Factors Beyond Lack of Antibody Govern Pulmonary Complications in Primary Antibody Deficiency.

PURPOSE: Pulmonary complications occur frequently in primary antibody deficiency (PAD). While the impact of antibody deficiency may appear implicit for certain respiratory infections, immunoglobulin replacement therapy does not completely ameliorate pulmonary complications in PAD. Thus, there may be antibody-independent factors influencing susceptibility to respiratory disease in PAD, but these remain incompletely defined. METHODS: We harnessed the multicenter US Immunodeficiency Network primary immunodeficiency registry to compare prevalence of asthma, bronchiectasis, interstitial lung disease (ILD), and respiratory infections between two forms of PAD: common variable immunodeficiency (CVID) and x-linked agammaglobulinemia (XLA). We also defined the clinical and immunological characteristics associated with ILD and asthma in CVID. RESULTS: Asthma, bronchiectasis, ILD, pneumonia, and upper respiratory infections were more prevalent in CVID than XLA. ILD was associated with autoimmunity, bronchiectasis, and pneumonia as well as fewer B and T cells in CVID. Asthma was the most common chronic pulmonary complication and associated with lower IgA and IgM in CVID. Age of symptom onset or CVID diagnosis was unrelated with ILD or asthma. CONCLUSION: Despite having less severe immunoglobulin deficiency than XLA, respiratory infections, ILD, and asthma were more common in CVID. Among CVID patients, ILD was associated with autoimmunity and reduced lymphocytes and asthma with lower immunoglobulins. Though our results are tempered by registry limitations, they provide evidence that factors beyond lack of antibody promote pulmonary complications in PAD. Efforts to understand how genetic etiology, nature of concurrent T cell deficiency, and propensity for autoimmunity shape pulmonary disease may improve treatment of PAD.

BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and is frequently complicated by interstitial lung disease (ILD) for which etiology is unknown and therapy inadequate. METHODS: Medical record review implicated B cell dysregulation in CVID ILD progression. This was further studied in blood and lung samples using culture, cytometry, ELISA, and histology. Eleven CVID ILD patients were treated with rituximab and followed for 18 months. RESULTS: Serum IgM increased in conjunction with ILD progression, a finding that reflected the extent of IgM production within B cell follicles in lung parenchyma. Targeting these pulmonary B cell follicles with rituximab ameliorated CVID ILD, but disease recurred in association with IgM elevation. Searching for a stimulus of this pulmonary B cell hyperplasia, we found B cell-activating factor (BAFF) increased in blood and lungs of progressive and post-rituximab CVID ILD patients and detected elevation of BAFF-producing monocytes in progressive ILD. This elevated BAFF interacts with naive B cells, as they are the predominant subset in progressive CVID ILD, expressing BAFF receptor (BAFF-R) within pulmonary B cell follicles and blood to promote Bcl-2 expression. Antiapoptotic Bcl-2 was linked with exclusion of apoptosis from B cell follicles in CVID ILD and increased survival of naive CVID B cells cultured with BAFF. CONCLUSION: CVID ILD is driven by pulmonary B cell hyperplasia that is reflected by serum IgM elevation, ameliorated by rituximab, and bolstered by elevated BAFF-mediated apoptosis resistance via BAFF-R. FUNDING: NIH, Primary Immune Deficiency Treatment Consortium, and Rare Disease Foundation.

Current perspectives on tree nut allergy: a review.

Tree nut (TN) allergy is common and often severe. It has become an important health concern as availability and consumption have increased. Prevalence varies by age and geographic region and appears to have increased in children. Accidental ingestion of TNs is common. Unfortunately, there is a lower likelihood of resolution of TN allergy, roughly 10%. TN-specific skin tests and serum immunoglobulin E levels can help aid in the diagnosis of TN allergy, but a careful medical history is important because a positive test in isolation is not typically diagnostic. Component-resolved diagnostic tests are being increasingly utilized and may improve accuracy. Management consists of strict avoidance of the causal nut(s) and prompt treatment of symptoms upon accidental exposure. A specific consideration with regard to the management of TN allergy is the decision to avoid all TNs or only the TNs to which a patient is clinically allergic. There are currently no data on the primary or secondary prevention of TN allergy. Treatment strategies are being evaluated.