About

Edward M Behrens, MD, is the Joseph Hollander Professor in Pediatric Rheumatology at the University of Pennsylvania's Perelman School of Medicine. He is an attending physician in the Division of Pediatric Rheumatology at the Children's Hospital of Philadelphia. His research primarily focuses on understanding the pathogenesis of Cytokine Storm Syndrome, a condition characterized by multi-organ failure resulting from an immune response marked by increased serum ferritin and Interferon gamma. His laboratory investigates the initiating, propagating, and regulatory factors that influence the development and outcome of cytokine storms using various murine models, including perforin deficient mice and systemic inflammation systems, with the goal of developing strategies for treatment and prevention. His current projects include exploring the roles of IL-33/ST2 in familial hemophagocytic lymphohistiocytosis, the impact of Interferon gamma, the microbiome's influence, and the regulation of Heme-oxygenase 1 in cytokine storm, as well as studying hematopoiesis during inflammation. Dr. Behrens is also recognized for his expertise in autoinflammatory syndromes and Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis.

Research topics

• Medicine
• Biology
• Bioinformatics
• Internal medicine
• Immunology
• Biochemistry
• Computational biology
• Endocrinology
• Pathology
• Virology
• Genetics

Selected publications

• T cell dysregulation and remodeling in pediatric obesity and weight loss

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-21

  articleOpen access

  Obesity is a chronic inflammatory disease associated with immune dysregulation. However, alterations in adaptive immune function remain unclear, particularly in the setting of childhood obesity and weight loss. We defined peripheral T cell dysregulation in a cross-sectional cohort of pediatric participants across weight categories and in a longitudinal cohort of adolescents with severe obesity undergoing bariatric surgery. We found increased expression of activation markers (including PD-1 and CD69) in non-naive CD8+ T cells whereas non-naive CD4+ T cells were skewed towards Tfh, Th17, and mixed Th2/Th17 populations. Consistent with a hyperactive state, T cells had enhanced capacity for inflammatory cytokine production (including IFN-γ and TNF-α) along with enrichment of gene sets associated with cytokine signaling, cell proliferation, and cell death across. Notably, these phenotypic, functional, and transcriptional alterations were not fully resolved after bariatric surgery, despite clinically meaningful weight loss. Together, these findings demonstrate that pediatric obesity leads to dysregulation of adaptive immune function with incomplete normalization after weight loss.

  PublisherDOI

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

  The Journal of Allergy and Clinical Immunology In Practice · 2025-04-04 · 2 citations

  articleOpen access

  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. Strengths and limitations of such tools as well as considerations for development and implementation are discussed. Two consensus statements were generated to support the development of successful multidisciplinary care teams to facilitate optimal evaluation of patients identified to be at risk of IEI. We discuss essential components for developing a multidisciplinary care team, including clinical interest, institutional and financial support, and crucial team members. Both of these approaches may increase diagnostic accuracy for patients with IEIs and lead to improvements in care.

  PublisherDOI

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

  Frontiers in Immunology · 2025-03-07 · 5 citations

  reviewOpen accessSenior authorCorresponding

  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]). However, published information on the composition and function of immMDTs is sparse, and there is little guidance for those seeking to establish or optimize an immMDT. To inform this review, we assembled a panel of 24 pediatric providers from multiple specialties who actively participate in immMDTs to provide expert opinion. We also conducted a search of the available information on pediatric immMDTs from PubMed. Based on these insights, we summarize the structure and function of active immMDTs across the United States and focus on best practices and context-dependent solutions that may enable institutions with varying goals, patient populations, and resources to establish an immMDT.

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• 37: DYSREGULATED STAT3 SIGNALING DEFINES A TARGETABLE, HIGH-MORTALITY SUBPHENOTYPE OF PEDIATRIC SEPSIS

  Critical Care Medicine · 2025-01-01

  article
  PublisherDOI

• TNFα signaling restores steady-state hematopoiesis in a TNFαKO mouse model of anemia of inflammation

  Blood · 2025-06-13 · 1 citations

  articleOpen access

  ABSTRACT: Anemia of inflammation (AI) is the second most common form of anemia and is prevalent in patients with chronic inflammatory states, such as infection, autoimmunity, and cancer. Interleukin 6 (IL-6) is well-known to induce the iron-sequestering hormone hepcidin, which results in iron-restricted anemia. The contributions of other proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interferon gamma (IFNγ), are less understood in the pathophysiology of AI. This study investigated the role of TNFα in a mouse model of AI by administering heat-killed Brucella abortus (HKBA) to germ line TNFα knockout (KO) mice. We hypothesized that TNFα possessed an important role in restoring steady-state erythropoiesis after inflammatory insult. TNFαKO injected with HKBA displayed a chronic anemia, with elevated proinflammatory IL12p40 and IFNγ cytokines that did not resolve. However, IFNγKO and TNFαKO/FNγKO double knockout mice showed reduced inflammation and anemia following HKBA administration. Because IFNγKO displayed normal serum TNFα and IL12p40 levels, we hypothesized that the persistent anemia was IFNγ induced and TNFα was necessary for AI cessation. However, treatment with recombinant TNFα (rTNFα) accelerated death, while reducing IFNγ using an anti-IFNγ antibody (Ab) only briefly improved anemia. Only the combination of both the Ab and rTNFα together reversed the hyperinflammatory phenotype, restored erythropoiesis, and prevented death of TNFαKO + HKBA mice. Our data provide compelling evidence for an anti-inflammatory role of TNFα that is necessary for the restoration of erythropoiesis and mitigation of proinflammatory IFNγ action in a mouse model of AI.

  PublisherOA PDFDOI

• VPS45 Deficiency with Features of Hemophagocytic Lymphohistiocytosis and Progressive Neurologic Involvement

  Journal of Human Immunity · 2025-04-25

  articleOpen access

  Background Biallelic mutations in VPS45 disrupt endosomal protein trafficking, leading to a rare immunodeficiency syndrome characterized by neutrophil dysfunction, with fewer than 40 cases reported. Key features of the condition include neutropenia, recurrent infections, hepatosplenomegaly, nephromegaly, and myelofibrosis. Neurodevelopmental abnormalities, such as global developmental delay, hypotonia, nystagmus, and cortical blindness, have been associated with a specific variant c.712G>A; p.Glu238Lys. Here we present a case with presumed familial hemophagocytic lymphohistiocytosis (HLH) in infancy and progressive neurological symptoms. Case Presentation The patient is a 15-year-old female, who initially presented at 4 weeks of age with severe mastoiditis. She was found to have poor NK cell function, perforin deficiency, and neutropenia. Bone marrow biopsy showed toxic granulation and cytoplasmic vacuolation in some neutrophils. Few histiocytes and no hemophagocytes were seen. She underwent bone marrow transplant (BMT) at 4 months old due to presumed HLH and a history of a brother with HLH who died from an infection post-BMT. She has a history of global developmental delay, dysgraphia, ADHD, primary ovarian insufficiency, multiple fractures, atypical bony development in the feet, and hypercholesterolemia. On examination, she has short stature, facial dysmorphism, atypical dentition, nystagmus, choreiform movements, and gait ataxia. Brain imaging at 10 years of age showed basal ganglia and subcortical white matter calcifications in the frontal lobes. Diagnostic Workup Extensive genetic testing, including genome sequencing and mitochondrial DNA sequencing, was negative. Research-based reanalysis revealed novel biallelic VPS45 missense variants (c.652C>T; p.Arg218Cys and c.1157G>A; p.Arg386His), confirmed by Sanger sequencing. Parental testing demonstrated the variants were inherited in trans from unaffected carriers and were also found in the deceased brother’s exome data. Discussion While a specific variant (p.Glu238Lys) has been linked to neurological symptoms in VPS45 deficiency, it was absent in our case. The patient’s progressive neurological phenotype, including chorea, basal ganglia, and subcortical white matter calcifications, suggests further phenotype expansion. The overlap with HLH and post-BMT complications underscores the diagnostic and therapeutic complexities, emphasizing the need for further research into VPS45-related pathophysiology and its clinical implications. Conclusion This case expands the understanding of VPS45 deficiency by highlighting pronounced neurological involvement, which appears more striking in our proband.

  PublisherDOI

• Enriched phenotypes in rare variant carriers suggest pathogenic mechanisms in rare disease patients

  BioData Mining · 2025-01-17 · 1 citations

  articleOpen access

  BACKGROUND: The mechanistic pathways that give rise to the extreme symptoms exhibited by rare disease patients are complex, heterogeneous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the underlying causes of diseases rather than merely the presenting symptoms. Moreover, the same dysfunctional series of interrelated symptoms implicated in rare recessive diseases may also lead to milder and potentially preventable symptoms in carriers in the general population. Seizures are a common and extreme phenotype that can result from diverse and often elusive pathways in patients with ultrarare or undiagnosed disorders. METHODS: In this pilot study, we present an approach to understand the underlying pathways leading to seizures in patients from the Undiagnosed Diseases Network (UDN) by analyzing aggregated genotype and phenotype data from the UK Biobank (UKB). Specifically, we look for enriched phenotypes across UKB participants who harbor rare variants in the same gene known or suspected to be causally implicated in a UDN patient's recessively manifesting disorder. Analyzing these milder but related associated phenotypes in UKB participants can provide insight into the disease-causing mechanisms at play in rare disease UDN patients. RESULTS: We present six vignettes of undiagnosed patients experiencing seizures as part of their recessive genetic condition. For each patient, we analyze a gene of interest: MPO, P2RX7, SQSTM1, COL27A1, PIGQ, or CACNA2D2, and find relevant symptoms associated with UKB participants. We discuss the potential mechanisms by which the digestive, skeletal, circulatory, and immune system abnormalities found in the UKB patients may contribute to the severe presentations exhibited by UDN patients. We find that in our set of rare disease patients, seizures may result from diverse, multi-step pathways that involve multiple body systems. CONCLUSIONS: Analyses of large-scale population cohorts such as the UKB can be a critical tool to further our understanding of rare diseases in general. Continued research in this area could lead to more precise diagnostics and personalized treatment strategies for patients with rare and undiagnosed conditions.

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• Precision targeting of pathogenic B cells and autoantibodies in systemic lupus erythematosus using CAR T cells against the IGHV4-34 B cell receptor

  Blood · 2025-11-03

  article

  Abstract Introduction: Systemic lupus erythematosus (SLE) is a serious autoimmune disease which chiefly involves B-cell dysregulation and activation, hypergammaglobulinemia, and autoantibody production. Studies have demonstrated that treatment with CART19, a CART targeting CD19, a pan B-cell marker, lead to clinical remissions of SLE. However, broadly targeting B cells with CART19 can lead to B-cell aplasia, hypogammaglobulinemia, and thereby leave patients prone to infections. Of note, in SLE, B cells and autoantibodies expressing the immunoglobulin heavy variable 4-34 (IGHV4-34) gene are highly enriched and associated with SLE severity. Therefore, we hypothesize that CART targeting the IGHV4-34 B-cell receptor (BcR) would preferentially deplete pathogenic B cells without immunosuppression. Methods and Results: To better define the significance of IGHV4-34 BcR as a target, we first aimed to deepen our understanding of how IGHV4-34 immunoglobulins (Ig) contribute to the SLE autoantibody repertoire. We depleted IGHV4-34 Ig from serum and then measured the reduction of specific autoantibodies using a bead-based antigen array. We used sera from SLE patients (n=3), depleted 98-100% of IGHV4-34 Ig, and found a >50% reduction in overall autoantibody levels. Furthermore, we saw reductions of SLE-associated autoantibodies (anti-Ro60, anti-SM, anti-Ribo P0, and anti-DNAse1L3) ranging from 10-100% following IGHV4-34 depletion. Higher levels of IGHV4-34 Ig in the serum have been associated with lupus nephritis (LN). Therefore, we assessed the presence of IGHV4-34+ Ig via immunohistochemistry in 11 randomly selected kidney biopsies from LN patients (5 pediatric LN, 6 adult LN) and 4 controls (1 pediatric C3 glomerulonephritis, 1 pediatric post-streptococcal glomerulonephritis, 2 normal pediatric kidneys). All 13/13 glomerulonephritis biopsies were positive for total IgG, reinforcing the role of immune complexes in nephritis. Remarkably, 10/11 LN biopsies but 0/2 glomerulonephritis controls had IGHV4-34+ antibodies in the affected glomeruli. We, therefore, developed anti-IGHV4-34 CART (CART4-34) using the 9G4 rat monoclonal antibody. Given the large size of the BcR antigen, we optimized CAR:IGHV4-34 immune synapse formation and in vitro and in vivo activity using a shorter CAR hinge domain (G4S hinge [5aa]) instead of the CD8 hinge (44aa). We co-cultured B-cell lines (HBL1, Mec1 WT or IGHV4-34+, Jeko1 WT or IGHV4-34+) with CART4-34 at 0.5-0.25 Effector:Target (E:T) ratios for 48-72hr and observed that CART4-34 exhibits potent activity specifically towards IGHV4-34+ B cells while sparing IGHV4-34-negative B cells (p<0.05). We then developed a model to assess whether CART4-34 could target SLE B cells and reduce autoantibody production. We obtained SLE patient-derived B cells, activated them for 48hr by co-culturing with CpG ODN2006, CD40L, IL2, IL10, and IL15 and differentiated them for 24hr into plasmablasts using IL6, IL2, IL10, and IL15. We then performed a 48hr 0.5 E:T co-culture with CART4-34, CART19, or untransduced T cells. We observed that CART4-34 specifically eliminated IGHV4-34+ B-cells (p=0.005), but not other B cells. Similarly, we measured co-culture total IgG and IGHV4-34+ IgG levels via ELISA and determined that while CART19 significantly depleted all IgG levels (p=0.0004), CART4-34 specifically depleted only IGHV4-34 IgG while simultaneously preserving total IgG. Next, we assessed whether soluble IGHV4-34 Ig could inhibit CART4-34 binding to the target. CART4-34 were co-cultured with HBL1 cells at a 1:1 E:T ratio with 0.1-100ug/ml IGHV4-34+ IgG1 antibody for 72hr. We observed nearly 100% inhibition of CART4-34 function at all Ig concentrations. To overcome this, we hypothesized that Ig depletion, as clinically obtained with plasmapheresis, could restore CART function. Indeed, Ig depletion led to a drastic reduction of the inhibitory effect of the IGHV4-34+ media (p<0.0001). Lastly, to confirm CART4-34 specificity and safety, we conducted next-generation sequencing from normal B-cells cocultured with CART4-34 and controls. CART4-34 led to a statistically significant reduction of only the IGHV4-34 genes out of 46 IGHV genes (p<0.01). Conclusions: These results support our hypothesis that IGHV4-34 Ig plays a role in SLE pathogenesis, particularly in LN. Importantly, CART4-34 can be used to generate potent, targeted, and safe therapy for SLE by targeting IGHV4-34+ B cells, while sparing normal B cells and most of the Ig repertoire.

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• Perforin-Deficient Hemophagocytic Lymphohistiocytosis (HLH) Presenting as Recurrent Shock in a Previously Healthy 13-Year-Old Girl

  Journal of Human Immunity · 2025-04-25

  articleOpen accessSenior author

  HLH is a systemic hyperinflammatory syndrome characterized by the inappropriate overactivation of T cells, NK cells, and macrophages, leading to infiltration and damage of multiple organs. Familial forms caused by genetic defects in granule-mediated cytotoxicity often present in infancy or early childhood and are fatal without treatment. Herein, we describe a previously healthy 13-year-old female with a delayed, indolent presentation of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) due to perforin deficiency. The patient had no significant past medical history and presented with 1 week of high fevers, a petechial rash, and pancytopenia progressing to fluid-refractory shock requiring multiple vasopressors. Her initial labs and exam demonstrated splenomegaly, pancytopenia (platelets 13,000, hemoglobin 8.0 g/dL, and ANC 770 cells/μL), triglycerides of 200 mg/dL, ferritin of 1,036 ng/ml, and sIL2R of 10,806 U/ml. Bone marrow biopsy revealed hemophagocytosis with hypocellular marrow (40%). Although these labs are consistent with HLH, they are nonspecific and could also be consistent with an infectious or oncologic etiology, which were highest on our differential. She was initially treated with broad-spectrum antibiotics, platelet and pRBC transfusions, and a single stress dose of hydrocortisone while she underwent extensive infectious, oncologic, and metabolic workups. Her condition stabilized, and after a week of clinical stability without further treatment, she was prepped for discharge. Unfortunately, her discharge was delayed by recrudescence of fever, pancytopenia, and hypotension. Further workup at this time revealed reduced NK activity and absent perforin staining (Figure 1). Whole-genome sequencing confirmed a diagnosis of perforin deficiency with compound heterozygous likely pathogenic variants in PRF1: a paternally inherited c.695G>A (p.Arg232His) variant and a maternally inherited c.1337A>C (p.Gln446Pro) (Figure 2). She was started on steroids and ruxolitinib for HLH-directed therapy and demonstrated rapid clinical improvement. She ultimately underwent a matched sibling donor hematopoietic stem cell transplant and remains in good clinical condition 6 months later with full donor chimerism and emerging immune reconstitution. Figure 1. Perforin and granzyme flow cytometry of patient and healthy sibling. Figure 2. Whole-genome sequencing results. Though typically presenting in infancy, later presentations of familial HLH are possible and can include atypical features. Providers should retain a high index of suspicion.

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• Emapalumab use in malignancy-associated hemophagocytic lymphohistiocytosis in the United States: the REAL-HLH study

  Blood Advances · 2025-12-03 · 1 citations

  articleOpen access

  ABSTRACT: Malignancy-associated hemophagocytic lymphohistiocytosis (mHLH), a hyperinflammatory syndrome, has poor prognosis and no standard therapy. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon gamma, is approved for treating primary hemophagocytic lymphohistiocytosis (pHLH). REAL-HLH, a retrospective chart review 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. Data are presented for the subset of patients with mHLH. Overall, 51 of 105 (48.6%) patients were categorized as having secondary HLH, of which 17 of 51 patients had HLH associated with an underlying malignancy (mHLH). At HLH diagnosis, the median age (range) was 15.0 (3.0-27.0) years, 6 of 14 (42.9%) patients with available data had a positive Optimized HLH Inflammatory index, indicating pathologic inflammation; 9 of 17 (52.9%) had infections; and 10 of 17 (58.8%) received emapalumab in an intensive care unit. Emapalumab was primarily initiated for treating refractory (10/17; 58.8%) or progressive (3/17, 17.7%) disease. Most patients received HLH-related therapies before (16/17; 94.1%) and/or concurrent with (15/17; 88.2%) emapalumab. Treatment with emapalumab-containing regimens normalized most key laboratory parameters and maintained normal values for others (fibrinogen [11/13; 84.6%], absolute neutrophil count [6/10; 60%], and chemokine ligand 9 [7/8; 87.5%]) per physician assessment. Overall survival at the end of follow-up and 12-month survival probability from emapalumab initiation were 23.5% and 22.1%, respectively. In conclusion, emapalumab-containing regimens normalized, improved, or maintained normal values for most laboratory parameters in patients with mHLH. Future studies are warranted to establish appropriate emapalumab dosing and utility in this high-risk population.

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Recent grants

• IL-33 Blockade as a Novel Therapeutic for T-cell Mediated Hypercytokinemia Syndromes

  NIH · $643k · 2016–2021

• The Opposing Roles of IL-10 and IFN-gamma in Macrophage Activation Syndrome

  NIH · $2.1M · 2013–2019

• Training Program/Rheumatic Diseases

  NIH · $1.8M · 2020–2030

• NIH Grant K08AI079396

  NIH · $670k · 2014

• IL-33 Blockade as a Novel Therapeutic for T-cell Mediated Hypercytokinemia Syndromes

  NIH · $2.4M · 2016–2021

Frequent coauthors

• Hamid Bassiri

  Children's Hospital of Philadelphia

  146 shared

• David T. Teachey

  Children's Hospital of Philadelphia

  131 shared

• Caroline Diorio

  Children's Hospital of Philadelphia

  127 shared

• Scott W. Canna

  Children's Hospital of Pittsburgh

  124 shared

• Kathleen E. Sullivan

  Children's Hospital of Philadelphia

  98 shared

• Chakkapong Burudpakdee

  Fox Chase Cancer Center

  90 shared

• Michele P. Lambert

  Children's Hospital of Philadelphia

  85 shared

• Sarah E. Henrickson

  University of Pennsylvania

  68 shared

Labs

• Behrens LaboratoryPI

Awards & honors

• Joseph Hollander Professor in Pediatric Rheumatology