulomatous disease in this mostly Caucasian CVID patient population.

Oxcarbazepine-Induced Immunoglobulin Deficiency

We are reporting the first case of oxcarbazepine-induced immunoglobulin deficiency. Although this is known to be a rare adverse reaction to various pharmacologics ([1][1], [4][2], [5][3]), including the anticonvulsant carbamazepine ([3][4], [6][5], [10][6], [11][7]), it has not been previously

Hypogammaglobulinemia with Facial Edema

Knight and colleagues discuss the diagnosis and management of a 35-year-old man with a past history of recurrent cellulitis and otitis media and a two-year history of facial swelling.