Functional genomics in inborn errors of immunity.

Inborn errors of immunity (IEI) comprise a diverse spectrum of 485 disorders as recognized by the International Union of Immunological Societies Committee on Inborn Error of Immunity in 2022. While IEI are monogenic by definition, they illuminate various pathways involved in the pathogenesis of polygenic immune dysregulation as in autoimmune or autoinflammatory syndromes, or in more common infectious diseases that may not have a significant genetic basis. Rapid improvement in genomic technologies has been the main driver of the accelerated rate of discovery of IEI and has led to the development of innovative treatment strategies. In this review, we will explore various facets of IEI, delving into the distinctions between PIDD and PIRD. We will examine how Mendelian inheritance patterns contribute to these disorders and discuss advancements in functional genomics that aid in characterizing new IEI. Additionally, we will explore how emerging genomic tools help to characterize new IEI as well as how they are paving the way for innovative treatment approaches for managing and potentially curing these complex immune conditions.

Early Peanut Introduction and Testing: A Framework for General Pediatrician Beliefs and Practices.

Background: Peanut introduction guidelines have undergone significant reversal since 2001 from recommending delayed introduction to rescinding the recommendations in 2008 to actively recommending early introduction of peanut between 4 and 11 months of age in high-risk infants in 2015. This qualitative study aims to explore pediatrician beliefs, practices, facilitators, and barriers regarding peanut introduction and testing. Methods: General pediatricians from academic, private, large group, and underserved practices in Northern California underwent individual semi-structured interviews in 2017. We asked about experiences surrounding infant peanut introduction, strategies for staying up-to-date with current recommendations, and barriers and facilitators to the new peanut introduction and testing recommendations. The data were coded, and using grounded theory methodology, a conceptual framework was developed around early peanut introduction and testing in infants. Results: Eighteen general pediatricians participated. We identified barriers that may contribute to pediatrician reluctance to recommending early peanut introduction or testing including lack of awareness, lack of agreement, lack of resources, and lack of outcome expectancy. A framework was created that suggests that pediatricians need to be knowledgeable about new recommendations, agree with the recommendations, have resources to carry out the counseling and testing, and have buy-in from the parents in order for successful uptake of peanut introduction guidelines. Conclusion: Recommending early peanut introduction or testing causes significant apprehension in some pediatricians, and there are many barriers to following recent early peanut introduction recommendations. A potential limitation of the study is that it was conducted right after the addendum guidelines were changed, leaving the possibility that attitudes and practices may have evolved since 2017. It is still likely that a multifaceted approach that addresses primary care provider guideline awareness, limited primary care resources for education and testing, and includes support and collaboration from subspecialty practices is more likely to lead to improved early peanut introduction uptake.

Meckel Diverticulum Presenting as Abdominal Pain and Subsequent Bowel Perforation.

BACKGROUND: Abdominal pain is a common presenting symptom with a broad array of potential etiologies. Meckel diverticulum (MD), the most common congenital gastrointestinal malformation, classically presents with painless gastrointestinal bleeding. However, it can also lead to diverticulitis, intussusception, or obstruction, manifesting as abdominal pain. CASE REPORT: A 2-year-old boy presented to the emergency department with intermittent abdominal pain, vomiting, and loose stools. Abdominal ultrasound findings were consistent with ileitis and ileocolic intussusception, but no such intussusception was seen during fluoroscopic air enema. The patient was admitted for serial abdominal examinations and subsequently developed an acute abdomen. Emergent laparotomy revealed a perforated MD. Small bowel resection and primary anastomosis were performed and no complications developed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The presence of an MD can lead to diverticulitis, intussusception, or obstruction, putting the patient at risk of bowel perforation. As such, it is important to consider MD in the differential diagnosis of patients with abdominal pain. In cases in which sonographic findings are ambiguous or transient, additional observation or alternative imaging, such as computed tomography, should be strongly considered.

Identification of a novel cis-regulatory element essential for immune tolerance.

Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.

Antigen-conjugated human IgE induces antigen-specific T cell tolerance in a humanized mouse model.

Dendritic cells (DCs) play an important role in immune homeostasis through their ability to present Ags at steady state and mediate T cell tolerance. This characteristic renders DCs an attractive therapeutic target for the induction of tolerance against auto-antigens or allergens. Accordingly, Ag-conjugated DC-specific Abs have been proposed to be an excellent vehicle to deliver Ags to DCs for presentation and tolerance induction. However, this approach requires laborious reagent generation procedures and entails unpredictable side effects resulting from Ab-induced crosslinking of DC surface molecules. In this study, we examined whether IgE, a high-affinity, non-cross-linking natural ligand of FcεRI, could be used to target Ags to DCs and to induce Ag-specific T cell tolerance. We found that Ag-conjugated human IgE Fc domain (Fcε) effectively delivered Ags to DCs and enhanced Ag presentation by 1000- to 2500-fold in human FcεRIα-transgenic mice. Importantly, this presentation resulted in a systemic deletion of Ag-specific T cells and prevented these mice from developing delayed-type hypersensitivity, which is critically dependent on Ag-specific T cell immunity. Thus, targeting FcεRI on DCs via Ag-Fcε fusion protein may serve an alternative method to induce Ag-specific T cell tolerance in humans.

Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development.

Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting T cell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust in vitro method to direct differentiation of human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) by precise regulation of TGFß, BMP4, RA, Wnt, Shh, and FGF signaling. The hESC-derived TEPs further mature into functional TECs that support T cell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce T cells capable of in vitro proliferation as well as in vivo immune responses. Thus, hESC-derived TEP grafts may have broad applications for enhancing engraftment in cell-based therapies as well as restoring age- and stress-related thymic decline.