A scoping review of psychological interventions and outcomes for avoidant and restrictive food intake disorder (ARFID).

OBJECTIVE: This scoping review identifies and describes psychological interventions for avoidant restrictive food intake disorder (ARFID) and summarizes how outcomes are measured across such interventions. METHOD: Five databases (Cochrane, Embase, Medline, PsycInfo, Web of Science) were searched up to December 22, 2022. Studies were included if they reported on psychological interventions for ARFID. Studies were excluded if participants did not have an ARFID diagnosis and if psychological interventions were not delivered or detailed. RESULTS: Fifty studies met inclusion criteria; almost half were single-case study designs (23 studies) and most studies reported on psychological interventions for children and adolescents with ARFID (42 studies). Behavioral interventions (16 studies), cognitive-behavioral therapy (10 studies), and family therapy (5 studies), or combinations of these therapeutic approaches (19 studies) were delivered to support patients with ARFID. Many studies lacked validated measures, with outcomes most commonly assessed via physical health metrics such as weight. DISCUSSION: This review provides a comprehensive summary of psychological interventions for ARFID since its introduction to the DSM-5. Across a range of psychological interventions and modalities for ARFID, there were common treatment components such as food exposure, psychoeducation, anxiety management, and family involvement. Currently, studies reporting on psychological interventions for ARFID are characterized by small samples and high levels of heterogeneity, including in how outcomes are measured. Based on reviewed studies, we outline suggestions for clinical practice and future research. PUBLIC SIGNIFICANCE: Avoidant restrictive food intake disorder (ARFID) is an eating disorder characterized by avoidance or restriction of food due to fear, sensory sensitivities, and/or a lack of interest in food. We reviewed the literature on psychological interventions for ARFID and the outcomes used to measure change. Several psychological interventions have been developed and applied to patients with ARFID. Outcome measurement varies widely and requires further development and greater consensus.

OBJETIVO: Esta revisión de alcance identifica y describe las intervenciones psicológicas para el Trastorno de Evitación y Restricción de la Ingesta de Alimentos (TERIA) y resume cómo se miden los resultados en dichas intervenciones. MÉTODO: Se hicieron búsquedas en cinco bases de datos (Cochrane, Embase, Medline, PsycInfo, Web of Science) hasta el 22 de diciembre de 2022. Se incluyeron los estudios que informaban sobre intervenciones psicológicas para TERIA. Se excluyeron los estudios si los participantes no tenían un diagnóstico de TERIA y si las intervenciones psicológicas no se administraban o detallaban. RESULTADOS: Cincuenta estudios cumplieron los criterios de inclusión; casi la mitad fueron diseños de estudio de caso único (23 estudios) y la mayoría de los estudios informaron sobre intervenciones psicológicas para niños y adolescentes que padecen TERIA (42 estudios). Se administraron intervenciones conductuales (16 estudios), terapia cognitivo-conductual (10 estudios) y terapia familiar (5 estudios), o combinaciones de estos enfoques terapéuticos (19 estudios) para apoyar a los pacientes con TERIA. Muchos estudios carecían de medidas validadas, y los resultados se evaluaron con mayor frecuencia mediante parámetros de salud física como el peso. DISCUSIÓN: Esta revisión proporciona un resumen exhaustivo de las intervenciones psicológicas para el TERIA desde su introducción en el DSM-5. A través de una gama de intervenciones y modalidades psicológicas para el TERIA, hubo componentes de tratamiento comunes como la exposición a los alimentos, la psicoeducación, el manejo de la ansiedad y la participación de la familia. Actualmente, los estudios que informan sobre las intervenciones psicológicas para el TERIA están dominados por muestras pequeñas y altos niveles de heterogeneidad, incluso en la forma en que se miden los resultados. Sobre la base de los estudios revisados, se esbozan sugerencias para la práctica clínica y la investigación futura.

Blood pressure responses are dependent on call type and related to hypertension status in firefighters.

BACKGROUND: Impaired cardiovascular health is a concern for firefighters, with over 50% of line-of-duty deaths having cardiac causes. Many firefighters have hypertension and <25% have their blood pressure (BP) controlled. The alarm response could be an unidentified cardiac risk, but interestingly, the BP response to different calls and on-the-job activity is unknown. PURPOSE: We aimed to measure the physiological stress resulting from different call types (fire, medical) and job activity (riding apparatus, pre-alert alarms) through ambulatory BP (ABP) monitoring in a population of firefighters. MATERIALS AND METHODS: During 111 12-h work shifts firefighters wore an ABP monitor. BP was measured at 30-min intervals and manual measurements were prompted when the pager went off or whenever they felt stress. RESULTS: Firefighters were hypertensive (124.3 ± 9.9/78.1 ± 6.7 mmHg), overweight (30.2 ± 4.6 kg/m2), middle-aged (40.5 ± 12.6 years) and experienced (17.3 ± 11.7 years). We calculated an average 11% increase in systolic and 10.5% increase in diastolic BP with alarm. Systolic BP (141.9 ± 13.2 mmHg) and diastolic BP (84.9 ± 11.1 mmHg) and the BP surges were higher while firefighters were responding to medical calls compared to fire calls. Between BP groups we found that medical call systolic BP (p = .001, d = 1.2), diastolic BP (p = .017, d = 0.87), and fire call systolic BP (p = .03, d = 0.51) levels were higher in the hypertensive firefighters. CONCLUSION: This is the first report of BP surge responses to alarms and to occupational activities in firefighters, and medical calls elicited the largest overall responses.PLAIN LANGUAGE SUMMARYCardiovascular disease and impaired cardiovascular health are substantially more prevalent in firefighters, with over 50% of line-of-duty deaths being cardiac related.Many firefighters are diagnosed with high blood pressure (hypertension), which is known to increase the risk of heart attacks, strokes, heart disease, and other serious health complications.Upon stress, our body enacts the 'fight or flight' response where sympathetic nervous system activity triggers an immediate increase in heart rate and blood pressure. This response can be dangerous when surges reach extreme levels due to underlying impaired cardiovascular function. It is known that alarm sounds trigger a stress response.Firefighters respond to different alarms while on the job, each indicating different call types, such as a house fire or a medical emergency. Due to the prevalence of impaired cardiovascular health in firefighters, the physical stress resulting from these alerts is cause for concern.The blood pressure surge response to different call types and job activities in healthy and hypertensive firefighters had not been measured before this study.Through the ambulatory blood pressure monitoring of 111 on-duty firefighters, this study discovered that medical calls caused the greatest blood pressure and heart rate surge.Also, firefighters with hypertension experienced a greater blood pressure surge in response to alarms than their non-hypertensive co-workers.

Civilians Have Higher Adherence and More Improvements in Health With a Mediterranean Diet and Circuit Training Program Compared With Firefighters.

OBJECTIVE: To examine the relationship between diet adherence and cardiovascular disease (CVD) risk-reduction between civilians and firefighters with a 6-week Mediterranean diet and tactical training intervention. METHODS: Forty firefighters and 30 civilians participated. Blood pressure, body composition, lipid levels, vascular measures, and aerobic capacity were measured pre- and post-intervention. Diet was self-report based on number of servings consumed. Weekly diet-scores were calculated. RESULTS: Both groups had improvements in blood pressure and body composition. Civilians had improved lipid levels, higher overall adherence, a relationship between total Med-diet score and cholesterol (R = 0.68), and higher servings consumed in foods typical of Mediterranean-dietary pattern ( P < 0.05). CONCLUSION: This is the first exercise and diet intervention comparing firefighters to civilians. Adherence to a Mediterranean-dietary pattern coupled with exercise is effective at improving cardiac health. These findings substantiate the need for wellness interventions in firefighters.

GATA2 deficiency phenotype associated with tandem duplication of GATA2 and overexpression of GATA2-AS1.

A 3-year-old girl of nonconsanguineous healthy parents presented with cervical and mediastinal lymphadenopathy due to Mycobacterium fortuitum infection. Routine blood analysis showed normal hemoglobin, neutrophils, and platelets but profound mononuclear cell deficiency (monocytes < 0.1 × 109/L; B cells 78/µL; NK cells 48/µL). A 548 902-bp region containing GATA2 was sequenced by targeted capture and deep sequencing. This revealed a de novo 187-kb duplication of the entire GATA2 locus, containing a maternally inherited copy number variation deletion of 25 kb (GRCh37: esv2725896 and nsv513733). Many GATA2-associated phenotypes have been attributed to amino acid substitution, frameshift/deletion, loss of intronic enhancer function, or aberrant splicing. Gene deletion has been described, but other structural variation has not been reported in the germline configuration. In this case, duplication of the GATA2 locus was paradoxically associated with skewed diminished expression of GATA2 messenger RNA and loss of GATA2 protein. Chimeric RNA fusion transcripts were not detected. A possible mechanism involves increased transcription of the anti-sense long noncoding RNA GATA2-AS1 (RP11-472.220), which was increased several fold. This case further highlights that evaluation of the allele count is essential in any case of suspected GATA2-related syndrome.

How to Ease the Pain of Taking a Diagnostic Point of Care Test to the Market: A Framework for Evidence Development.

Bringing a diagnostic point of care test (POCT) to a healthcare market can be a painful experience as it requires the manufacturer to meet considerable technical, financial, managerial, and regulatory challenges. In this opinion article we propose a framework for developing the evidence needed to support product development, marketing, and adoption. We discuss each step in the evidence development pathway from the invention phase to the implementation of a new POCT in the healthcare system. We highlight the importance of articulating the value propositions and documenting the care pathway. We provide guidance on how to conduct care pathway analysis as little has been published on this. We summarize the clinical, economic and qualitative studies to be considered for developing evidence, and provide useful links to relevant software, on-line applications, websites, and give practical advice. We also provide advice on patient and public involvement and engagement (PPIE), and on product management. Our aim is to help device manufacturers to understand the concepts and terminology used in evaluation of in vitro diagnostics (IVDs) so that they can communicate effectively with evaluation methodologists, statisticians, and health economists. Manufacturers of medical tests and devices can use the proposed framework to plan their evidence development strategy in alignment with device development, applications for regulatory approval, and publication.

Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation.

BACKGROUND: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. OBJECTIVE: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. METHODS: Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. RESULTS: Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. CONCLUSIONS: This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation.

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells.

Heterozygous GATA2 mutation is associated with immunodeficiency, lymphedema, and myelodysplastic syndrome. Disease presentation is variable, often coinciding with loss of circulating dendritic cells, monocytes, B cells, and natural killer (NK) cells. Nonetheless, in a proportion of patients carrying GATA2 mutation, NK cells persist. We found that peripheral blood NK cells in symptomatic patients uniformly lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF), as well as expression of intracellular signaling proteins FcεRγ, spleen tyrosine kinase (SYK), and EWS/FLI1-Activated Transcript 2 (EAT-2) in a variegated manner. Moreover, consistent with an adaptive identity, NK cells from patients with GATA2 mutation displayed altered expression of cytotoxic granule constituents and produced interferon-γ upon Fc-receptor engagement but not following combined interleukin-12 (IL-12) and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, GATA-binding protein-2 (GATA-2) was expressed in hematopoietic stem cells, but not in NK-cell progenitors, CD3-CD56bright, canonical, or adaptive CD3-CD56dim NK cells. Peripheral blood NK cells from individuals with GATA2 mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients with GATA2 mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.

Haematopoietic and immune defects associated with GATA2 mutation.

Heterozygous familial or sporadic GATA2 mutations cause a multifaceted disorder, encompassing susceptibility to infection, pulmonary dysfunction, autoimmunity, lymphoedema and malignancy. Although often healthy in childhood, carriers of defective GATA2 alleles develop progressive loss of mononuclear cells (dendritic cells, monocytes, B and Natural Killer lymphocytes), elevated FLT3 ligand, and a 90% risk of clinical complications, including progression to myelodysplastic syndrome (MDS) by 60 years of age. Premature death may occur from childhood due to infection, pulmonary dysfunction, solid malignancy and MDS/acute myeloid leukaemia. GATA2 mutations include frameshifts, amino acid substitutions, insertions and deletions scattered throughout the gene but concentrated in the region encoding the two zinc finger domains. Mutations appear to cause haplo-insufficiency, which is known to impair haematopoietic stem cell survival in animal models. Management includes genetic counselling, prevention of infection, cancer surveillance, haematopoietic monitoring and, ultimately, stem cell transplantation upon the development of MDS or another life-threatening complication.

Langerin-expressing dendritic cells in human tissues are related to CD1c+ dendritic cells and distinct from Langerhans cells and CD141high XCR1+ dendritic cells.

Langerin is a C-type lectin expressed at high level by LCs of the epidermis. Langerin is also expressed by CD8(+)/CD103(+) XCR1(+) cross-presenting DCs of mice but is not found on the homologous human CD141(high) XCR1(+) myeloid DC. Here, we show that langerin is expressed at a low level on DCs isolated from dermis, lung, liver, and lymphoid tissue and that langerin(+) DCs are closely related to CD1c(+) myeloid DCs. They are distinguishable from LCs by the level of expression of CD1a, EpCAM, CD11b, CD11c, CD13, and CD33 and are found in tissues and tissue-draining LNs devoid of LCs. They are unrelated to CD141(high) XCR1(+) myeloid DCs, lacking the characteristic expression profile of cross-presenting DCs, conserved between mammalian species. Stem cell transplantation and DC deficiency models confirm that dermal langerin(+) DCs have an independent homeostasis to LCs. Langerin is not expressed by freshly isolated CD1c(+) blood DCs but is rapidly induced on CD1c(+) DCs by serum or TGF-ß via an ALK-3-dependent pathway. These results show that langerin is expressed outside of the LC compartment of humans and highlight a species difference: langerin is expressed by the XCR1(+) "DC1" population of mice but is restricted to the CD1c(+) "DC2" population of humans (homologous to CD11b(+) DCs in the mouse).

A targeted oligonucleotide enhancer of SMN2 exon 7 splicing forms competing quadruplex and protein complexes in functional conditions.

The use of oligonucleotides to activate the splicing of selected exons is limited by a poor understanding of the mechanisms affected. A targeted bifunctional oligonucleotide enhancer of splicing (TOES) anneals to SMN2 exon 7 and carries an exonic splicing enhancer (ESE) sequence. We show that it stimulates splicing specifically of intron 6 in the presence of repressing sequences in intron 7. Complementarity to the 5' end of exon 7 increases U2AF65 binding, but the ESE sequence is required for efficient recruitment of U2 snRNP. The ESE forms at least three coexisting discrete states: a quadruplex, a complex containing only hnRNP F/H, and a complex enriched in the activator SRSF1. Neither hnRNP H nor quadruplex formation contributes to ESE activity. The results suggest that splicing limited by weak signals can be rescued by rapid exchange of TOES oligonucleotides in various complexes and raise the possibility that SR proteins associate transiently with ESEs.

Human dermal CD14⁺ cells are a transient population of monocyte-derived macrophages.

Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system.

The evolution of cellular deficiency in GATA2 mutation.

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.

A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice.

In the search for the most efficacious antisense oligonucleotides (AOs) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (-10, -34), PMO18 (-10, -27), and PMO20 (-10, -29), complementary to the SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon 7 inclusion in vitro in spinal muscular atrophy (SMA) patient fibroblasts and in vitro splicing assays. PMO25 and PMO18 were compared further in a mouse model of severe SMA. After a single intracerebroventricular (ICV) injection in neonatal mice, PMO25 increased the life span of severe SMA mice up to 30-fold, with average survival greater by 3-fold compared with PMO18 at a dose of 20 µg/g and 2-fold at 40 µg/g. Exon 7 inclusion was increased in the CNS but not in peripheral tissues. Systemic delivery of PMO25 at birth achieved a similar outcome and produced increased exon 7 inclusion both in the CNS and peripherally. Systemic administration of a 10-µg/g concentration of PMO25 conjugated to an octaguanidine dendrimer (VMO25) increased the life span only 2-fold in neonatal type I SMA mice, although it prevented tail necrosis in mild SMA mice. Higher doses and ICV injection of VMO25 were associated with toxicity. We conclude that (1) the 25-mer AO is more efficient than the 18-mer and 20-mer in modifying SMN2 splicing in vitro; (2) it is more efficient in prolonging survival in SMA mice; and (3) naked Morpholino oligomers are more efficient and safer than the Vivo-Morpholino and have potential for future SMA clinical applications.

Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells.

Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8(+) T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141(hi) DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c(+) and CD14(+) tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141(hi) DCs were closely related to blood CD141(+) DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.

Glucocorticoid regulation of SLIT/ROBO tumour suppressor genes in the ovarian surface epithelium and ovarian cancer cells.

The three SLIT ligands and their four ROBO receptors have fundamental roles in mammalian development by promoting apoptosis and repulsing aberrant cell migration. SLITs and ROBOs have emerged as candidate tumour suppressor genes whose expression is inhibited in a variety of epithelial tumours. We demonstrated that their expression could be negatively regulated by cortisol in normal ovarian luteal cells. We hypothesised that after ovulation the locally produced cortisol would inhibit SLIT/ROBO expression in the ovarian surface epithelium (OSE) to facilitate its repair and that this regulatory pathway was still present, and could be manipulated, in ovarian epithelial cancer cells. Here we examined the expression and regulation of the SLIT/ROBO pathway in OSE, ovarian cancer epithelial cells and ovarian tumour cell lines. Basal SLIT2, SLIT3, ROBO1, ROBO2 and ROBO4 expression was lower in primary cultures of ovarian cancer epithelial cells when compared to normal OSE (P<0.05) and in poorly differentiated SKOV-3 cells compared to the more differentiated PEO-14 cells (P<0.05). Cortisol reduced the expression of certain SLITs and ROBOs in normal OSE and PEO-14 cells (P<0.05). Furthermore blocking SLIT/ROBO activity reduced apoptosis in both PEO-14 and SKOV-3 tumour cells (P<0.05). Interestingly SLIT/ROBO expression could be increased by reducing the expression of the glucocorticoid receptor using siRNA (P<0.05). Overall our findings indicate that in the post-ovulatory phase one role of cortisol may be to temporarily inhibit SLIT/ROBO expression to facilitate regeneration of the OSE. Therefore this pathway may be a target to develop strategies to manipulate the SLIT/ROBO system in ovarian cancer.

Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency.

The human syndrome of dendritic cell, monocyte, B and natural killer lymphoid deficiency presents as a sporadic or autosomal dominant trait causing susceptibility to mycobacterial and other infections, predisposition to myelodysplasia and leukemia, and, in some cases, pulmonary alveolar proteinosis. Seeking a genetic cause, we sequenced the exomes of 4 unrelated persons, 3 with sporadic disease, looking for novel, heterozygous, and probably deleterious variants. A number of genes harbored novel variants in person, but only one gene, GATA2, was mutated in all 4 persons. Each person harbored a different mutation, but all were predicted to be highly deleterious and to cause loss or mutation of the C-terminal zinc finger domain. Because GATA2 is the only common mutated gene in 4 unrelated persons, it is highly probable to be the cause of dendritic cell, monocyte, B, and natural killer lymphoid deficiency. This disorder therefore constitutes a new genetic form of heritable immunodeficiency and leukemic transformation.

The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency.

Congenital or acquired cellular deficiencies in humans have the potential to reveal much about normal hematopoiesis and immune function. We show that a recently described syndrome of monocytopenia, B and NK lymphoid deficiency additionally includes the near absence of dendritic cells. Four subjects showed severe depletion of the peripheral blood HLA-DR(+) lineage(-) compartment, with virtually no CD123(+) or CD11c(+) dendritic cells (DCs) and very few CD14(+) or CD16(+) monocytes. The only remaining HLA-DR(+) lineage(-) cells were circulating CD34(+) progenitor cells. Dermal CD14(+) and CD1a(+) DC were also absent, consistent with their dependence on blood-derived precursors. In contrast, epidermal Langerhans cells and tissue macrophages were largely preserved. Combined loss of peripheral DCs, monocytes, and B and NK lymphocytes was mirrored in the bone marrow by complete absence of multilymphoid progenitors and depletion of granulocyte-macrophage progenitors. Depletion of the HLA-DR(+) peripheral blood compartment was associated with elevated serum fms-like tyrosine kinase ligand and reduced circulating CD4(+)CD25(hi)FoxP3(+) T cells, supporting a role for DC in T reg cell homeostasis.