A functional role for CCR6 on proallergic T cells in the gastrointestinal tract.

BACKGROUND & AIMS: CCL20 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. METHODS: We evaluated the role of CCR6 in allergic diarrhea induced by sensitization and oral challenge with ovalbumin (OVA) using CCR6(+/+) and CCR6(-/-) mice. RESULTS: CCR6(-/-) 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. CONCLUSIONS: These studies highlight a mast cell- and immunoglobulin E-independent role for CCR6-bearing T cells in the pathogenesis of gastrointestinal allergic disease.

A boy with fever, lymphadenopathy, hepatosplenomegaly, and lymphocytosis.

Proliferation of the lymphoid system should arouse suspicion of a potentially serious illness. We present a 4.5-year-old boy who developed fever, vomiting, diarrhea, lymphadenopathy, hepatosplenomegaly, lymphocytosis, anemia, thrombocytopenia, and increased liver enzymes. Lymph node and bone marrow biopsies showed lymphoproliferation, Epstein-Barr virus (EBV) infection, and hemophagocytosis leading to the diagnosis of hemophagocytic lymphohistiocytosis (HLH). Chemotherapy was initiated for HLH with dexamethasone, etoposide, and cyclosporine. Because of a high level of EBV viremia, rituximab was added a few days later and resulted in a remarkable drop in the EBV in the circulation but not in the cerebrospinal fluid. However, the patient succumbed to encephalitis, pneumonia, and cardiopulmonary failure. Autopsy revealed the presence of EBV in the brain, indicating the ineffectiveness of rituximab therapy in treating central nervous system infection with EBV.

Common variable immune deficiency: reviews, continued puzzles, and a new registry.

BACKGROUND: Common variable immune deficiency (CVID) is a clinically and immunologically heterogenous primary immune deficiency first described more than 50 years ago. The main features are hypogammaglobulinemia, recurrent infections, and other complications. While CVID is considered as a genetic immune defect, and several genes have been reported as leading to the CVID phenotype, one of the most puzzling features of CVID is the sporadic inheritance pattern and the relatively late onset. In most cases, no other family members have any immune defect. The mean age at diagnosis is between 25 and 45 years of age. These features suggest the interplay between either several or numerous genes with or without potential environmental factors.

CD4 T cells activated in the mesenteric lymph node mediate gastrointestinal food allergy in mice.

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.

Risk factors for the development of food allergy.

Both genetic and environmental factors seem to predispose to the development of food allergy. A most notable factor is diet, particularly during infancy. Possible other factors include maternal diet during pregnancy and lactation, birth by cesarean section, exposure to tobacco smoke, multivitamin supplementation, and intake of antacids. It is important to identify and control such risk factors to reduce the development of 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.

Diagnosis of food allergy.

The diagnosis of food allergy requires obtaining a detailed medical history and consideration of differential diagnosis. The offending food(s) may be identified by the medical history, trials of elimination diets, SPT, food-specific IgE measurement, or some combination. However, the reliability of these methods is usually suboptimal, and confirmation of the offending food(s) requires well-designed challenge tests.

Skin prick test to egg white provides additional diagnostic utility to serum egg white-specific IgE antibody concentration in children.

BACKGROUND: Levels of IgE antibody to egg white of greater than 7 kIU/L are highly predictive of clinical reactivity to egg, and lower levels often require evaluation with oral food challenge (OFC) to establish definitive diagnosis. OFCs have inherent risks, and diagnostic criteria indicating high likelihood of passing would be clinically useful. OBJECTIVE: We sought to determine whether the size of the skin prick test (SPT) to egg white adds diagnostic utility for children with low egg white-specific IgE antibody levels. METHODS: A retrospective analysis of clinical history, egg white-specific IgE antibody levels, SPT responses, and egg OFC outcomes was performed. RESULTS: Children who passed (n = 29) egg OFCs and those who failed (n = 45) did not differ significantly in age, clinical characteristics, or egg white-specific IgE levels. There were, however, significant differences between both egg white SPT wheal response size and egg/histamine SPT wheal index. Children who failed egg OFCs had a median wheal of 5.0 mm; those who passed had a median wheal of 3.0 mm (P = .003). Children who failed egg OFCs had a median egg/histamine index of 1.00; those who passed had a median index of 0.71 (P = .001). For egg white-specific IgE levels of less than 2.5 kIU/L, an SPT wheal of 3 mm or an egg/histamine index of 0.65 was associated with a 50% chance of passing. CONCLUSION: In children with low egg white-specific IgE levels, those with smaller SPT wheal responses to egg were more likely to pass an egg OFC than those with larger wheal responses. The size of the egg white SPT response might provide additional information to determine the timing of egg OFC. CLINICAL IMPLICATIONS: The size of the egg white SPT wheal response might provide the clinician with additional information to determine the timing of egg OFC in children with low egg white-specific IgE antibody levels.

Inflammatory and autoimmune complications of common variable immune deficiency.

Common variable immune deficiency (CVID) is associated with autoimmune and inflammatory complications in addition to recurrent infections. The most common conditions are idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, sarcoid-like granulomatous disease and gastrointestinal inflammation. IVIG administration reduces the frequency of infections, but does not always prevent autoimmunity or inflammation. TNF antagonists and anti-CD20 immunomodulators have shown some efficacy in CVID in a few patients; further controlled studies are needed to determine the best management of these conditions in the setting of immunodeficiency.

Alcohol-induced rash caused by topical tacrolimus.

BACKGROUND: Topical 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. OBJECTIVE: To increase awareness of a drug interaction with alcohol that can mimic food allergy. METHODS: We describe 3 patients who used topical tacrolimus, 2 with an atopic history and 1 without, who presented with a flushing reaction after ingesting alcohol. RESULTS: Cessation of topical tacrolimus use resolves the alcohol-related skin reaction. CONCLUSIONS: A 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.