FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice.

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Modulation of bone marrow and peripheral blood cytokine levels by age and clonal hematopoiesis in healthy individuals.

Aging is associated with bone marrow (BM) inflammaging and, in some individuals, with the onset of clonal hematopoiesis (CH) of indeterminate potential. In this study conducted on 94 strictly healthy volunteers (18 to 80 yo), we measured BM and peripheral blood (PB) plasma levels of 49 hematopoietic and inflammatory cytokines. With aging, 7 cytokines increased in BM (FLT3L, CXCL9, HGF, FGF-2, CCL27, IL-16, IL-18) and 8 decreased (G-CSF, TNF, IL-2, IL-15, IL-17A, CCL7, IL-4, IL-10). In PB, 10 cytokines increased with age (CXCL9, FLT3L, CCL27, CXCL10, HGF, CCL11, IL-16, IL-6, IL-1 beta, CCL2). CH was associated with higher BM levels of MIF and IL-1 beta, lower BM levels of IL-9 and IL-5 and higher PB levels of IL-15, VEGF-A, IL-2, CXCL8, CXCL1 and G-CSF. These reference values provide a useful tool to investigate anomalies related to inflammaging and potentially leading to the onset of age-related myeloid malignancies or inflammatory conditions.

Prognostic impact of early minimal residual disease combined with complete molecular evaluation in acute myeloid leukemia with mutated NPM1: a single center study.

We evaluated prognostic factors in 83 intensively treated adult patients with NPM1 mutated AML. Targeted next-generation sequencing revealed high frequency of co-mutations in epigenetic modifiers or proliferation pathways. NPM1 minimal residual disease (MRD), assessed in bone marrow by specific polymerase chain reaction after one chemotherapy course, was >0.01% in 50 patients considered poor responders (PR). On multivariate analysis, including all variables with a p value <.1 on univariate analysis, age >60, performance status (PS) ≥1, presence of FLT3 mutations, DNMT3A-R882, and PR status, were independently associated with lower leukemia-free survival. Age >60, a previous hematological disease and PR status were independent negative predictive factors for overall survival. In our study, early NPM1 MRD was confirmed as an important prognostic factor. All FLT3 and DNMT3A-R882 mutations have also an independent prognostic value. We support the rational for in-depth investigations for a better approach in patients who achieving a first complete remission.

Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms.

The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

High prevalence of clonal hematopoiesis in the blood and bone marrow of healthy volunteers.

Clonal hematopoiesis (CH) of indeterminate potential has been described in blood samples from large series of patients. Its prevalence and consequences are still not well understood because sequencing methods vary and because most studies were performed in cohorts comprising individuals with nonhematologic diseases. Here, we investigated the frequency of CH in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers. Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. In bone marrow samples, clones were found in almost 40% of healthy volunteers more than 50 years old. The most frequent mutations were found in DNMT3A and TET2, with 1 individual carrying 3 variants. Variant allele frequencies were highly concordant between blood and bone marrow samples. Blood parameters were normal except for those in 2 individuals: 1 had a mild macrocytosis and 1 had a mild thrombocytosis. Furthermore, no morphologic abnormalities or dysplasia were detected when bone marrow smears were carefully evaluated. Individuals with CH differed from others by age (62.8 vs 38.6 years; P < .0001) and platelet count (294 vs 241 ×109/L; P = .0208), the latter being no more significant when removing the 2 individuals who carried the JAK2 p.V617F mutation. These results confirm that CH is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or the bone marrow.

Clonal haematopoiesis is increased in early onset in systemic sclerosis.

OBJECTIVES: SSc is an autoimmune disease characterized by fibrosis, microangiopathy and immune dysfunctions including dysregulation of proinflammatory cytokines. Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations in haematopoietic stem cells leading to detectable clones in the blood. Recent data have shown a higher risk of cardiovascular disease in patients with CHIP resulting from increased production of proinflammatory cytokines and accelerated atherosclerosis. Eventual links between CHIP and autoimmune diseases are undetermined. The aim of our study was to evaluate the prevalence of CHIP in SSc patients and its association with clinical phenotype. METHODS: Forty-one genes frequently mutated in myeloid malignancies were sequenced in peripheral blood mononuclear cells from 90 SSc patients and 44 healthy donors. RESULTS: A total of 15 somatic variants were detected in 13/90 SSc patients (14%) and four somatic variants in 4/44 (9%) healthy donors (HD) (P = 0.58). The prevalence of CHIP was significantly higher in younger SSc patients than in HD: 25% (6/24) vs 4% (1/26) (P = 0.045) under 50 years and 17% (7/42) vs 3% (1/38) (P = 0.065) under 60 years. The prevalence of CHIP in patients over 70 years was similar in SSc patients and healthy donors. The most common mutations occurred in DNMT3A (seven variants). No major clinical differences were observed between SSc patients with or without CHIP. CONCLUSION: Whether CHIP increases the risk to develop SSc or is a consequence of a SSc-derived modified bone marrow micro-environment remains to be explored.

A novel variant in the neutrophil cytosolic factor 2 (NCF2) gene results in severe disseminated BCG infectious disease: A clinical report and literature review.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder (PID) affecting NADPH oxidase activity. The rarest form of the disease is considered to be caused by NCF2 gene bi-allelic variant. Here, we report the clinical and molecular characterization of a patient presenting with early-onset severe disease due to bi-allelic NCF2 variant. METHODS: Gene mutational analysis was performed by whole-exome and Sanger sequencing. RESULTS: The patient presented with a history of fever and rash since the age of 1 month, followed by destructive osteomyelitis and necrotizing lymphadenopathy. The patient received the Bacillus Calmette-Guérin (BCG) vaccine at birth; she was subsequently diagnosed with disseminated BCG infection. Whole-exome sequencing identified a private (unreported) homozygous variant in NCF2 (c.290C > A) that results in a nonconservative change, p.Ala97Asp, in the p67phox protein. The variant is located in the third helix of the TRP domain, which is crucial for the binding of GTPase RAC2 to the NADPH oxidase complex. CONCLUSION: We identified a novel NCF2 variant located in the region interacting with RAC2 that is linked to a severe and early CGD phenotype in the setting of disseminated BCG infection. Our findings support postponing BCG vaccination until 6-12 months of age and after PID assessment.

Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

Skewed X-inactivation in a Female Carrier with X-linked Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocytic NADPH oxidase, causing a complete lack or significant decrease in the production of microbicidal reactive oxygen metabolites. It mainly affects male children; however, there are scarce reports of adult females diagnosed with X-linked-CGD attributed to an extremely skewed X-chromosome inactivation. This condition is characterized by severe and recurrent infections that usually develop after childhood. In clinical practice, physicians who usually confront these patients should suspect this entity and differentiate it from a secondary immunodeficiency. Here, we report a 38-year-old Mexican female with juvenile-onset X linked-CGD, caused by a de novo mutation and extremely skewed X-inactivation, whose clinical features were similar to those in patients with classic X-linked-CDG.

IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis.

BACKGROUND: Inflammatory activation of CD8+ T cells can, when left unchecked, drive severe immunopathology. Hyperstimulation of CD8+ T cells through a broad set of triggering signals can precipitate hemophagocytic lymphohistiocytosis (HLH), a life-threatening systemic inflammatory disorder. OBJECTIVE: The mechanism linking CD8+ T-cell hyperactivation to pathology is controversial, with excessive production of IFN-γ and, more recently, excessive consumption of IL-2, which are proposed as competing hypotheses. We formally tested the proximal mechanistic events of each pathway in a mouse model of HLH. METHODS: In addition to reporting a complete autosomal recessive IFN-γ receptor 1-deficient patient with multiple aspects of HLH pathology, we used the mouse model of perforin (Prf1)KO mice infected with lymphocytic choriomeningitis virus to genetically eliminate either IFN-γ production or CD25 expression and assess the immunologic, hematologic, and physiologic disease measurement. RESULTS: We found a striking dichotomy between the mechanistic basis of the hematologic and inflammatory components of CD8+ T cell-mediated pathology. The hematologic features of HLH were completely dependent on IFN-γ production, with complete correction after loss of IFN-γ production without any role for CD8+ T cell-mediated IL-2 consumption. By contrast, the mechanistic contribution of the immunologic features was reversed, with no role for IFN-γ production but substantial correction after reduction of IL-2 consumption by hyperactivated CD8+ T cells. These results were complemented by the characterization of an IFN-γ receptor 1-deficient patients with HLH-like disease, in whom multiple aspects of HLH pathology were observed in the absence of IFN-γ signaling. CONCLUSION: These results synthesize the competing mechanistic models of HLH pathology into a dichotomous pathogenesis driven through discrete pathways. A holistic model provides a new paradigm for understanding HLH and, more broadly, the consequences of CD8+ T-cell hyperactivation, thereby paving the way for clinical intervention based on the features of HLH in individual patients.

Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

Microbial Disease Spectrum Linked to a Novel IL-12Rß1 N-Terminal Signal Peptide Stop-Gain Homozygous Mutation with Paradoxical Receptor Cell-Surface Expression.

Patients with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) exhibit variable vulnerability to infections by mycobacteria and other intramacrophagic bacteria (e.g., Salmonella and Klebsiella) and fungi (e.g., Histoplasma, Candida, Paracoccidioides, Coccidioides, and Cryptococcus). The hallmark of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or the lack of response to it. Mutations in the interleukin (IL)-12 receptor subunit beta 1 (IL12RB1) gene accounts for 38% of cases of MSMD. Most IL12RB1 pathogenic allele mutations, including ten known stop-gain variants, cause IL-12Rß1 complete deficiency (immunodeficiency-30, IMD30) by knocking out receptor cell-surface expression. IL12RB1 loss-of-function genotypes impair both IL-12 and IL-23 responses. Here, we assess the health effects of a rare, novel IL12RB1 stop-gain homozygous genotype with paradoxical IL-12Rß1 cell-surface expression. We appraise four MSMD children from three unrelated Brazilian kindreds by clinical consultation, medical records, and genetic and immunologic studies. The clinical spectrum narrowed down to Bacillus Calmette-Guerin (BCG) vaccine-related suppurative adenitis in all patients with one death, and recrudescence in two, histoplasmosis, and recurrence in one patient, extraintestinal salmonellosis in one child, and cutaneous vasculitis in another. In three patients, we established the homozygous Trp7Ter predicted loss-of-function inherited genotype and inferred it from the heterozygote parents of the fourth case. The Trp7Ter mutation maps to the predicted IL-12Rß1 N-terminal signal peptide sequence. BCG- or phytohemagglutinin-blasts from the three patients have reduced cell-surface expression of IL-12Rß1 with impaired production of IFN-γ and IL-17A. Screening of 227 unrelated healthy subjects from the same geographic region revealed one heterozygous genotype (allele frequency 0.0022) vs. one in over 841,883 public genome/exomes. We also show that the carriers bear European ancestry-informative alleles and share the extended CACCAGTCCGG IL12RB1 haplotype that occurs worldwide with a frequency of 8.4%. We conclude that the novel IL12RB1 N-terminal signal peptide stop-gain loss-of-function homozygous genotype confers IL-12Rß1 deficiency with varying severity and early-onset age through diminished cell-surface expression of an impaired IL-12Rß1 polypeptide. We firmly recommend attending to warning signs of IMD30 in children who are HIV-1 negative with a history of adverse effects to the BCG vaccine and presenting with recurrent Histoplasma spp. and extraintestinal Salmonella spp. infections.

Homeobox protein TLX3 activates miR-125b expression to promote T-cell acute lymphoblastic leukemia.

The oncogenic mechanisms driven by aberrantly expressed transcription factors in T-cell acute leukemia (T-ALL) are still elusive. MicroRNAs (miRNAs) play an important role in normal development and pathologies. Here, we examined the expression of 738 miRNA species in 41 newly diagnosed pediatric T-ALLs and in human thymus-derived cells. We found that expression of 2 clustered miRNAs, miR-125b/99a, peaks in primitive T cells and is upregulated in the T leukemia homeobox 3 (TLX3)-positive subtype of T-ALL. Using loss- and gain-of-function approaches, we established functional relationships between TLX3 and miR-125b. Both TLX3 and miR-125b support in vitro cell growth and in vivo invasiveness of T-ALL. Besides, ectopic expression of TLX3 or miR-125b in human hematopoietic progenitor cells enhances production of T-cell progenitors and favors their accumulation at immature stages of T-cell development resembling the differentiation arrest observed in TLX3 T-ALL. Ectopic miR-125b also remarkably accelerated leukemia in a xenograft model, suggesting that miR125b is an important mediator of the TLX3-mediated transformation program that takes place in immature T-cell progenitors. Mechanistically, TLX3-mediated activation of miR-125b may impact T-cell differentiation in part via repression of Ets1 and CBFß genes, 2 regulators of T-lineage. Finally, we established that TLX3 directly regulates miR-125b production through binding and transactivation of LINC00478, a long noncoding RNA gene, which is the host of miR-99a/Let-7c/miR-125b. Altogether, our results reveal an original functional link between TLX3 and oncogenic miR-125b in T-ALL development.

IL12Rß1 defect presenting with massive intra-abdominal lymphadenopathy due to Mycobacterium intracellulare infection.

Infections due to non-tuberculous mycobacteria species are problematic for immunodeficient individuals. Mendelian susceptibility to mycobacterial diseases (MSMD) defines a group of genetic defects affecting cellular interactions and the interferon (IFN)-γ pathway. Patients with MSMD may present with a disseminated infection resulting from the Bacillus Calmette-Guerin vaccine, Mycobacterium tuberculosis complex, environmental nontuberculous mycobacteria or Salmonella species. Atypical mycobacterial infections and deficient granuloma or giant cell formation are important indicators for MSMD, especially in patients with a family history of parental consanguineous marriage. Herein we report the case of a boy with an IL-12Rß1 defect who presented with massive intraabdominal lymphadenopathy due to Mycobacterium intracellulare infection. The patient was born to consanguineous parents, both heterozygous for the IL-12Rß1 defect mutation. Debulking surgery was planned in order to decrease the abdominal mass, but could not be performed due to a high risk of fatal outcomes. He has been receiving linezolid, levofloxacin, azithromycin, rifabutin and IFN-γ therapy for the past 14 months. At follow-up, the patient showed significant clinical improvement and weight gain.

Visceral leishmaniasis in two patients with IL-12p40 and IL-12Rß1 deficiencies.

Mutations of the IL12B and IL12RB1 genes underlie the development of IL-12 p40 and IL-12Rß1 deficiencies, respectively, both of which cause predisposition to infection with weakly virulent mycobacteria and Salmonella. Infections with other intramacrophagic organisms have only been rarely observed. We identified two patients with visceral leishmaniasis who had autosomal recessive IL-12 p40 and IL-12Rß1 deficiencies, respectively. This finding demonstrates the importance of IFN-γ immunity in the control of leishmaniasis. We also searched the literature for similar reports in patients with these and other primary immunodeficiencies.