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HM Wolsk, BL Chawes, NV Folsgaard. Allergy. 2016;71(6);820–828 To determine whether having siblings affects the airway immune response in healthy neonates, a characteristic that could be attributed to an underlying immune modulatory pathway. Five hundred seventy-one 1-month-old, asymptomatic neonates from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) birth cohort were studied. Unstimulated airway mucosal lining fluid was sampled via the nose at 1 month …

Asthma and related respiratory tract allergic diseases are among the most common chronic diseases of adults and children. Despite their importance, disease course cannot be predicted and treatment remains non-specific and potentially hazardous, with no means for cure. Improved clinical management of asthma will require an improved understanding of the fundamental factors that initiate allergic inflammation, especially T helper type 2 (T(H)2) cell induction.In this review, we explore the Proteinase Hypothesis of allergic airway disease, considering specifically how organismal proteinases contribute to the expression of allergic disease and potentially important proteinase signaling pathways.Proteinases from diverse sources (bacteria, fungi, plants) may cause occupational asthma by acting as immune adjuvant factors that specifically elicit T(H)2 cell-dependent allergic inflammation. However, more conventional allergic airway diseases (asthma, allergic sinusitis) are more likely to arise from contained fungal or viral infections of the airway in which proteinases are produced and serve as major virulence factors. Proteinases may elicit allergic disease by disrupting numerous cellular proteins, potentially including Toll like receptor (TLR) 4, but critical proteinase-activated signaling pathways remain largely unknown.Clarification of how proteinases cause allergic disease, specifically confirming an infectious basis for airway proteinase exposure, will likely radically advance how asthma and related respiratory tract disorders are diagnosed and treated. This article is part of a Special Issue entitled Biochemistry of Asthma.

Allergic asthma is an obstructive lung disease linked to environmental exposures that elicit allergic airway inflammation and characteristic antigen-specific immunoglobulin reactions termed atopy. Analyses of asthma pathogenesis using experimental models have shown that T helper cells, especially T helper type 2 (Th2) cells and Th2 cytokines such as interleukin 4 (IL-4) and IL-13, are critical mediators of airway obstruction following allergen challenge, but the environmental initiators of lung Th2 responses are less defined. Our studies demonstrate that fungal-derived proteinases that are commonly found in home environments are requisite immune adjuvants capable of eliciting robust Th2 responses and allergic lung disease in mice. We have further shown that common household fungi readily infect the mouse respiratory tract and induce both asthma-like disease and atopy to otherwise innocuous bystander antigens through the secretion of proteinases. These findings support the possibility that asthma and atopy represent a reaction to respiratory tract fungal infection, suggesting novel means for diagnosis and therapy of diverse allergic disorders.

Active fungal proteinases are powerful allergens that induce experimental allergic lung disease strongly resembling atopic asthma, but the precise relationship between proteinases and asthma remains unknown. Here, we analyzed dust collected from the homes of asthmatic children for the presence and sources of active proteinases to further explore the relationship between active proteinases, atopy, and asthma. Active proteinases were present in all houses and many were derived from fungi, especially Aspergillus niger. Proteinase-active dust extracts were alone insufficient to initiate asthma-like disease in mice, but conidia of A. niger readily established a contained airway mucosal infection, allergic lung disease, and atopy to an innocuous bystander antigen. Proteinase produced by A. niger enhanced fungal clearance from lung and was required for robust allergic disease. Interleukin 13 (IL-13) and IL-5 were required for optimal clearance of lung fungal infection and eosinophils showed potent anti-fungal activity in vitro. Thus, asthma and atopy may both represent a protective response against contained airway infection due to ubiquitous proteinase-producing fungi.

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency affecting approximately 1 to 3 per million live male births. Patients are generally healthy until facing a viral infection such as Epstein-Barr Virus and then may develop fulminant infectious mononucleosis and die. XLP patients are also at increased risk of hemophagocytic lymphohistiocytosis (HLH), which may be triggered by assorted viruses. Here we report a novel case of HLH in a patient with XLP. Significant to his presentation is a paradoxical increase in natural killer (NK) cell activity. We hypothesize that this indicates that Parvovirus B19 activates NK cells via a signaling lymphocytic activation molecule-associated protein (SAP)-independent mechanism. Our case demonstrates an important etiology to consider in the differential diagnosis of XLP patients with nonfocal findings and febrile illnesses.

Background Between 1981 and 1995, 20 children with severe combined immunodeficiency (SCID; median age at transplant, 6.5 [range, 0.5-145] mo, 12 with serious infection) were treated with haploidentical T cell–depleted (anti-CD6 antibody) bone marrow (median number of 5.7 [0.8-18.8] × 10 8 nucleated cells/kg) from mismatched related donors (MMRDs), and 5 children with SCID (median age at transplant, 1.8 [0.5-5.0] mo, 1 with serious infection) were given unmanipulated bone marrow from matched related donors (MRDs). No conditioning or graft-versus-host disease (GvHD) prophylaxis was used. Objective To assess the outcomes of patients with SCID who received bone marrow from MMRDs or MRDs. Methods We reviewed the medical records of these 25 consecutive patients with SCID (4 with Omenn syndrome). Results Of the 20 patients who received bone marrow from MMRDs, 12 engrafted, 10 survived at a median age of 15.2 [10.0-19.1] years, 4 had chronic GvHD (lung, intestine, skin), 5 required intravenous immunoglobulin, and 8 attended school or college. Two of 5 patients who died had chronic GvHD, and 2 developed lymphoproliferative disease. Of the 5 patients who received bone marrow from MRDs, 5 engrafted, 5 survived at a median age of 23.3 [18.5-26] years, 1 had chronic GvHD (lung, skin), 2 required intravenous immunoglobulin, and 4 attended school or college. Conclusions Treatment of critically ill patients with SCID with anti-CD6 antibody T cell–depleted MMRD marrow resulted in an overall 50% long-term survival of patients (83% survival of those engrafted). The principal barriers to long-term survival were delay in diagnosis, life-threatening infection, failure to engraft, and chronic GvHD. Educational goals were achieved in most of the survivors.

A 5-week-old female infant with vertical HIV-1 exposure, progressive cough, and failure to thrive was given a diagnosis of bilateral diffuse nodular lung lesions. The child was without fever, leukocytosis, anemia, peripheral adenopathy, or hepatosplenomegaly, and the results of repeated blood tests for HIV-1 DNA were negative. A needle biopsy of the lungs revealed granulomatous inflammation and giant cells, with fungal organisms suggestive of Aspergillus species. A nitroblue tetrazolium dye test performed on the patient's blood specimen demonstrated absence of dye reduction, suggesting a diagnosis of chronic granulomatous disease. Further analysis revealed that the child had a deficiency of the p47(phox) component of the nicotinamide adenine dinucleotide phosphate oxidase system. Thus this child with vertical HIV-1 exposure and diffuse pulmonary nodules actually had an autosomal recessive form of chronic granulomatous disease. This case study clearly demonstrates that children with suspected HIV-1 infection might also need evaluation for primary immunodeficiency and that the clinical immunology laboratory is a powerful adjunct in coming to a correct diagnosis.

To determine the efficacy of high doses of intravenous gammaglobulin (IVIG) for the treatment of severe, steroid-dependent asthma in patients between 6 and 68 years of age, a randomized, double-blind, placebo-controlled multicenter clinical trial was conducted in private and university hospitals in the United States. Patients were randomized to one of three treatment arms: 2 g IVIG/kg/month (16 patients); 1 g IVIG/kg/month (9 patients); or 2 g iv albumin (placebo)/kg/month (15 patients). The treatment consisted of seven monthly infusions followed by a posttreatment observation period. The primary outcome measurement was mean daily prednisone-equivalent dose requirements, determined during the observation month preceding initiation of treatment and compared to the month preceding the seventh infusion. Secondary clinical endpoints measured were pulmonary function, frequency of emergency room visits or hospitalizations, and number of days absent from school or work. When adjusted for body weight, the mean dose requirements fell by 33, 39, and 33% in the placebo, IVIG (1 g/kg), and IVIG (2 g/kg) treatment arms, respectively. The differences between therapies were not statistically different (P = 0.9728). The mean percentage-of-predicted FEV1 fell in all three treatment groups during the treatment period but there was no significant difference between treatment groups (P = 0.8291). There was also no significant difference in the percentage of subjects requiring emergency room visits or hospitalizations or missing days of work/school, among the three treatment groups. The trial was terminated prematurely after interim analysis determined the adverse experience rate was different between the three groups. Three patients, all randomized to the 2-g/kg IVIG dose group, were hospitalized with symptoms consistent with aseptic meningitis. In summary, in this randomized, double-blind, placebo-controlled multicenter study, high doses of IVIG did not demonstrate a clinically or statistically significant advantage over placebo (albumin) infusions for the treatment of corticosteroid-dependent asthma. Subgroup analysis failed to identify markers predicting responsiveness. High-dose IVIG can also be associated with a significant incidence of serious adverse events.

Nineteen children with human immunodeficiency virus (HIV) infection were treated with recombinant human gamma interferon (rIFN-γ) (50 μg/m 2 subcutaneously three times each week during weeks 1 through 12 and 100 μg/m 2 subcutaneously three times each week during weeks 13 through 24) in a phase I/II clinical trial. All children continued to receive previously prescribed therapy with oral zidovudine or didanosine. Children were assessed clinically and with laboratory studies during 24 weeks of study treatment and for 12 weeks after completion of rIFN-γ therapy. In general, rIFN-γ therapy was well tolerated. There were two clinical or laboratory adverse events thought to be possibly or probably study drug associated. One child developed acute pancreatitis; another child developed granulocytopenia. Median CD4 + -lymphocyte counts and plasma HIV RNA concentrations did not change significantly during therapy. In vitro neutrophil bactericidal activity against Staphylococcus aureus and superoxide production were not significantly affected by rIFN-γ therapy. We conclude that rIFN-γ therapy in HIV-infected children receiving single-agent antiretroviral therapy is safe and does not produce consistent changes in CD4 + -lymphocyte count, plasma HIV RNA concentration, or in vitro neutrophil function.

Background The effect of pretransplantation conditioning on the long-term outcomes of patients receiving hematopoietic stem cell transplantation for severe combined immunodeficiency (SCID) has not been completely determined. Objective We sought to assess the outcomes of 23 mostly conditioned patients with SCID and compare their outcomes with those of 25 previously reported nonconditioned patients with SCID who underwent transplantation. Methods In the present study we reviewed the medical records of these 23 consecutive, mostly conditioned patients with SCID who underwent transplantation between 1998 and 2007. Results Eighteen patients (median age at transplantation, 10 months; range, 0.8-108 months) received haploidentical mismatched related donor, matched unrelated donor, or mismatched unrelated donor transplants, 17 of whom received pretransplantation conditioning (with 1 not conditioned); 13 (72%) patients engrafted with donor cells and survive at a median of 3.8 years (range, 1.8-9.8 year); 5 (38%) of 13 patients require intravenous immunoglobulin; and 6 of 6 age-eligible children attend school. Of 5 recipients (median age at transplantation, 7 months; range, 2-23 months) of matched related donor transplants, all 5 engrafted and survive at a median of 7.5 years (range, 1.5-9.5 year), 1 recipient requires intravenous immunoglobulin, and 3 of 3 age-eligible children attend school. Gene mutations were known in 16 cases: mutation in the common γ chain of the IL-2 receptor (IL2RG) in 7 patients, mutation in the α chain of the IL-7 receptor (IL7RA) in 4 patients, mutation in the recombinase-activating gene (RAG1) in 2 patients, adenosine deaminase deficiency (ADA) in 2 patients, and adenylate kinase 2 (AK2) in 1 patient. Early outcomes and quality of life of the previous nonconditioned versus the present conditioned cohorts were not statistically different, but longer-term follow-up is necessary for confirmation. Conclusions Hematopoietic stem cell transplantation in patients with SCID results in engraftment, long-term survival, and a good quality of life for the majority of patients with or without pretransplantation conditioning.

Background: Growth failure often precedes secondary infections in HIV-infected infants and children, suggesting that inadequate protein deposition may be an early manifestation of infection by the virus. However, the protein metabolic response elicited by the virus in young children is unknown. Objective: We compared children with HIV infection and agematched children without HIV infection with regard to wholebody and splanchnic protein kinetics and synthesis of acute phase proteins (APPs). Design: Whole-body and splanchnic leucine kinetics and fractional and absolute synthesis rates of 2 positive and 4 negative APPs were measured in 6 asymptomatic, HIV-infected children (4 males and 2 females) aged 6‐17 mo and 4 uninfected children (3 females and 1 male) aged 7‐9 mo who were in the fed state. Results: Compared with the control children, the HIV-infected children had significantly lower dietary energy and protein intakes and leucine balance and significantly faster leucine flux and fractional splanchnic leucine extraction; there was no significant difference between the groups in leucine oxidation rates. The HIVinfected children also had significantly higher plasma concentrations and absolute synthesis rates of the positive APPs and a significantly higher fractional synthesis rate of fibrinogen. The concentrations of 2 of the 4 negative APPs, albumin and HDL apolipoprotein A-I, were significantly lower in the HIV-infected children but were not associated with slower synthesis rates. Conclusions: Children with HIV infection but without secondary infection have reduced protein balance because of an inability to down-regulate protein catabolism. Furthermore, the acute phase protein response elicited by HIV infection is characterized by higher concentrations and synthesis rates of positive APPs without lower concentrations of some negative APPs. Am J Clin Nutr 2003;78:182‐9.

Background: Available information suggests that IgE levels are elevated in adults infected with human immunodeficiency virus (HIV), and that increased IgE levels correlate with allergic disease, with decreased CD4 counts, and with a poor prognosis. Data with respect to these factors in children are scant. Objective: We investigated whether serum IgE levels are elevated in children with HIV and, if so, whether the serum IgE level correlates with the degree of immunodeficiency and/or objective indicators of allergic disease. Methods: Serum IgE levels, CD4 counts, absolute eosinophil counts, and immediate hypersensitivity skin test (IHST) results were collected from 43 children with symptomatic HIV infection (mean age 7.2 years). Associations between serum IgE levels, CD4 counts, and eosinophil counts were investigated by multiple stepwise linear regression analysis. Data were stratified according to IHST positivity, and analysis of variance was used to compare mean values for age, CD4 counts, IgE levels, and eosinophil counts between the two groups. Results: Serum IgE values were elevated more than 2 SDs above control age-matched mean values in 17 of 43 patients (40%). IHST results were positive in 12 of 43 patients (28%). CD4 counts were less than 200/mm 3 in 17 of 43 patients (40%). Stepwise linear regression failed to demonstrate any correlation between serum IgE levels and either CD4 or eosinophil counts. With data divided into two groups according to IHST results (positive vs negative), analysis of variance failed to reveal significant differences between means for patient age, CD4 counts, IgE levels, or eosinophil counts. Conclusions: Our findings confirm that serum IgE levels are increased in children infected with HIV, just as in adults. However, an elevated serum IgE level did not correlate with allergic disease as measured by IHST results and eosinophil counts, nor with the degree of immune dysfunction as approximated by CD4 counts. The mechanism and significance of elevated serum IgE levels remain unclear in children with HIV, and warrant further investigation. (J Allergy Clin Immunol 1997;100:707-11.)

S de Kivit, E Saeland, AD Kraneveld. Allergy. 2012;67(3):343–352 To investigate whether galectin-9 has a role in the mechanism of suppression of allergic skin reactions and mast cell degranulation induced by dietary synbiotics. Three-week-old specific pathogen-free C3H/HeOuJ mice were studied in a cow’s milk allergy model with or without a probiotic or prebiotic. Ninety human infants with atopic dermatitis were studied in a double-blind, placebo-controlled multicenter trial in which they received a hydrolyzed formula with or without synbiotics. Mice were sensitized orally to whey …

MT Salam, TM Bastain, EB Rappaport. Allergy. 2011;66(3):412–419 Elevated fractional exhaled nitric oxide (FeNO) has been shown to be a sensitive biomarker for airway inflammation in children with asthma. This study examined whether a relationship could be demonstrated between genetic variants in nitric-oxide synthase and arginase genes and FeNO in asthma. Subjects aged 5 to 7 years were recruited from 13 Southern California communities for a Children's …

A patient wit angioimmunoblastic lymphadenopathy had low serum immunoglobulin values and no antibodies to injected immunogens. This occurred despite the proliferation of polyclonal B cells. T cells were deficient in number and in lymphoproliferative responses, but their helper and suppressor functions were maintained. Ia-antigen bearing leukocytes from the patient stimulated poorly in mixed leukocyte culture. In vitro immunoglobulin synthesis by mononuclear leukocytes form the patient was severely impaired. These leukocytes actively suppressed immunoglobulin synthesis by normal cells from healthy subjects in co-culture. The responsible cell had characteristics of a monocyte. The suppression was selective for humoral immunity and was manifest despite normal numbers of monocytes. It appears that heterogeneous immunoregulatory abnormalities can underlie the syndrome of angioimmunoblastic lymphadenopathy. Furthermore, monocyte suppressor abnormalities may be implicated in clinical disease phenomena.

We have investigated the cellular and antigenic requirements for incubation of secondary proliferative responses by human T lymphocytes. Two distinct properties of antigen-presenting peripheral blood mononuclear cells were studied: (a) the ability for appropriate cell surface constituents to construct an immunogenic moiety, and (b) the ability to present similar antigenic determinants when they are not covalently bound. Only Ia+ hapten-modified cells were effective stimulators. In contrast, both Ia+ and Ia- cell sonicates could stimulate secondary proliferative responses, but only in the presence of an accessory cell. This accessory cell was present in Ia+ macrophage, but not in Ia+ non-T lymphocyte, preparations. In contrast, macrophages or soluble factors produced by macrophages were not required for primed T cells to undergo hapten-specific proliferation in response to hapten-modified Ia+ stimulator cells. Thus, although all Ia+ cells tested can stimulate primed cells to proliferate, not all Ia+ cells can function as accessory cells for responses to sonicates. This may reflect the unique ability of a subpopulation(s) of Ia+ cells to bind or process sonicates or soluble antigens for appropriate recognition by primed T cells.

To investigate mechanisms by which antigen, macrophages, and interleukin 2 (IL2) participate in the induction of secondary T-cell proliferative responses, trinitrophenyl (TNP) was presented in three distinct modes: (i) TNP-modified peripheral blood mononuclear cells (TNP-PBMC), (ii) TNP-PBMC cell sonicates, and (iii) TNP-ovalbumin (TNP-OVA). Stimulators were depleted of Mac-120+ macrophages using Mac-120 monoclonal antibody plus complement. TNP-Mac-120 macrophages stimulated primed T cells nearly as well as TNP-unfractionated macrophages (which were about 40% Mac-120+). In contrast, although greater than 70% DR+, Mac-120- macrophages plus either TNP-OVA or TNP-PBMC sonicate elicited minimal responses compared to unfractionated macrophages plus antigen. After 21-28 days of in vitro priming, macrophage-depleted T cells were not stimulated to proliferate by either IL2 alone or sonicates alone. IL2 plus TNP-PBMC sonicates, however, stimulated significant proliferation. Furthermore, this response was considerably greater than that to IL2 plus either TNP-T cell sonicates or TNP-mouse spleen sonicates. Thus, the Mac-120+ macrophage population may have an important antigen-presenting and/or accessory function in the stimulation of primed T cells by soluble or particulate antigen, although it is unnecessary for responses to intact TNP-Ia+ PBMC. In addition, the data suggest that Ia+ sonicates alone may suffice for induction of IL2 responsiveness, but not for endogenous IL2 production and subsequent proliferation by primed T cells.

Clearer definition of the recognitive structures of human T lymphocytes for antigens will be required to elucidate the molecular basis of diseases and immunological responses induced or regulated by normal or abnormal T-cell function. For this purpose we have investigated the cellular requirements for immune responses in vitro to trinitrophenyl-conjugated peripheral blood mononuclear cells. The responding cell was characterized as a T cell on the basis of rosetting with sheep erythrocytes. T-cell recognition of hapten in proliferative responses depended upon presentation of antigen in an appropriate stimulator-cell context. Neither autologous hapten-modified erythrocytes nor T cells restimulated responses of in vitro-primed lymphocytes. Moreover, hapten-conjugated non-T cells were more effective than modified unfractionated cells in restimulating proliferative responses. Both macrophages and non-T lymphocytes effectively restimulated hapten-conjugate responses. Cell-mixing experiments indicated that the failure of haptenated T cells to stimulate proliferative responses was not because of a lack of fresh macrophages; these experiments suggested instead that T cells do not express appropriate structures necessary to present haptenic determinants in an immunogenic form. Hapten-modified T cells, however, were capable of inducing primed lymphocytes to become efficient cytotoxic effector cells, indicating that T-cell recognitive units for stimulation of proliferative and cytotoxic responses are different. These data support the concept that for induction of proliferative responses, human T cells recognize conventional antigens in association with HLA-D-region-encoded Ia-like molecules.