Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML.

Juvenile myelomonocytic leukemia (JMML) originates from mutated hematopoietic stem cells. The mechanism by which mutant stem cells are sustained, leading to leukemia development, remains elusive. By comprehensively examining transcriptomic profiles, cell compositions, developmental trajectories, and cell-cell interactions across various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML, we find that Ptpn11 mutant stem cells exhibit de novo activation of the myeloid transcriptional program and markedly increased expression of innate immunity-associated antimicrobial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8.

Eculizumab is Associated With Increased Infection Rates and Infection Related Mortality in Children With Thrombotic Microangiopathy After HCT.

Complement C5 inhibition can be used to treat hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) but may impact infectious organism clearance, impeding opsonization and lysis. The infectious risks of eculizumab exposure after hematopoietic cell transplant (HCT) are unknown. In this single center, retrospective case-control study, we included allogeneic HCT recipients transplanted from January 2019 to January 2023.

Perspectives on the current diagnostic and treatment paradigms in secondary hemophagocytic lymphohistiocytosis (HLH).

Improved awareness of hemophagocytic lymphohistiocytosis (HLH) among clinicians has led to an increase in its diagnosis. Often diagnosis is made based on the HLH- 2004 criteria. While these criteria have considerable strengths, they lack specificity and may be fulfilled in the setting of many pro-inflammatory disorders.

Biomarkers of Immune Dysregulation and What They Tell Us: Gene Sequencing Is Not the Answer to Every Question.

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity, with autoimmune, hyperinflammatory, and lymphoproliferative manifestations as presenting features rather than recurrent infections. Genetic testing remains the primary tool for diagnosing patients with immune defects. Not all suspected PIRDs have a known genetic cause.

Expert-Based, Institutional Approaches for Reducing the Diagnostic Odyssey of Patients With Inborn Errors of Immunity.

Inborn errors of immunity (IEIs) are a heterogeneous group of genetic disorders with long diagnostic delay that negatively impacts patient outcomes. To combat delay, 8 multidisciplinary experts from different disciplines convened to generate 11 consensus-based statements that address approaches that could reduce the diagnostic journey of patients with IEIs. Nine of these statements relate to the development and implementation of automated decision support tools to improve rapidity of diagnosis by augmenting clinical decision-making for practitioners with or without IEI experience.

Multidisciplinary approach to treating complex immune dysregulation disorders: an adaptive model for institutional implementation.

Patients with immune dysregulation may present with varying combinations of autoimmunity, autoinflammation, immunodeficiency, atopy, lymphoproliferation, and/or malignancy, often with multisystem involvement. Recognizing specific patterns of immune dysregulation, coordinating and interpreting complex diagnostic testing, and choosing initial (often empiric) treatment can be challenging. Centers are increasingly assembling multidisciplinary teams (MDTs) to standardize evaluation and optimize treatment of patients with complex immune dysregulation (immune dysregulation MDTs [immMDTs]).

Characterizing the heterogeneity of Castleman disease and oligocentric subtype: findings from the ACCELERATE registry.

Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8-negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm-driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described.

Allogeneic haematopoietic stem-cell transplantation for children with refractory systemic juvenile idiopathic arthritis and associated lung disease: outcomes from an international, retrospective cohort study.

Background: Systemic juvenile idiopathic arthritis-related lung disease (sJIA-LD) is a severe complication in patients with treatment-refractory systemic juvenile idiopathic arthritis (sJIA). The objective of this study was to evaluate the effect of allogeneic haematopoietic stem-cell transplantation (HSCT) in a cohort of children with sJIA-LD.

Methods: This international, retrospective cohort study was performed in nine hospitals across the USA and Europe in children with sJIA-LD who had received allogeneic HSCT.

Systemic T-cell activation and IFN-γ activity in indeterminate severe hepatitis are reminiscent of hemophagocytic lymphohistiocytosis: Implications for T-cell- and IFN-γ-directed therapies.

Background: Severe hepatitis cases in children are increasingly recognized, but the exact etiology remains unknown in a significant proportion of patients. Cases of indeterminate severe hepatitis (iSH) may progress to indeterminate pediatric acute liver failure (iPALF), so understanding its immunobiology is critical to preventing disease progression. Hemophagocytic lymphohistiocytosis (HLH) is a systemic hyperinflammatory disorder associated with T-cell and macrophage activation with liver injury.

Prototypical innate immune mechanism hijacked by leukemia-initiating mutant stem cells for selective advantage and immune evasion in Ptpn11-associated juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML), a clonal hematologic malignancy, originates from mutated hematopoietic stem cells (HSCs). The mechanism sustaining the persistence of mutant stem cells, leading to leukemia development, remains elusive. In this study, we conducted comprehensive examination of gene expression profiles, transcriptional factor regulons, and cell compositions/interactions throughout various stages of tumor cell development in Ptpn11 mutation-associated JMML.

Pediatric lymphoproliferative disorders associated with inborn errors of immunity.

Both non-malignant and malignant lymphoproliferative disorders (LPD) are commonly seen in patients with inborn errors of immunity (IEI), which may be the presenting manifestations or may develop during the IEI disease course. Here we review the clinical, histopathological, and molecular features of benign and malignant LPD associated with IEI and recognize the diagnostic challenges.

HLH and Recurrent EBV Lymphoma as the presenting manifestation of MAGT1 Deficiency: A Systematic Review of the Expanding Disease Spectrum.

Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists.

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days).

Real-world treatment patterns and outcomes in patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon gamma, is approved in the United States to treat primary HLH (pHLH) in patients with refractory, recurrent, or progressive disease, or intolerance with conventional HLH treatments. REAL-HLH, a retrospective study, conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with ≥1 dose of emapalumab between 20 November 2018 and 31 October 2021.

Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia.

Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had <10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.

Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study.

Background: P47phox (neutrophil cytosolic factor-1) deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well-described.

Objectives: We sought to study HCT for p47phox CGD in North America.

Part 5: Allogeneic HSCT in refractory SJIA with lung disease; recent cases from centers in North America & Europe.

It has been increasingly recognized that there is a subset of patients with refractory systemic JIA, who have failed all available medications and may benefit from HSCT. The increasing experience with HSCT in SJIA, suggests that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remission or reduced burden of disease. Longer follow-up, however, is needed to better define the long-term outcomes.