Pamela A. Frischmeyer-Guerrerio

Loeys-Dietz syndrome: a primer for diagnosis and management.

Loeys–Dietz syndrome is a connective tissue disorder predisposing individuals to aortic and arterial aneurysms. Presenting with a wide spectrum of multisystem involvement, medical management for some individuals is complex. This review of literature and expert opinion aims to provide medical guidelines for care of individuals with Loeys–Dietz syndrome.Genet Med 16 8, 576–587.Genetics in Medicine (2014); 16 8, 576–587. doi:10.1038/gim.2014.11

TGFβ Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease

Patients with mutations in the receptors for TGFβ (Loeys-Dietz syndrome) exhibit an increased prevalence of allergic diseases. Allergy Unveiled Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder closely related to Marfan syndrome caused by mutations in the genes encoding receptor subunits for transforming growth factor–β (TGFβ). Patients with LDS are predisposed to aortic aneurisms and other connective tissue disorders. Now, Frischmeyer-Guerrerio et al. report that patients with LDS are more likely to develop allergic diseases. Allergy occurs when the immune system responds to normally harmless substances. The authors observed that LDS patients had elevated incidence of allergic diseases, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. These patients had elevated levels of immune responses thought to contribute to allergy, including allergen-specific IgE, eosinophilia, and TH2 cytokines. Because regulatory T cell (Treg) development is regulated by TGFβ, the authors then examined Treg number and function in these patients. They found that the frequency of Tregs was increased in LDS patients, but that these cells produced TH2 effector cytokines, and in vitro studies suggested that LDS mutations promote TH2 inflammation. What’s more, children with allergic disease, but not LDS, had similar changes in Treg number and function. These data suggest that altered TGFβ signaling could promote allergic disease and support testing for U.S. Food and Drug Administration–approved drugs that affect TGFβ for treating allergy. Transforming growth factor–β (TGFβ) is a multifunctional cytokine that plays diverse roles in physiologic processes as well as human disease, including cancer, heart disease, and fibrotic disorders. In the immune system, TGFβ regulates regulatory T cell (Treg) maturation and immune homeostasis. Although genetic manipulation of the TGFβ pathway modulates immune tolerance in mouse models, the contribution of this pathway to human allergic phenotypes is not well understood. We demonstrate that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding receptor subunits for TGFβ, TGFBR1 and TGFBR2, are strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. LDS patients exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in their plasma. They had an increased frequency of CD4+ T cells that expressed both Foxp3 and interleukin-13, but retained the ability to suppress effector T cell proliferation. TH2 cytokine–producing cells accumulated in cultures of naïve CD4+ T cells from LDS subjects, but not controls, after stimulation with TGFβ, suggesting that LDS mutations support TH2 skewing in naïve lymphocytes in a cell-autonomous manner. The monogenic nature of LDS demonstrates that altered TGFβ signaling can predispose to allergic phenotypes in humans and underscores a prominent role for TGFβ in directing immune responses to antigens present in the environment and foods. This paradigm may be relevant to nonsyndromic presentations of allergic disease and highlights the potential therapeutic benefit of strategies that inhibit TGFβ signaling.

Suppression of the immunologic response to peanut during immunotherapy is often transient

BACKGROUND Studies suggest that oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) for food allergy hold promise; however, the immunologic mechanisms underlying these therapies are not well understood. OBJECTIVE We sought to generate insights into the mechanisms and duration of suppression of immune responses to peanut during immunotherapy. METHODS Blood was obtained from subjects at baseline and at multiple time points during a placebo-controlled trial of peanut OIT and SLIT. Immunologic outcomes included measurement of spontaneous and stimulated basophil activity by using automated fluorometry (histamine) and flow cytometry (activation markers and IL-4), measurement of allergen-induced cytokine expression in dendritic cell (DC)-T-cell cocultures by using multiplexing technology, and measurement of MHC II and costimulatory molecule expression on DCs by using flow cytometry. RESULTS Spontaneous and allergen-induced basophil reactivity (histamine release, CD63 expression, and IL-4 production) were suppressed during dose escalation and after 6 months of maintenance dosing. Peanut- and dust mite-induced expression of TH2 cytokines was reduced in DC-T-cell cocultures during immunotherapy. This was associated with decreased levels of CD40, HLA-DR, and CD86 expression on DCs and increased expression of CD80. These effects were most striking in myeloid DC-T-cell cocultures from subjects receiving OIT. Many markers of immunologic suppression reversed after withdrawal from immunotherapy and in some cases during ongoing maintenance therapy. CONCLUSION OIT and SLIT for peanut allergy induce rapid suppression of basophil effector functions, DC activation, and TH2 cytokine responses during the initial phases of immunotherapy in an antigen-nonspecific manner. Although there was some interindividual variation, in many patients suppression appeared to be temporary.

Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice

The random nature of T-cell receptor-β (TCR-β) recombination needed to generate immunological diversity dictates that two-thirds of alleles will be out-of-frame. Transcripts derived from nonproductive rearrangements are cleared by the nonsense-mediated mRNA decay (NMD) pathway, the process by which cells selectively degrade transcripts harboring premature termination codons. Here, we demonstrate that the fetal thymus in transgenic mice that ubiquitously express a dominant-negative form of Rent1/hUpf1, an essential trans-effector of NMD, shows decreased cell number, reduced CD4CD8 double-positive thymocytes, diminished expression of TCR-β, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous Vβ-to-DβJβ rearrangements, whereas Dβ-to-Jβ rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-β rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-β transgene that precludes generation of out-of-frame transcripts, suggesting direct mRNA-mediated trans-dominant effects. These data document that NMD has been functionally incorporated into developmental programs during eukaryotic evolution.

Inhibition of Nonsense-Mediated RNA Decay Activates Autophagy

ABSTRACT Nonsense-mediated RNA decay (NMD) is an mRNA surveillance mechanism which rapidly degrades select cytoplasmic mRNAs. We and others have shown that NMD is a dynamically regulated process inhibited by amino acid deprivation, hypoxia, and other cellular stresses commonly generated by the tumor microenvironment. This inhibition of NMD can result in the accumulation of misfolded, mutated, and aggregated proteins, but how cells adapt to these aberrant proteins is unknown. Here we demonstrate that the inhibition of NMD activates autophagy, an established protein surveillance mechanism, both in vitro and in vivo. Conversely, the hyperactivation of NMD blunts the induction of autophagy in response to a variety of cellular stresses. The regulation of autophagy by NMD is due, in part, to stabilization of the documented NMD target ATF4. NMD inhibition increases intracellular amino acids, a hallmark of autophagy, and the concomitant inhibition of autophagy and NMD, either molecularly or pharmacologically, leads to synergistic cell death. Together these studies indicate that autophagy is an adaptive response to NMD inhibition and uncover a novel relationship between an mRNA surveillance system and a protein surveillance system, with important implications for the treatment of cancer.

Recognizing gastrointestinal and hepatic manifestations of primary immunodeficiency diseases

Given the complex immune function of the gastrointestinal (GI) tract, it is not surprising that many children with primary immunodeficiencies present with GI tract manifestations. Although many immunodeficiency disorders present with overt evidence of immune dysregulation, a few can present in older children with more subtle signs and symptoms. Such children may present first to a gastroenterologist with common symptoms, including malabsorption, diarrhea, hepatomegaly, or inflammatory bowel disease, which may actually be a manifestation of their underlying immune disorder. A thorough clinical history in combination with a careful review of histology from biopsies may reveal clues that one is dealing with a disease entity outside the norm and may prompt additional laboratory studies beyond the usual set of screening laboratory tests. Once the true underlying diagnosis is revealed, more appropriate therapy can be initiated. Additionally, more appropriate anticipatory guidance regarding the expected disease course, response to medications, and any additional risks that therapy may entail can be provided to the family.

Modulation of dendritic cell innate and adaptive immune functions by oral and sublingual immunotherapy.

Sublingual (SLIT) and oral immunotherapy (OIT) are promising treatments for food allergy, but underlying mechanisms are poorly understood. Dendritic cells (DCs) induce and maintain Th2-type allergen-specific T cells, and also regulate innate immunity through their expression of Toll-like receptors (TLRs). We examined how SLIT and OIT influenced DC innate and adaptive immune responses in children with IgE-mediated cows milk (CM) allergy. SLIT, but not OIT, decreased TLR-induced IL-6 secretion by myeloid DCs (mDCs). SLIT and OIT altered mDC IL-10 secretion, a potent inhibitor of FcεRI-dependent pro-inflammatory responses. OIT uniquely augmented IFN-α and decreased IL-6 secretion by plasmacytoid DCs (pDCs), which was associated with reduced TLR-induced IL-13 release in pDC-T cell co-cultures. Both SLIT and OIT decreased Th2 cytokine secretion to CM in pDC-T, but not mDC-T, co-cultures. Therefore, SLIT and OIT exert unique effects on DC-driven innate and adaptive immune responses, which may inhibit allergic inflammation and promote tolerance.

Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut

Background Peanut allergy (PA) is potentially life‐threatening and generally persists for life. Recent data suggest the skin might be an important route of initial sensitization to peanut, whereas early oral exposure to peanut is protective. In mice regulatory T (Treg) cells are central to the development of food tolerance, but their contribution to the pathogenesis of food allergy in human subjects is less clear. Objective We sought to quantify and phenotype CD4+ peanut‐specific effector T (ps‐Teff) cells and peanut‐specific regulatory T (ps‐Treg) cells in children with and without PA or PS. Methods ps‐Teff and ps‐Treg cells were identified from peripheral blood of children with PA, children with PS, and nonsensitized/nonallergic (NA) school‐aged children and 1‐year‐old infants based on upregulation of CD154 or CD137, respectively, after stimulation with peanut extract. Expression of cytokines and homing receptors was evaluated by using flow cytometry. Methylation at the forkhead box protein 3 (FOXP3) locus was measured as a marker of Treg cell stability. Results Differential upregulation of CD154 and CD137 efficiently distinguished ps‐Teff and ps‐Treg cells. A greater percentage of ps‐Teff cells from infants with PA and infants with PS expressed the skin‐homing molecule cutaneous lymphocyte antigen, suggesting activation after exposure through the skin, compared with NA infants. Although ps‐Teff cells in both school‐aged and infant children with PA produced primarily TH2 cytokines, a TH1‐skewed antipeanut response was seen only in NA school‐aged children. The frequency, homing receptor expression, and stability of ps‐Treg cells in infants and school‐aged children were similar, regardless of allergic status. Conclusions Exposure to peanut through the skin can prime the development of TH2 ps‐Teff cells, which promote sensitization to peanut, despite the presence of normal numbers of ps‐Treg cells. Graphical abstract Figure. No Caption available.

Impact of Food Allergy on the Growth of Children with Moderate-Severe Atopic Dermatitis

Summary Children with moderate-severe atopic dermatitis and food allergy (especially milk) exhibit reduced weight and height, while those with atopic dermatitis alone are often overweight or obese, and their body mass index correlates with eczema severity.