Failure of B Cell Tolerance in CVID.

Common variable immunodeficiency (CVID) comprises a group of related disorders defined by defects in B cell function and antibody production. Concurrent autoimmune features are common, but the underlying pathogenic mechanisms of autoimmunity in CVID are poorly understood. Overlap in some clinical and laboratory features suggests a shared pathogenesis, at least in part, with systemic lupus erythematosus (SLE). One important part of SLE pathogenesis is loss of B cell tolerance, an aspect that warrants further study in CVID. The study of inherently autoreactive 9G4+ B cells has led to a greater understanding of B cell tolerance defects in lupus. Study of these B cells in CVID has yielded conflicting results, largely due to differences in methodological approaches. In this study, we take a comprehensive look at 9G4+ B cells throughout B cell development in CVID patients and compare patients both with and without autoimmune features. Using flow cytometry to examine B cell subpopulations in detail, we show that only those CVID patients with autoimmune features demonstrate significant expansion of 9G4+ B cells, both in naïve and multiple memory populations. Examination of two autoreactive B cell subsets recently characterized in SLE, the activated naïve (aNAV) and double negative 2 (DN2) B cells, reveals an expanded 9G4+ DN2 population to be common among CVID patients. These results reveal that both multiple central and peripheral B cell tolerance defects are related to autoimmunity in CVID. Furthermore, these data suggest that the autoreactive DN2 B cell population, which has not previously been examined in CVID, may play an important role in the development of autoimmunity in patients with CVID.

Effects of omalizumab on changes in pulmonary function induced by controlled cat room challenge.

BACKGROUND: Environmental exposure to cat allergen is common, and sensitization to cat allergens is strongly associated with asthma. OBJECTIVE: We sought to examine the efficacy of omalizumab in preventing acute bronchoconstriction induced by environmental exposure to cat allergen. METHODS: Patients with a history of cat allergen-induced asthma were randomized to treatment with omalizumab or placebo and exposed to cat allergen in a controlled chamber for up to 1 hour at baseline and after 16 weeks of treatment. The primary efficacy outcome was area under the curve for percentage decrease from prechallenge FEV(1) at week 16 for omalizumab-treated versus placebo-treated patients. FEV(1) was recorded before and every 10 minutes during the 1-hour challenge. Chest, nasal, and ocular symptoms were also monitored during cat chamber exposure as secondary end points. RESULTS: The area under the curve for percentage decrease in FEV(1) was 15.2% per hour for omalizumab-treated patients (n = 32) and 27.3% per hour for placebo-treated patients (n = 33), reflecting 44% less reduction in FEV(1) and a treatment difference of -12.1% per hour (P = .0009; 95% CI, -19.0 to -5.2). Compared with placebo-treated patients, omalizumab-treated patients were also able to tolerate longer allergen exposure (P = .0006) and demonstrated significant reductions from prechallenge values in their chest symptom score (P < .0001) and nasal-ocular symptom score (P = .0002). CONCLUSIONS: The severity of acute airway reactions and symptoms caused by controlled cat room exposure to allergens was significantly reduced by treatment with omalizumab.

The natural history of wheat allergy.

BACKGROUND: Wheat allergy is 1 of the most common food allergies in children, yet few data are available regarding its natural history. OBJECTIVES: To define the natural course of wheat allergy and identify factors that help predict outcome in a large referral population of children with wheat allergy. METHODS: Patients were included in the study if they had a history of a symptomatic reaction to wheat and a positive wheat IgE test result. Clinical history, laboratory results, and final outcome were recorded for 103 patients who met the inclusion criteria. Resolution of wheat allergy was determined based on food challenge results. Kaplan-Meier survival curves were generated to depict resolution of wheat allergy. RESULTS: Rates of resolution were 29% by 4 years, 56% by 8 years, and 65% by 12 years. Higher wheat IgE levels were associated with poorer outcomes. The peak wheat IgE level recorded was a useful predictor of persistent allergy (P < .001), although many children outgrew wheat allergy with even the highest levels of wheat IgE. CONCLUSION: The median age of resolution of wheat allergy is approximately 6 1/2 years in this population. In a significant minority of patients, wheat allergy persists into adolescence.

New HLA-A, -B, and -C locus-specific primers for PCR amplification from cDNA: application in clinical immunology.

The individual cellular immune response to intracellular antigens is modeled by the highly polymorphic major histocompatibility complex (HLA) class I molecules. The epitopes presented and the T cell repertoire that recognizes them depend on the HLA constitution of the individual. Therefore, to monitor and to modify an individual's HLA class I-driven cellular immune response, it is necessary to know the HLA class I alleles of the person and the possible epitopes of the target antigen presented by those alleles. In particular, this is necessary in order to design peptide-based vaccines and immune therapies for the treatment of diseases caused by viruses, intracellular parasites or cancer, and to monitor the immune response during those treatments. We describe a new set of HLA-A, -B, and -C locus-specific primers for the polymerase chain reaction (PCR) amplification of the whole coding sequence of these genes from complementary DNA (cDNA). We describe their use for typing and for the production of a library of recombinant HLA class I genes. We discuss two downstream applications of this gene collection: production of soluble HLA molecules and discovery of new epitopes.