Aubert Lavoie

Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans.

Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications; patients with hyper-IgM syndromes who are deficient in activation-induced cytidine deaminase (AID), which is required for class-switch recombination and somatic hypermutation, are prone to develop autoimmune diseases. To investigate the impact of AID-deficiency on early B-cell tolerance checkpoints in humans, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from AID-deficient patients. New emigrant/transitional and mature naive B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance. In addition, B-cell tolerance was further breached in AID-deficient patients as illustrated by the detection of anti-nuclear IgM antibodies in the serum of all patients. Thus, we identified a major and previously unsuspected role for AID in the removal of developing autoreactive B cells in humans.

Allergic rhinitis to ragweed pollen: II. Modulation of histamine-releasing factor production by specific immunotherapy

A number of cytokines, including histamine-releasing factors (HRFs), have a role to play in IgE-mediated asthma. However, the influence of HRF in allergic rhinitis without asthma remains to be revealed. This article presents a double-blind, placebo-controlled study on the role of HRF in ragweed-allergic rhinitis and its modulation by natural pollen exposure and specific immunotherapy (IT). Twenty-seven patients allergic to ragweed were randomly assigned to receive either preseasonal alum-precipitated aqueous extracts of ragweed or placebo. Before the onset of therapy and during the ragweed-pollen season, subjects were evaluated for each of the following: clinical scores, ragweed IgE and IgG antibody levels, and spontaneous and allergen-driven HRF production. Thirteen nonatopic volunteers were also studied in the same protocol. First, before the initiation of therapy, more HRF was produced by both unstimulated and ragweed-stimulated mononuclear cells (MNCs) of atopic subjects as compared to MNCs of nonatopic subjects. Second, MNCs of the placebo-treated group produced significantly more spontaneous and ragweed-specific HRF during the pollen season compared to the preseasonal values. Finally, specific IT not only improved the clinical manifestation of allergy but also prevented the seasonal rise of spontaneous and ragweed-driven HRF production, along with a well-known change in other immunologic parameters associated with successful IT.

Chronic idiopathic urticaria: Profiles of skin mast cell histamine release during active disease and remission

Chronic idiopathic urticaria (CIU) is characterized by the increased releasability of histamine by mast cells in normal-appearing skin. In active CIU, this abnormality is consistently present. To determine if this finding subsides when the disease goes into remission phase, we analyzed the histamine secretion in patients with CIU in remission (CIUR) compared with that of patients with CIU and in normal control (NC) subjects, with the skin-chamber technique. The profiles of histamine release in sites challenged with compound 48/80 were significantly different in the groups with CIU and CIUR. Furthermore, patients with CIUR did not differ from NC subjects in terms of histamine releasability under compound 48/80 stimulation (p greater than 0.1). These data suggest that the state of excessive skin mast cell sensitivity is a reversible and transient phenomenon in CIU disease.

Chronic idiopathic urticaria: Possible contribution of histamine-releasing factor to pathogenesis

BACKGROUND Histamine-releasing factor was recently shown to be clinically relevant in allergic rhinitis and asthma. HRF could also be involved in the pathogenicity of chronic idiopathic urticaria (CU). The purpose of this study was to investigate the role of HRF in the pathophysiology of CU. METHODS Blisters were induced on lesional and nonlesional skin of 12 patients with CU and on normal skin of five control subjects. HRF activity and histamine content were measured in all samples recovered from each skin site. RESULTS Significantly more HRF was found in blister fluids from lesional skin of patients with CU as compared with nonlesional skin and skin of control subjects. In addition, histamine content in blister fluids from affected skin of patients with CU was significantly higher in comparison with both nonlesional skin of patients with CU and skin of control subjects. HRF activity was also higher in blister fluids from nonlesional skin of patients with CU than that of control subjects, in spite of equivalent histamine content. CONCLUSION These data suggest that the inflammatory reaction found in CU disease is associated with the cutaneous release of HRF.

Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance

Activation-induced cytidine deaminase (AID), the enzyme-mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.

In utero acute graft-versus-host disease in a neonate with severe combined immunodeficiency

We describe a male neonate with severe combined immunodeficiency who at birth had acute graft-versus-host disease (GVHD) as a result of maternal-fetal transfusion during pregnancy. Several clinical signs helped establish this diagnosis. Findings of a skin biopsy specimen confirmed the diagnosis of acute GVHD. Immunologic evaluation disclosed an absence of T and B lymphocytes. Acute GVHD in severe combined immunodeficiency most often occurs during the first weeks of life; intrauterine occurrence is unusual.

Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint

Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM. The low frequency of autoreactive mature naive B cells in UNG-deficient patients resembled that of healthy subjects, revealing that impaired CSR does not interfere with the peripheral B cell tolerance checkpoint. In contrast, we observed decreased frequencies of SHM in memory B cells from AD-AID patients and AID+/- subjects, who were unable to prevent the accumulation of autoreactive mature naive B cells. In addition, the individuals with AICDA mutations, but not UNG-deficient patients, displayed Tregs with defective suppressive capacity that correlated with increases in circulating T follicular helper cells and enhanced cytokine production. We conclude that SHM, but not CSR, regulates peripheral B cell tolerance through the production of mutated antibodies that clear antigens and prevent sustained interleukin secretions that interfere with Treg function.

Recurrent acute epiglottitis in adults: defective antibody response

BACKGROUND Recurrent acute epiglottitis is uncommon in adults. In the medical literature, very little is known about the immune status of this population. OBJECTIVE To evaluate the immune system of a group of four adult patients with recurrent acute epiglottitis, in what represents the largest series ever reported. METHODS The clinical course of these episodes was carefully evaluated and a basic immune deficiency work-up was carried out for each patient. RESULTS All four patients displayed clinical and laboratory evidence of impaired humoral immunity. One patient was splenectomized. Another patient had a below normal immunoglobulin G level. At the time of their first evaluation, none of our patients had specific antibodies against Haemophilus influenzae and one had a subnormal Streptococcus pneumoniae immunoglobulin G level for a majority of serotypes. After specific vaccination, two patients had persistent abnormalities in their response to one or more polysaccharides or conjugate-polysaccharide antigens. In the other two, the transient abnormalities were corrected by immunization. CONCLUSIONS When recurrent acute epiglottitis occurs in adults, it is important to investigate the immune system because a quantitative or a specific antibody deficiency could be found. It also follows that these patients will be successfully treated either by immunization or antibody replacement.

Effects of systemic corticosteroids on cutaneous histamine secretion and histamine-releasing factor in patients with chronic idiopathic urticaria

Background Enhanced skin mast cell releasability of histamine, increased production of histamine releasing factor (HRF), and cutaneous inflammatory process are the hallmarks of chronic idiopathic urticaria (CU). Although H1‐antihistamines are known to alleviate the symptoms effectively in most cases, systemic corticosteroids (CS) are given in more resistant patients. Their mode of action remains a matter of controversy.

Comparison of Histamine-Releasing Factor Recovered from Skin and Peripheral Blood Mononuclear Cells of Patients with Chronic Idiopathic Urticaria

BACKGROUND The pathogenesis of chronic idiopathic urticaria is characterized by defective histamine release. Skin mast cells show an increased release of histamine while circulating basophils are less responsive to immunologic stimulus. OBJECTIVE The purpose of the study was to examine and compare the production of the histamine-releasing factor in the skin and within the peripheral blood of patients with chronic idiopathic urticaria and normal control subjects, as a possible factor responsible for the difference observed in the releasability of both skin mast cells and basophils. METHODS Using the skin chamber technique, histamine-releasing factor production and histamine concentration were assessed in normal-appearing skin of patients with chronic idiopathic urticaria (n = 12) and normal controls (n = 5) over a 2-hour observation period. In both groups, histamine-releasing factor production by peripheral blood mononuclear cells was also measured. RESULTS The weighted average of histamine-releasing factor production during the 2-hour observation period was higher in the non-lesional skin of patients with chronic idiopathic urticaria as compared with normal controls (5.6 +/- 1.4% versus 0.7 +/- 0.6%, P < .01). In contrast, less histamine-releasing factor was produced by peripheral blood mononuclear cells in chronic urticaria as opposed to normal controls (17.2 +/- 2.1% versus 25.7 +/- 2.8%, P < .03). Spontaneous histamine concentration was not significantly different in patients with chronic urticaria than in normal controls. CONCLUSION Histamine-releasing factor production is increased in the skin, and decreased in the peripheral blood of patients with chronic idiopathic urticaria when compared with nonatopic controls. The lower production of histamine releasing factor in the blood could be explained by the migration of activated T-lymphocytes in the skin.