The role of dupilumab in the treatment of eosinophilic esophagitis.

Dupilumab has been approved to treat a variety of atopic disorders and was the first US FDA-approved medication for the treatment of eosinophilic esophagitis (EoE), initially approved in May 2022, with expansion in use to patients as young as 1 year of age weighing at least 15 kg in January 2024. It is a fully human monoclonal antibody that inhibits both IL-4 and IL-13 signaling, suppressing TH2-mediated proinflammatory cytokines, chemokines and IgE implicated in EoE pathogenesis. Phase II and III trials in EoE have demonstrated histologic, endoscopic and symptomatic improvement in disease activity with an overall favorable safety profile.

Inborn Errors of the Immune System Associated With Atopy.

Atopic disorders, including atopic dermatitis, food and environmental allergies, and asthma, are increasingly prevalent diseases. Atopic disorders are often associated with eosinophilia, driven by T helper type 2 (Th2) immune responses, and triggered by disrupted barrier function leading to abnormal immune priming in a susceptible host. Immune deficiencies, in contrast, occur with a significantly lower incidence, but are associated with greater morbidity and mortality.

Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1.

Background: We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection.

Objectives: We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias.

Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution!

The COVID-19 pandemic is one of the greatest infectious challenges in recent history. Presently, few treatment options exist and the availability of effective vaccines is at least one year away. There is an urgent need to find currently available, effective therapies in the treatment of patients with COVID-19 infection.

RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness.

Background: Decreased TNF-α production in whole blood after ex vivo LPS stimulation indicates suppression of the Toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether antiviral immune signaling pathways are also suppressed in these patients is unclear.

Impact of Gastroesophageal Reflux Disease on Mucosal Immunity and Atopic Disorders.

Atopic disorders and gastroesophageal reflux disease (GERD) are some of the most common medical conditions treated by primary care physicians and specialists alike. The observation that atopic disorders, like asthma, allergic rhinitis and sinusitis, food allergies, atopic dermatitis, contact dermatitis, and eosinophilic esophagitis are common comorbidities in patients with GERD raises the question of the nature of the relationship that may exist between GERD and atopic disorders. In this article, we review the pathophysiology of GERD, its effect on the immune system, the effect of acid-blocking medications on allergic responses, as well as several common atopic conditions that have been associated with GERD including asthma, chronic rhinosinusitis (CRS), allergic rhinitis (AR), atopic dermatitis (AD), contact dermatitis (CD), food allergies, proton pump inhibitor (PPI)-responsive esophageal eosinophilia (PPI-REE), and eosinophilic esophagitis (EoE).

Defective TLR9-driven STAT3 activation in B cells of patients with CVID.

B cell activation by Toll-like receptor 9 (TLR9) ligands is dependent on STAT3 and is important for optimal antibody responses to microbial antigens. B cells from patients with common variable immune deficiency (CVID) have impaired proliferation and differentiation in response to the TLR9 ligand CpG, despite normal levels of TLR9 expression. We demonstrate that CpG-driven STAT3 phosphorylation, but not activation of NFκB and p38, is selectively impaired in B cells from CVID patients.

Hematopoietic stem cell transplantation outcomes for 11 patients with dedicator of cytokinesis 8 deficiency.

Background: Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcomes are still limited.

Objective: We sought to analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution.

Intraoperative anaphylaxis to gelatin in topical hemostatic agents during anterior spinal fusion: a case report.

Background Context: The use of topical hemostatic agents is widespread and has been shown to reduce bleeding during a wide variety of surgical procedures. Nonetheless, as biologically active agents, there is potential for allergic reactions to these products.

Purpose: This is a report of intraoperative anaphylaxis to gelatin associated with the use of two topical hemostatic agents.

DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation.

The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27(+) memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not.

TH17 deficiency in human disease.

The differentiation of naive T cells into distinct subsets of effector T cells is critical for effective immunity against a wide variety of infectious agents in the environment. Activation of innate immune responses by Candida species through pattern-recognition receptors directs the subsequent development of naive T cells into T(H)17 cells, which are essential for effective mucosal immunity against fungi. Thorough analyses of cohorts of patients with unusual susceptibility to chronic mucocutaneous candidiasis resulting from T(H)17 deficiency have confirmed the role of T(H)17 cells and T(H)17 cytokines in human host defense against Candida species and have provided valuable insights into the complex process of T(H)17 cell development.

Successful engraftment of donor marrow after allogeneic hematopoietic cell transplantation in autosomal-recessive hyper-IgE syndrome caused by dedicator of cytokinesis 8 deficiency.

A child with homozygous partial deletion of the gene showed characteristic clinical findings of autosomal recessive hyper-IgE syndrome and full donor chimerism early after matched sibling bone marrow transplantation.

Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients.

Background: IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood.

Objective: We sought to evaluate T-cell function in IRAK-4 deficient patients.

Immune deficiency caused by impaired expression of nuclear factor-kappaB essential modifier (NEMO) because of a mutation in the 5' untranslated region of the NEMO gene.

Background: Nuclear factor-kappaB (NF-kappaB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IkappaB kinase gamma/NF-kappaB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency.

Objective: To determine the genetic cause of recurrent sinopulmonary infections and dysgammaglobulinemia in a patient with a normal NEMO coding sequence and his affected brother.

Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency.

Background: Nuclear factor kappaB (NF-kappaB) is a master transcriptional regulator critical for ectodermal development and normal innate and adaptive immune function. Mutations in the IkappaB kinase gamma/NF-kappaB essential modifier have been described in male subjects with the syndrome of X-linked ectodermal dysplasia with immune deficiency that results from impaired activation of NF-kappaB.

Objectives: We sought to determine the genetic cause of ectodermal dysplasia with immune deficiency in a female patient.

Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor-dependent innate antiviral immune responses.

Background: Engagement of all known Toll-like receptors (TLRs) causes the production of inflammatory cytokines, including TNF-alpha, whereas in humans, engagement of TLRs 3, 7, 8, and 9 also induces type I IFNs. IRAK-4 is a critical effector in signaling by TLRs and the IL-1 receptor, which share homology in their intracellular domain and recruit IRAK-4 via the adaptor myeloid differentiation factor 88 (MyD88). Patients with IRAK-4 deficiency are susceptible to invasive bacterial infections but have so far not been reported to be susceptible to viral infection.

Lessons learned from molecular defects in nuclear factor kappaB dependent signaling.

Nuclear factor (NF) kappaB is a ubiquitously expressed transcription factor that plays critical roles in normal development and inflammation. Characterization of naturally occurring defects in signaling pathways leading to activation of NFkappaB, complemented by mouse knockout models, has demonstrated the vital role of NFkappaB in normal host defense.

A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation.

Senile plaques found in the Alzheimer's disease brain are foci of local inflammatory reactions mediated by plaque-associated microglia. The interaction of microglia with compacted deposits of beta-amyloid (Abeta) fibrils results in the stimulation of intracellular Tyr kinase-based signaling cascades and cellular activation, leading to the secretion of proinflammatory molecules. This study identifies a cell surface receptor complex that mediates the binding of microglia to Abeta fibrils and the subsequent activation of intracellular signaling pathways leading to a proinflammatory response.