Anthony L. 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.

Choline intake in a large cohort of patients with nonalcoholic fatty liver disease

BACKGROUND There is significant histologic and biochemical overlap between nonalcoholic fatty liver disease (NAFLD) and steatohepatitis associated with choline deficiency. OBJECTIVE We sought to determine whether subjects with biopsy-proven NAFLD and evidence of an inadequate intake of choline had more severe histologic features. DESIGN We performed a cross-sectional analysis of 664 subjects enrolled in the multicenter, prospective Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with baseline data on diet composition (from a recall-based food-frequency questionnaire) within 6 mo of a liver biopsy. Food questionnaires were analyzed with proprietary software to estimate daily intakes of choline. Liver biopsies were centrally read, and consensus was scored with the NASH CRN-developed scoring system. Because choline needs vary by age, sex, and menopausal status, participants were segregated into corresponding categories (children 9-13 y old, males ≥14 y old, premenopausal women ≥19 y old, and postmenopausal women) on the basis of the Institute of Medicines definition of adequate intake (AI) for choline. Deficient intake was defined as <50% AI. RESULTS Postmenopausal women with deficient choline intake had worse fibrosis (P = 0.002) once factors associated with NAFLD (age, race-ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use) were considered in multiple ordinal logistic regression models. Choline intake was not identified as a contributor to disease severity in children, men, or premenopausal women. CONCLUSION Decreased choline intake is significantly associated with increased fibrosis in postmenopausal women with NAFLD. The Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis trial was registered at clinicaltrials.gov as NCT00063622, and the Treatment of Nonalcoholic Fatty Liver Disease in Children trial was registered at clinicaltrials.gov as NCT00063635.

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.

Dendritic Cell and T cell Responses in Children with Food Allergy

Background Food allergy (FA) and eosinophilic oesophagitis (EE) are increasingly common clinical problems. Dendritic cells (DCs) are key regulators of the sensitization and effector phases of allergic immune responses, but their role in these diseases is largely unknown.

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.

Oral choline supplementation in children with intestinal failure.

Choline deficiency leads to steatohepatitis, elevated transaminases, susceptibility to septic shock, and an increased risk of central catheter thrombosis. Children with intestinal failure (IF) are at risk for choline deficiency. In an unblinded, open-label study, we studied 7 children with IF on parenteral nutrition, measured their plasma free choline level, and, if low, supplemented enterally with adequate intake (AI) doses of choline. Four to 6 weeks later we remeasured their plasma free choline. Unlike adults, infants did not respond to oral choline supplementation at AI doses. Additionally, we have calculated plasma free choline percentiles versus age for normal children.

Diagnosis of congenital and acquired focal lesions in the neck, abdomen, and pelvis with contrast-enhanced ultrasound: a pictorial essay

Contrast-enhanced ultrasound (CEUS) is a versatile imaging modality that improves the diagnostic potential of conventional ultrasound. It allows for portable imaging at the bedside. In this paper, we illustrate how CEUS can be used in evaluating several focal lesions in the pediatric population, including liver hemangioma, telangiectasias, splenic hamartomas, and bladder lesions. We describe the ultrasound findings and contrast enhancement patterns associated with these lesions. Findings are correlated with MRI, CT, and/or pathology when available. This paper demonstrates the value of CEUS in improving characterization of many focal lesions in the pediatric population.Conclusion: CEUS is a valuable bedside technique for use in the pediatric population to evaluate focal lesions in various organs, and will allow for safe, more efficient diagnostic imaging.What is Known:• CEUS offers many advantages over CT and MRI and is underutilized in the United States.• It is only FDA approved for vesicoureteral reflux and liver in the pediatric population. However, off label uses are well described.What is New:• This pictorial essay describes ultrasound findings and contrast enhancement patterns associated with liver hemangioma, liver telangiectasia, splenic hamartoma, hemorrhagic ovarian cyst, urachal remnant, spinning top urethras, and kaposiform hemangioendothelioma.• We demonstrate the utility of CEUS in expanding the diagnostic potential of conventional ultrasound.