Long-Term Treatment With Selective PI3Kδ Inhibitor Leniolisib in Adults With Activated PI3Kδ Syndrome.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life assessed through a clinician-reported questionnaire. We observed improvements in health-related quality of life: 5/6 patients experienced an increase in physical capabilities and socialization and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated following year 2 with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4-5 nor deemed leniolisib-related. Collectively, we saw an enhancement in health-related quality of life as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. (Funded by Novartis Pharmaceuticals Corporation and Pharming Group NV; ClinicalTrials.gov identifier: NCT02859727.).

PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond.

The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action.

Autoimmune lymphoproliferative immunodeficiencies (ALPIDs): A proposed approach to redefining ALPS and other lymphoproliferative immune disorders.

Chronic nonmalignant lymphoproliferation and autoimmune cytopenia are relevant manifestations of immunohematologic diseases of childhood. Their diagnostic classification is challenging but important for therapy. Autoimmune lymphoproliferative syndrome (ALPS) is a genetically defined inborn error of immunity combining these manifestations, but it can explain only a small proportion of cases. Diagnostic categories such as ALPS-like disease, common variable immunodeficiency, or Evans syndrome have therefore been used. Advances in genetics and increasing availablity of targeted therapies call for more therapy-oriented disease classification. Moreover, recent discoveries in the (re)analysis of genetic conditions affecting FAS signaling ask for a more precise definition of ALPS. In this review, we propose the term autoimmune lymphoproliferative immunodeficiencies for a disease phenotype that is enriched for patients with genetic diseases for which targeted therapies are available. For patients without a current molecular diagnosis, this term defines a subgroup of immune dysregulatory disorders for further studies. Within the concept of autoimmune lymphoproliferative immunodeficiencies, we propose a revision of the ALPS classification, restricting use of this term to conditions with clear evidence of perturbation of FAS signaling and resulting specific biologic and clinical consequences. This proposed approach to redefining ALPS and other lymphoproliferative conditions provides a framework for disease classification and diagnosis that is relevant for the many specialists confronted with these diseases.

Interim analysis: Open-label extension study of leniolisib for patients with APDS.

BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. RESULTS: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P = .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727.

Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals.

BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.

Purpose: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI. Methods: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. Results: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone. Conclusion: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome.

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis.

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αß T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αß and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αß T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αß T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ-producing T cell subsets, thereby underlying TB.

The contribution of rare copy number variants in FAS toward pathogenesis of autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphadenopathy, splenomegaly, cytopenias, and other autoimmune manifestations. ALPS is caused by lymphocyte accumulation from defects in FAS-mediated apoptosis. Heterozygous germline or somatic pathogenic single nucleotide variants in FAS are the most common molecular etiology of ALPS. Through the Centralized Sequencing Program at the National Institute of Allergy and Infectious Diseases, we performed exome sequencing on subjects with a clinical diagnosis of ALPS, with a subset receiving copy number variant (CNV) analysis. In this cohort, we identified 3 subjects from unrelated families with CNVs at the FAS locus. One subject had a de novo ∼0.828 Mb copy number loss encompassing all of FAS. The second subject had a maternally inherited ∼1.004 Mb copy number loss encompassing all of FAS. The third subject had a paternally inherited ∼0.044 Mb copy number loss encompassing exons 7 through 9 of FAS. Subjects with deletions in FAS had clinical presentations and biomarker profiles similar to those with ALPS and with germline and somatic FAS variants. We demonstrate that CNV analysis should be pursued if there is clinical and biomarker evidence of ALPS because it can lead to a molecular diagnosis and appropriate treatment when FAS sequencing is inconclusive.

Elevated Detection of Dual Antibody B Cells Identifies Lupus Patients With B Cell-Reactive VH4-34 Autoantibodies.

About 5% of B cells in healthy mice and humans are allelically or isotypically included and hence co-express two different antibodies. In mice, dual antibody B cells (B2R) expand with systemic autoimmunity, co-express autoreactive and non-autoreactive antibodies, and participate in immune responses, but this phenomenon is strain dependent. This study was developed with two goals: 1) to establish the contribution of TLR and IFN receptor signaling to the development of germinal center B cells that express two antibodies in MRL/lpr mice; and 2) to determine whether B2R B cells are increased and particularly activated in a subset of adult patients diagnosed with systemic lupus erythematosus (SLE). Results from the MRL/lpr studies indicate that the enhanced differentiation of dual-κ B cells into germinal center B cells is due to a heightened response to TLR7 and TLR9 signaling, further fueled by an increased response to type II IFN. To understand the clinical and translational implications of our observations in mouse B2R B cells, cohorts of SLE patients and healthy controls were recruited and evaluated for expression of dual BCRs. Results from flow cytometry and microscopy revealed supraphysiological frequencies of κ+λ+ B2R cells in one fourth of the SLE patients. Abnormal numbers of κ+λ+ B cells correlated with higher frequencies of activated naïve B cells and age-associated B cells, and a lower proportion of "B cells that are naïve IgD+" (BND). However, results from single cell V(D)J sequencing demonstrated that these high κ+λ+ SLE patients harbored normal frequencies of κ+λ+ and other B2R B cells. and we further show that their B cells were instead decorated by κ and λ VH4-34 autoantibodies. Thus, our findings indicate that elevated flow cytometric detection of isotypically-included B cells can identify patients with high titers of B cell-reactive VH4-34 autoantibodies and abnormal distribution of B cell subsets relevant to autoimmunity.

Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity.

BACKGROUND: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. OBJECTIVE: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. METHODS: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. RESULTS: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. CONCLUSION: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.

Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency.

Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, and there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer-dependent and p65:p65 homodimer-independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10-15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.

Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αß T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Multibatch Cytometry Data Integration for Optimal Immunophenotyping.

High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https://github.com/casanova-lab/iMUBAC).

Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder.

BACKGROUNDCytotoxic T lymphocyte antigen 4 (CTLA4) is essential for immune homeostasis. Genetic mutations causing haploinsufficiency (CTLA4h) lead to a phenotypically heterogenous, immune-mediated disease that can include neuroinflammation. The neurological manifestations of CTLA4h are poorly characterized.METHODSWe performed an observational natural history study of 50 patients with CTLA4h who were followed at the NIH. We analyzed clinical, radiological, immunological, and histopathological data.RESULTSEvidence for neuroinflammation was observed in 32% (n = 16 of 50) of patients in this cohort by magnetic resonance imaging (MRI) and/or by cerebrospinal fluid analysis. Clinical symptoms were commonly absent or mild in severity, with headaches as the leading complaint (n = 13 of 16). The most striking findings were relapsing, large, contrast-enhancing focal lesions in the brain and spinal cord observed on MRI. We detected inflammation in the cerebrospinal fluid and leptomeninges before the parenchyma. Brain biopsies of inflammatory lesions from 10 patients showed perivascular and intraparenchymal mixed cellular infiltrates with little accompanying demyelination or neuronal injury.CONCLUSIONSNeuroinflammation due to CTLA4h is mediated primarily by an infiltrative process with a distinct and striking dissociation between clinical symptoms and radiological findings in the majority of patients.FUNDINGNIAID, NIH, Division of Intramural Research, NINDS, NIH, Division of Intramural Research, and the National Multiple Sclerosis Society-American Brain Foundation.TRIAL REGISTRATIONClinicalTrials.gov NCT00001355.

HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.

The Role of Bone Marrow Evaluation in Clinical Allergy and Immunology Practice: When and Why.

Allergists and immunologists rely on other specialists for higher risk procedures such as biopsies of the lung or gastrointestinal tract. However, we perform and interpret a handful of procedures ourselves. Training programs have historically required competency for prescribing immunoglobulin infusions, patch testing, rhino laryngoscopy, lung function testing, and provocation testing for airway hyperreactivity even though other specialists often perform them. Bone marrow aspirations and biopsies are not included in fellowship training assessments despite a significant number of marrow evaluations being requested by allergists and immunologists. For example, nearly 1 marrow assessment per month has been requested over 2 years for patients in the Allergy Immunology Clinic at Walter Reed National Military Medical Center. Marrow assessments are often required for diagnosis, monitoring, and treatment-related toxicities. Interpretive and procedural competency would benefit the field given the range of diseases in clinical immunology practice that require marrow assessment. We have generated a comprehensive list of the major conditions that might require bone marrow assessments in any Allergy and Immunology practice. We then summarize the specific tests that must be ordered and show how to determine sample quality. Finally, some providers may desire procedural competency and for those individuals we discuss tips for the procedure.