TH2-driven manifestations of inborn errors of immunity.

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward TH2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with TH2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations.

Advanced computational analysis of CD40LG variants in atypical X-linked hyper-IgM syndrome.

X-Linked Hyper-IgM Syndrome is caused by pathogenic variants in CD40LG. Three patients with atypical clinical and immunological features were identified with variants in CD40LG requiring further characterization. Flow cytometry was used to evaluate CD40L protein expression and binding capacity to a surrogate receptor, CD40-muIg. Though functional anomalies were observed, there was still a lack of clarity regarding the underlying mechanism. We developed structural models for wild-type and the three variants of CD40L protein observed in these patients (p. Lys143Asn, Leu225Ser and Met36Arg) to evaluate structural alterations by molecular mechanic calculations, and assess protein movement by molecular dynamic simulations. These studies demonstrate that functional analysis of variants of unknown significance in CD40LG can be supplemented by advanced computational analysis in atypical clinical contexts. These studies in combination identify the deleterious effects of these variants and potential mechanisms for protein dysfunction.

T-follicular helper cell expansion and chronic T-cell activation are characteristic immune anomalies in Evans syndrome.

Pediatric Evans syndrome (pES) is increasingly identified as the presenting manifestation of several inborn errors of immunity. Despite an improved understanding of genetic defects in pES, the underlying immunobiology of pES is poorly defined, and characteristic diagnostic immune parameters are lacking. We describe the immune characteristics of 24 patients with pES and compared them with 22 patients with chronic immune thrombocytopenia (cITP) and 24 healthy controls (HCs). Compared with patients with cITP and HC, patients with pES had increased circulating T-follicular helper cells (cTfh), increased T-cell activation, and decreased naïve CD4+ T cells for age. Despite normal or high immunoglobulin G (IgG) in most pES at presentation, class-switched memory B cells were decreased. Within the cTfh subset, we noted features of postactivation exhaustion with upregulation of several canonical checkpoint inhibitors. T-cell receptor ß chain (TCR-ß) repertoire analysis of cTfh cells revealed increased oligoclonality in patients with pES compared with HCs. Among patients with pES, those without a known gene defect had a similar characteristic immune abnormality as patients with defined genetic defects. Similarly, patients with pES with normal IgG had similar T-cell abnormalities as patients with low IgG. Because genetic defects have been identified in less than half of patients with pES, our findings of similar immune abnormalities across all patients with pES help establish a common characteristic immunopathology in pES, irrespective of the underlying genetic etiology.

Effects of perinatal risk factors on common neonatal respiratory morbidities beyond 36 weeks of gestation.

OBJECTIVE: To assess the incidence of respiratory morbidity (RM) in all single live neonates born more than 36 weeks of gestation, and the effects of perinatal characteristics on these morbidities. METHODS: This is a prospective hospital based study covering a 12-month period. The study took place at the Department of Pediatrics, Jordan University Hospital, Amman, Jordan, between January and December 2009. The effects of different perinatal characteristics on RM including transient tachypnea of the newborn (TTN) and respiratory distress syndrome (RDS) were analyzed. RESULTS: A total of 2282 newborns were included. One thousand two hundred and seventy-six (55.9%) of the newborns were delivered by vaginal delivery and 1,006 (44%) by cesarean section (CS) (24.5% by emergency CS and 19.5% by elective CS). Respiratory morbidity was reported in 3.7%. The incidence of TTN was 2.9% and RDS was 0.7%. Elective CS was found to be a risk factor for RM development when the gestational age was less than 39 weeks. Maternal hypertension and diabetes mellitus, and the absence of labor were independent risk factors for RM. The emergency CS and large for gestational age babies were risk factors for TTN, while male gender and GA less than 37 0+6 weeks were risk factor for RDS. CONCLUSION: The collaborative obstetric and neonatology responsibility helps to identify the risk factors for adverse respiratory outcome when considering the time and mode of delivery. The pregnant mother should be informed regarding this possibility if delivery by elective CS is performed before the 39 0+6 weeks of gestation.