Immune tolerance breakdown in inborn errors of immunity: Paving the way to novel therapeutic approaches.

Up to 25% of the patients with inborn errors of immunity (IEI) also exhibit immunodysregulatory features. The association of immune dysregulation and immunodeficiency may be explained by different mechanisms. The understanding of mechanisms underlying immune dysregulation in IEI has paved the way for the development of targeted treatments. In this review article, we will summarize the mechanisms of immune tolerance breakdown and the targeted therapeutic approaches to immune dysregulation in IEI.

Vasculitis and vasculopathy associated with inborn errors of immunity: an overview.

Systemic autoinflammatory diseases (SAIDs) are disorders of innate immunity, which are characterized by unprovoked recurrent flares of systemic inflammation often characterized by fever associated with clinical manifestations mainly involving the musculoskeletal, mucocutaneous, gastrointestinal, and nervous systems. Several conditions also present with varied, sometimes prominent, involvement of the vascular system, with features of vasculitis characterized by variable target vessel involvement and organ damage. Here, we report a systematic review of vasculitis and vasculopathy associated with inborn errors of immunity.

Inherited defects in the complement system.

The complement system plays an essential role in both innate and adaptive immune responses. Any dysregulation in this system can disturb normal host defense and alter inflammatory response leading to both infections and autoimmune diseases. The complement system can be activated through three different pathways. Inherited complement deficiencies have been described for all complement components and their regulators. Despite being rare diseases, complement deficiencies are often severe, with a frequent onset during childhood. We provide an overview of clinical disorders related to these disorders and describe current diagnostic strategies required for their comprehensive characterization and management.

Primary atopic disorders and chronic skin disease.

Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper-IgE syndromes, Omenn syndrome, Wiskott-Aldrich syndrome, IPEX-linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.

Activated phosphoinositide 3-dinase delta syndrome (APDS): An update.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3-kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients' quality of life and prognosis.

Inborn errors of immunity with atopic phenotypes: A practical guide for allergists.

Inborn errors of immunity (IEI) are a heterogeneous group of disorders, mainly resulting from mutations in genes associated with immunoregulation and immune host defense. These disorders are characterized by different combinations of recurrent infections, autoimmunity, inflammatory manifestations, lymphoproliferation, and malignancy. Interestingly, it has been increasingly observed that common allergic symptoms also can represent the expression of an underlying immunodeficiency and/or immune dysregulation. Very high IgE levels, peripheral or organ-specific hypereosinophilia, usually combined with a variety of atopic symptoms, may sometimes be the epiphenomenon of a monogenic disease. Therefore, allergists should be aware that severe and/or therapy-resistant atopic disorders might be the main clinical phenotype of some IEI. This could pave the way to target therapies, leading to better quality of life and improved survival in affected patients.

Immunological basis of virus-host interaction in COVID-19.

COVID-19 is a complex new viral disease, in which a strict balance between anti-viral immune response and the ensuing organ inflammation has a critical role in determining the clinical course. In adults, compelling evidence exists indicating that an uncontrolled inflammatory response ("cytokine storm") is pivotal in determining disease progression and mortality. Children may rarely present with severe disease. Modulating factors related to the host's genetic factors, age-related susceptibility, and the capability to mount appropriate immune responses might play a role in control virus load at an early stage and regulating the inflammatory reaction. Elucidating these mechanisms seems crucial in developing target therapies according to patient's age, immunologic status, and disease evolution in COVID-19.

The possible implication of the S250C variant of the autoimmune regulator protein in a patient with autoimmunity and immunodeficiency: in silico analysis suggests a molecular pathogenic mechanism for the variant.

Autoimmunity can develop from an often undetermined interplay of genetic and environmental factors. Rare forms of autoimmune conditions may also result from single gene mutations as for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, an autosomal recessive disease associated with mutated forms of the autoimmune regulator gene. It was proposed that genetic variability in the autoimmune regulator locus, in particular heterozygous loss-of-function mutations, might favor the development of organ-specific autoimmunity by affecting the presentation of self-antigens in the thymus. Indeed, heterozygous mutations of the autoimmune regulator gene were reported in patients with organ-specific autoimmunity. Also, in primary immunodeficiencies, a breakdown in central/peripheral tolerance frequently produces association with autoimmunity. The causative link may involve a common genetic background and several gene defects have been identified as putative culprits. We report a unique patient, a 14 year old male from Lazio region, affected by common variable immunodeficiency associated with autoimmune manifestations (alopecia, onychodystrophy) and heterozygote for the S250C variant located in the SAND domain of the autoimmune regulator gene protein. To our knowledge this is the first report of the S250C variant in a patient bearing this unusual combination of autoimmunity and immunodeficiency. To obtain insights into the possible molecular effects of the S250C variant, we have carried out an in silico analysis of the SAND domain structure of the autoimmune regulator protein. In particular, homology modeling has allowed us to observe that the cysteine introduced by the S250C variant is surrounded by cationic residues, and by means of molecular dynamics simulations together with pKa calculations, we have shown that these residues remain stably proximal to cysteine-250 lowering its pKa and thus conferring high chemical reactivity to the mutated residue. We propose that the enhanced reactivity of cysteine-250, which is likely to impair the protein function but probably insufficient to produce alone a phenotype as a heterozygous S250C variant due to compensation mechanisms, might become manifest when combined with other genetic/environmental factors. These results can provide the rationale for the patient's unusual phenotype, shedding new light into the pathogenesis of the clinical association of autoimmunity and immunodeficiency.

Correlation of Der p 2 T-cell responses with clinical characteristics of children allergic to house dust mite.

BACKGROUND: An understanding of the mechanisms responsible for the development and maintenance of allergic inflammation and their clinical implications is needed to develop specific and successful treatment for allergy. OBJECTIVES: To characterize in vitro T-cell responses to Der p 2, one of the major allergens of house dust mite (HDM), and investigate potential correlations between clinical and laboratory parameters. METHODS: Forty-two patients monosensitized to HDM and 10 age-matched, healthy children were studied. Dendritic cells pulsed with Der p 2 were used to stimulate autologous CD14(-) cells. Der p 2-specific T-cell activation markers, proliferation, and cytokine production profiles were examined. RESULTS: Der p 2-specific T-cell activation markers, proliferation, and T(H)2 cytokine production were significantly higher in HDM patients compared with healthy controls. Moreover, a significant correlation between proliferation and T(H)2 cytokine production was observed. Within the allergic group, skin reaction to HDM was significantly stronger in patients with a Der p 2-specific T-cell response. Levels of HDM-specific IgE directly correlated with interleukin 5 and interleukin 13 levels and with skin prick test results and, ultimately, with the patient's family history of allergy. Furthermore, the presence of atopic march correlated with T-cell proliferation. CONCLUSION: We found that, in HDM patients, Der p 2-specific T(H)2 responses, promoted by autologous dendritic cells in vitro, correlate with clinical parameters.

Happy air®, a successful school-based asthma educational and interventional program for primary school children.

BACKGROUND: To investigate whether an active partnership between schools, parents, and pediatricians can improve the management of asthma and quality of life of children with asthma. METHODS: A comprehensive asthma program (Happy Air®), based on a strong family-physician-school relationship, was carried out over a period of 3 years in six primary schools (2765 children). This program provides educational intervention to families, school staff, and students, as well as the administration of written questionnaires to identify children with asthma, asthma diagnosis and management, and, last but not least, extracurricular activities to improve respiratory and psychological conditions. Quality of life of children and parents, at the beginning and end of the program, was assessed using PedsQL™ 4.0 (Pediatric Quality of Life Inventory) measurement model. RESULT: Asthma was diagnosed in 135 children, of which 37 (27%) were diagnosed de novo. In all children, both single item and total clinical asthma scores showed a significant increase (p < .001) at the end of the Happy Air® program. The average scores of both the total PedsQL™ 4.0 and the four Scales were significantly increased (p < .001). CONCLUSION: Happy Air® is a model for a strategy of education- and school-based intervention for children with asthma and their families. This multi-action program for diagnosis, clinical follow-up, education, self-management, and quality-of-life control aims to minimize the socioeconomic burden of asthma disease.

Dendritic cells modification during sublingual immunotherapy in children with allergic symptoms to house dust mites.

BACKGROUND: the importance of dendritic cells (DCs) in the initiation of the Th2-mediated inflammatory response to allergens is well known and more recently it has been proposed that DCs have a pivotal role in maintaining tolerance to allergens. The aim of this study was to investigate whether the success of sublingual immunotherapy (SLIT) in allergic asthma is mediated by the induction of changes of DCs functions. METHODS: ten children with allergic asthma sensitive to house dust mite were studied before and after 12 months of SLIT. Immature DCs were derived from peripheral blood monocytes cultured for 6 days in presence of interleukin (IL)-4 and GM-CSF and stimulated with lipopolysaccharide for the last 24 hours to induce maturation. RESULTS: after 12 months of SLIT, mature DCs derived from SLIT-treated patients showed a statistically significant defect of CD86 up-regulation, an increase of IL-10, and a reduction of IL-12 production. CONCLUSION: SLIT induces changes in DCs functions that might be responsible for an impairment of T cell activation or drive T cells towards a regulatory activity, thus restoring immune tolerance to allergens.

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.

Identification of a Btk mutation in a dysgammaglobulinemic patient with reduced B cells: XLA diagnosis or not?

The identification of a Btk mutation in a male patient with <2% CD19(+) B cells warrants making the diagnosis of X-linked Agammaglobulinemia (XLA). Herein we report the case of a 31 year-old male with a gradual decline of peripheral B lymphocytes and low IgA and IgM but normal IgG levels. His clinical history revealed recurrent respiratory and skin infections, sclerosing cholangitis and chronic obstructive pancreatitis. Molecular studies revealed a novel aminoacidic substitution in Btk protein (T316A). His mother, maternal aunts and a maternal female cousin were heterozygotes for the same Btk mutation and were variably affected with pulmonary emphysema. This is a puzzling case where the patient's clinical history and laboratory findings divorce molecular genetics. Either this case confirms the variable expressivity of XLA disease or the T316A change in Btk SH2 domain is a novel non-pathogenic mutation and another unknown gene alteration is responsible for the disease.

Temporary henna tattoo is unsafe in atopic children.

UNLABELLED: Temporary henna tattoos have become increasingly popular as a safe alternative to permanent tattoos among American and European children and teenagers during the summer holidays. Currently, temporary henna tattoos contain not only henna, but also other additives such as para-phemylenediamine (PPD), which is considered to be the chemical agent that most frequently causes skin reactions associated with the use of commercial black henna. In this report, we describe an 11-year-old boy who applied a temporary black henna tattoo on his right arm during the summer holidays in Greece and developed a severe contact dermatitis at the tattoo site with residual hypopigmentation. He had no previous history of contact dermatitis, however he did suffer from seasonal allergic rhinitis and atopic dermatitis. Patch testing revealed a strong reaction to PPD, a substance commonly contained in temporary henna tattoo preparations. CONCLUSION: Henna tattoos are an increasing problem worldwide since they carry an increased risk of severe skin reactions; therefore we suggest that the use of temporary henna tattoos in children be discouraged.