L Chini

The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever

BACKGROUND Sensitization to profilins and other cross-reacting molecules might hinder proper specific immunotherapy (SIT) prescription in polysensitized patients with pollen-related allergic rhinitis (AR). In these patients, component-resolved diagnosis (CRD) might modify SIT prescription by improving the identification of the disease-eliciting pollen sources. OBJECTIVES We sought to measure the effect of CRD on SIT prescription in children with pollen-related AR. METHODS Children (n = 651) with moderate-to-severe pollen-related AR were recruited between May 2009 and June 2011 in 16 Italian outpatient clinics. Skin prick test (SPT) reactivity to grass, cypress, olive, mugwort, pellitory, and/or Betulaceae pollen was considered clinically relevant if symptoms occurred during the corresponding peak pollen season. IgE sensitization to Phl p 1, Phl p 5, Bet v 1, Cup a 1, Art v 1, Ole e 1, Par j 2, and Phl p 12 (profilin) was measured by using ImmunoCAP. SIT prescription was modeled on SPT responses first and then remodeled considering also CRD according to GA(2)LEN-European Academy of Allergology and Clinical Immunology guidelines and the opinions of 14 pediatric allergists. RESULTS No IgE to the respective major allergens was detected in significant proportions of patients with supposed clinically relevant sensitization to mugwort (45/65 [69%]), Betulaceae (146/252 [60%]), pellitory (78/257 [30%]), olive (111/390 [28%]), cypress (28/184 [15%]), and grass (56/568 [10%]). IgE to profilins, polcalcins, or both could justify 173 (37%) of 464 of these SPT reactions. After CRD, the SPT-based decision on SIT prescription or composition was changed in 277 (42%) of 651 or 315 (48%) of 651 children according to the European or American approach, respectively, and in 305 (47%) of 651 children according to the opinion of the 14 local pediatric allergists. CONCLUSIONS In children with pollen-related AR, applying CRD leads to changes in a large proportion of SIT prescriptions as opposed to relying on clinical history and SPT alone. The hypothesis that CRD-guided prescription improves SIT efficacy deserves to be tested.

Analysis of polyunsaturated fatty acids in newborn sera: a screening tool for atopic disease?

It has been demonstrated that patients with atopic disease have anomalies of fatty acid composition, as a result of altered metabolism or abnormal incorporation of fatty acids into the tissues. In the present study, in 57 newborns‘at risk’for atopic disease, the polyunsaturated fatty acid (PUFA) levels were found to be lower in cord blood in infants who subsequently developed atopic disease than in nonatopics. In all babies, levels of arachidonic acid and dihomo‐gamma‐linolenic acid in sera at 1 and 3 months of age were lower than those in cord blood. These changes were more marked in children who subsequently developed atopic disease, and in those who, independently of signs and/or symptoms of atopic disease, were formula‐fed.

A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: results from the Italian Primary Immunodeficiency Network.

Transient hypogammaglobulinemia of infancy (THI) is a heterogenous disorder characterized by reduced serum IgG levels in early infancy. A putative diagnosis is initially made after exclusion of other causes of hypogammaglobulinemia while a definitive diagnosis of THI can only be made a posteriori in patients with normalization of IgG levels. The aim of this study is to characterize clinical and immunological features of children with an initial diagnosis of THI in correlation to natural outcome, and to assess predictive laboratory parameters of clinical evolution for this disorder. We prospectively analysed clinical and immunological characteristics of 77 THI children at initial diagnosis and of 57 patients at follow-up. Memory B cell subsets and in vitro immunoglobulin production were evaluated. Seventy patients (91%) showed clinical symptoms. Patients suffered from infections (91%), allergies (47%) and autoimmune disease (4%). During follow-up 41/57 children (72%) normalized IgG values, mostly within 24 months of age (p<0.001), allowing the diagnosis of THI. The 16 children who did not normalize their IgG levels showed a higher frequency of severe infections and autoimmune disease (p<0.01). Moreover, they expressed a reduced frequency of IgM and switched memory B cells (p<0.01) and an inability to produce IgG in vitro (p<0.02). We conclude that most patients with an initial diagnosis of THI spontaneously recover within 24 months of age and have a benign clinical course, while a subgroup of children with undefined hypogammaglobulinemia share a clinical and immunological profile with other primary immunodeficiencies. Early recognition of children with hypogammaglobulinemia during infancy who are likely to suffer from permanent immunodeficiencies later in life would allow prompt and appropriate laboratory and clinical interventions.

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites.

BACKGROUND Dendritic cells (DCs) regulate the immune response to allergens in the lung; they induce either effector or regulatory T cells, which promote or suppress, respectively, the development of allergy. IL-10 is a potent immunosuppressive cytokine that induces type 1 regulatory (Tr1) T cells. OBJECTIVE To generate allergen-specific Tr1 cells in vitro from children with allergy. METHODS Monocyte-derived DCs from children with allergy to house dust mites (HDM) were generated by incubating the cells with IL-10 and pulsing them with Der p 2, a major HDM allergen, or by pulsing them with Der p 2 and incubating them with IL-10 during their last 2 days of differentiation. RESULTS Der p 2-specific T-cell proliferation and T(H)2 cytokine production were significantly reduced when T cells from patients with allergy to HDM were activated with autologous Der p 2-pulsed DCs that had been differentiated or incubated with IL-10. T-cell lines generated with Der p 2-pulsed DCs that were differentiated with IL-10 were hyporesponsive to reactivation with Der p 2 and able to suppress Der p 2-specific T(H)2 effector cells. CONCLUSION Dendritic cells differentiated in the presence of IL-10 and pulsed with allergen gave rise to a population of tolerogenic DCs that induced allergen-specific Tr1 cells. This finding represents an important step forward to the prospective clinical application of tolerogenic DCs to modulate allergen-specific T-cell responses.

Pollen-induced allergic rhinitis in 1360 Italian children: comorbidities and determinants of severity.

Pollen‐induced allergic rhinoconjunctivitis (AR) is highly prevalent and rapidly evolving during childhood. General practitioners may not be fully aware of the nature and severity of symptoms experienced by patients and might underestimate the prevalence of moderate or severe disease. Thus, the relevance of early diagnosis and intervention may be overlooked.

Co-Localization of Susceptibility Loci for Psoriasis (PSORS4) and Atopic Dermatitis (ATOD2) on Human Chromosome 1q21

Psoriasis (PS) is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and altered differentiation. Atopic dermatitis (ATOD) is a chronic inflammatory, pruritic and eczematous disease frequently associated with respiratory atopy. These diseases are associated with distinct immunologic abnormalities and represent typical examples of complex diseases triggered by both genetic and environmental factors, as demonstrated by independent twin studies. Genome wide linkage studies have mapped susceptibility loci on several chromosomes (PSORS1–9; ATOD1–5). Four of them overlap on chromosomes 1q21, 3q21, 17q25 and 20p although ATOD is quite distinct from PS and these two diseases rarely occur together in the same patient. An association fine-mapping study has been performed to refine PSORS4 and ATOD2 susceptibility loci on chromosome 1q21 analyzing two independently collected cohorts of 128 PS and 120 ATOD trios. Genotype and haplotype analysis of PSORS4 and ATOD2 led us to detect significant p value for haplotypes defined by MIDDLE and ENDAL16 markers in both PS (p = 0.0000036) and ATOD (p = 0.0276), suggesting a strict co-localization within an interval of 42 kb. This genomic interval contains a single gene, LOR, encoding for loricrin. Polymorphic markers mapping in regulatory and coding regions did not show evidence of association in neither of the two diseases. However, expression profiles of LOR in skin biopsies have shown reduced levels in PS and increased levels in ATOD, suggesting the existence of a specific misregulation in LOR mRNA production.

Full Sequencing of the FLG Gene in Italian Patients with Atopic Eczema: Evidence of New Mutations, but Lack of an Association

TO THE EDITOR Atopic eczema (AE) (OMIM %603165) is the most common chronic inflammatory skin disease, characterized by xerosis, pruritus, and erythematous lesions with increased transepidermal water loss. In recent years, it has been suggested that the epidermal skin barrier has a significant role in AE disease susceptibility and severity (Smith et al., 2006; Cork et al., 2009). Sandilands et al. (2006) demonstrated that null mutations within the filaggrin gene (FLG) strongly predispose individuals to AE. Two FLG null alleles (R501X and 2282del4) have been shown to be significantly associated with AE in several European populations (Palmer et al., 2006; Weidinger et al., 2007). Recently, a meta-analysis of the most common FLG variants in European populations, involving 5,791 eczema cases and 26,454 controls (Rodriguez et al., 2009), revealed that there is a high risk conferred by R501X and 2282del4 across the studies, with an overall odds ratio of 3.14 and 2.78, respectively. Indeed, large differences in carrier frequencies exist across Europe, ranging from 1.4% in an Italian population (Giardina et al., 2008) to 63% in an Irish population (Palmer et al., 2006). Recently, we observed that in Italian patients the frequencies of R501X and 2282del4 are strongly reduced with respect to those described in other patients of European origin, and the frequencies are similar between cases and controls (0.6 vs. 0.0% and 0.9 vs. 0.5%, respectively). In order to determine whether other mutations located elsewhere in FLG confer risk to AE, we performed a full sequencing of FLG in Italian patients. We performed a sequencing of the full FLG gene in a cohort of 220 Italian AE patients (recruited by IDI-Istituto Dermopatico dell’Immacolata and Fatebenefratelli Hospital). We then determined the frequency of variations and mutations in a cohort of 201 healthy subjects. The diagnosis of AE in our case cohort was made by experienced dermatologists or by a pediatric allergologist. The cohort consisted of 85% of cases with the intrinsic subtype and 15% with the extrinsic form of AE. These subtypes and severity of AE have been established based on the total IgE level (extrinsic subtype 4500 ng l ) and using the scoring atopic dermatitis. Further clinical details of Italian patients are available in Abbreviations: AE, atopic eczema; FLG, filaggrin gene; LD, linkage disequilibrium

Methylprednisolone bolus: a novel therapy for severe atopic dermatitis

Seven children suffering from severe atopic dermatitis, unresponsive to standard therapy, received an iv bolus dose of methylprednisolone (20 mg/kg/day) for three days. Immunological parameters were evaluated before and after treatment. At the end of bolus therapy both skin lesions and itching improved for several months in five of seven patients. No side effects were observed, but a significant and transient lymphopenic response occurred, with lower CD4 + than CD8 + lymphocyte counts. Our data suggest that this therapy may be a novel and safe therapeutic approach in severe atopic dermatitis.

Trans fatty acids and atopic eczema/dermatitis syndrome : The relationship with a free radical cis-trans isomerization of membrane lipids

The formation of trans FA residues in membrane phospholipids may be due to a free radical-catalyzed isomerization process occurring to the cis unsaturated FA moieties. Radical stress is well documented in inflammatory processes of atopic diseases, but no data are yet available about a possible association with trans FA detected in these patients. We investigated the presence of trans lipid isomers in the erythrocyte and T-lymphocyte membranes of 26 children affected by atopic eczema/dermatitis syndrome (AEDS). Trans lipid isomers were found in both cell membranes, up to a total content of 2.7 and 4.9% of the FA composition, respectively. By using the geometrical trans lipid library derived from in vitro models of thiyl radical-catalyzed isomerization, oleic and arachidonic acid isomers were detected. The statistical significance was evaluated by comparison with an age-matched control group. These results suggest the role of an endogenous free radical isomerization path occurring to membrane unsaturated lipids, complementary to the dietary contribution, which can be involved in the lipid impairment in AEDS. This study contributes to lipidomic research regarding the double bond structure and the influence of a geometrical change of membrane lipids in physiology and diseases.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

Pollen‐food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens.