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The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

•Autoimmune hypoglycemia belongs to the clinical spectrum of HHV8+MCD and rituximab is an effective treatment of this condition.•This rare complication is related to autoantibodies directed toward the insulin receptor and activating the insulin signaling pathway.

Introduction

Congenital neutropenia (CN) are characterized by chronic neutropenia with frequent co-morbidities. Approximately 30 different entities have been described with various clinical phenotypes and genotypes (PMID: 28875503). As survival rates and life expectancy improve, fertility and pregnancies becomes a common issue. Only one study had addressed this question, reporting 38 pregnancies in women with idiopathic neutropenia (n=6) or CN (n=16) (PMID: 24997149 ).

ABSTRACTIn a recently published article we report the metagenomic analysis of human gut microbiomes evolved in the absence of immunoglobulin A (IgA). We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. While our study underlines a rather expected pathobiont expansion, we at the same time highlight a less expected depletion in some typically beneficial symbionts. We also show that IgM partially supply IgA deficiency, explaining the relatively mild clinical phenotype associated with the early steps of this condition. Microbiome studies in patients should consider potential issues such as cohort size, human genetic polymorphism and treatments. In this commentary, we discuss how such issues were taken into account in our own study.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), a life-threatening, virally induced B-cell lymphoproliferative disorder. HHV-8 is a B-lymphotropic γ-herpesvirus closely related to the Epstein-Barr virus (EBV). Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8–related diseases. We analyzed iNKT cells in both blood (n = 26) and spleen (n = 9) samples from 32 patients with HHV-8 MCD and compared them with patients with KS (n = 24) and healthy donors (n = 29). We determined that both circulating and splenic iNKT cell frequencies were markedly decreased in patients with HHV-8 MCD and were undetectable in 6 of them. Moreover, iNKT cells from patients with HHV-8 MCD displayed a proliferative defect after stimulation with α-galactosylceramide. These iNKT cell alterations were associated with an imbalance in B-cell subsets, including a significant decrease in memory B cells, particularly of marginal zone (MZ) B cells. Coculture experiments revealed that the decrease in iNKT cells contributed to the alterations in the B-cell subset distribution. These observations contribute to a better understanding of the complex interactions between HHV-8 and immune cells that cause HHV-8–related MCD.

L’histiocytose sinusale de Rosai–Dorfmanest une prolifération histiocytaire bénigne réalisant d’importantes masses ganglionnaires, le plus souvent cervicales. Les atteintes viscérales sont fréquentes. Le diagnostic est histologique : infiltration histiocytaire intrasinusale avec images d’empéripolèse. Les histiocytes ont un phénotype normal activé. Il s’agit vraisemblablement d’un groupe hétérogènede pathologies partageant des caractéristiques histologiques communes. Une association à des anomalies immunologiques ou des manifestations auto-immunes, le plus souvent à des cytopénies auto-immunes, est possible. Cette association est un facteur de mauvais pronostic. L’évolution est parfois spontanément favorable. Toutefois, le risque de compression lié aux importantes masses tumorales est important, surtout en cas d’atteinte rétro-orbitaire ou épidurale. L’abstention thérapeutique est souvent justifiée. Les indications thérapeutiques sont réservées aux formes directement menaçantes, aux formes progressives, ou devant la présence de facteurs de mauvais pronostic. Le traitement, lorsqu’il est indiqué, n’est pas codifié. Il comprend selon les cas chirurgie, corticoïdes, immunosuppresseur et/ou interféron alpha.

In 2014, the European Society for Immune Deficiencies (ESID) revised the common variable immunodeficiency (CVID) diagnosis criteria by incorporating new clinical and biological markers. The new definition appeared more restrictive but had not yet been evaluated in a large cohort of patients.

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+ αβ T lymphocytopenia with a concomitant expansion of CD4−CD8− double-negative (DN) αβ 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 αβ 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 αβ 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.

Specific impairment of expression and chemotactic function of CXCR4 in NK cells from patients with GATA2 deficiency. GATA2 deficiency—formerly described as MonoMAC syndrome; dendritic cells, monocytes, B cells, and natural killer cell deficiency; familial myelodysplastic syndrome/acute myeloid leukemia; or Emberger syndrome—encompasses a range of hematologic and nonhematologic anomalies, mainly characterized by monocytopenia, B lymphopenia, natural killer cell cytopenia, neutropenia, immunodeficiency, and a high risk of developing acute myeloid leukemia. Herein, we present 7 patients with GATA2 deficiency recruited into the French Severe Chronic Neutropenia Registry, which enrolls patients with all kinds of congenital neutropenia. We performed extended immunophenotyping of their whole blood lymphocyte populations, together with the analysis of their chemotactic responses. Lymphopenia was recorded for B and CD4+T cells in 6 patients. Although only 3 patients displayed natural killer cell cytopenia, the CD56brightnatural killer subpopulation was nearly absent in all 7 patients. Natural killer cells from 6 patients showed decreased CXCL12/CXCR4‐dependent chemotaxis, whereas other lymphocytes, and most significantly B lymphocytes, displayed enhanced CXCL12‐induced chemotaxis compared with healthy volunteers. Surface expression of CXCR4 was significantly diminished in the patients’ natural killer cells, although the total expression of the receptor was found to be equivalent to that of natural killer cells from healthy individual controls. Together, these data reveal that GATA2 deficiency is associated with impaired membrane expression and chemotactic dysfunctions of CXCR4. These dysfunctions may contribute to the physiopathology of this deficiency by affecting the normal distribution of lymphocytes and thus potentially affecting the susceptibility of patients to associated infections.

Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Renard:Jazz Pharmaceuticals: Research Funding. Tournilhac:ABBVIE: Consultancy, Honoraria, Other: Travle grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant.

Haioun: Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Roche: Honoraria; Servier: Honoraria; Miltenyi: Honoraria. Mahevas:GSK: Research Funding. Michel:Rigel: Consultancy; Bioverativ: Consultancy; Alexion Pharmaceuticals: Consultancy. Godeau:Novartis: Honoraria; Amgen: Honoraria; Amgen: Research Funding; LFB: Honoraria.

Hermine: Roche: Consultancy; Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Novartis: Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. cohen Beaussant:X4 Pharmaceuticals, Inc.: Current Employment.

Background:Adult immune thrombocytopenia (ITP) is a rare autoimmune disease that can affect women of childbearing age. The effect of pregnancy on women with a pregestational diagnosis of ITP is still unclear and has never been prospectively studied. Objective:Investigate the effect of pregnancy on the course of ITP. Methods:We conducted a nationwide prospective multicenter observational case-control study (ClinicalTrials.gov NCT02892630). Thirty-three centers from the French ITP reference center network participated in the study. Over a two years period, we enrolled 131 pregnant women with a pregestational diagnosis of ITP and 131 non pregnant women of childbearing age with ITP who served as controls. Matching criteria included: history of splenectomy, disease status (defined as non-responder, responder or complete responder depending on platelet count and the need of treatment modification in the last 2 months) and ITP duration (i.e; persistent (<1 year) or chronic). Cases and controls were followed up for 15 months and platelets counts, hemorrhagic complications and treatment initiation or intensification for ITP were recorded. We defined ITP worsening by a combined score including the occurrence of bleeding and/or occurrence of severe thrombocytopenia (i.e. < 30 G/L) and/or changes in ITP disease status. Results:ITP worsening was significantly increased in pregnant women with ITP when compared to matched controls, affecting respectively 52.7% versus 38.2% (p= 0.05) of patients (figure 1). It occurred mainly during the second and third trimesters. However, the frequency of severe thrombocytopenia (28.2% vs 25.2%, p= 0.69) and incidence of bleeding (22.9% vs 15.3%, p= 0.15) were similar in both groups, even when considering severe bleeding only (Khellaf’s bleeding score >7) (16% vs 9.2%, p= 0.11).In contrast, initiation and intensification of therapy were significantly increased in pregnant women compared to matched controls, respectively 32.1% versus 20.6% (p= 0.01) of patients. Importantly, this increased need for therapy did not lead to an increase in maternal and obstetrical complications. In particular, we found no increase of complications that could have been exacerbated by corticosteroid and intravenous immunoglobulins use such as gestational diabetes or high blood pressure. Also compared to pre-gestational period, at 6 months post-partum, only 16.8% of pregnant women showed disease worsening. This frequency was comparable in the control group after 15 months follow-up (16.8%, p= 0.57). Conclusion:The current guidelines on therapy for pregnant women with pregestational ITP are mostly based on expert opinions and retrospective studies that mainly recommend treatment for pregnant women with a platelet count < 30 x 109/L. This prospective observational study investigating ITP progression during pregnancy shows that women with ITP were more intensively treated during pregnancy compared with matched controls. Paradoxically, this does not coincide with an increased of clinical or biological worsening in pregnant womenwhich raises questions of the relevance of this therapeutic conduct although we cannot exclude that these therapies may have prevented disease progression during pregnancy. Finally in late post-partum period, disease worsening was low and seems to be link to the natural course of the disease.

Introduction:Hematological complications (HC) as Aplastic anemia (AA) and myelodysplasia and acute leukemia (MDS/AL) are frequent and life threatening in patients with Shwachman Diamond Syndrome (SDS) with SBDSmutations. The therapy of such events is based on Hematopoetic stem cell transplantation (HSCT), which results remain quite poor, especially in case of malignancy. So far, it is difficult to anticipate to such HC and a lot is expected from the study of clonal evolution prior HC.

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6–dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96 of the patients), memory B-cell lymphopenia (94.5), and hypereosinophilia (80). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus(all patients) and Candida albicans(85). Up to 90 of the patients had pneumonia, mostly caused by Staph. aureus(31) or Streptococcus pneumoniae(30). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67), as well as secondary aspergillosis (22). Up to 92 of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95), retention of decidual teeth (65), osteopenia (50), and hyperextensibility (50). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90 of patients), antifungal prophylaxis (50), and IgG infusions (53) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

HIV-associated multicentric Castleman disease (MCD) is associated with a high risk of developing nonHodgkin lymphoma (NHL). Rituximab is effective in HIV-MCD, but its impact on NHL incidence remains unknown. From a single-center prospective cohort, 113 patients were identified with a diagnosis of HIV-MCD for the present study. To compare the incidence of NHL between patients who had received a rituximab-based treatment (R+ group) and those who had not (R− group), data were analyzed before and after matching on propensity scores and after multiple imputation. The mean follow-up was 4.2 years. In the R− group (n = 65), 17 patients developed NHL (incidence, 69.6 of 1000 person years). In the R+ group (n = 48), only 1 patient developed NHL (incidence, 4.2 of 1000 person years). Based on the propensity score-matching method, a significant decrease in the incidence of NHL was observed in patients who had been treated with rituximab (hazard ratio, 0.09; 95% confidence interval, 0.01-0.70). Ten Kaposi sarcoma (KS) exacerbations and 1 newly diagnosed KS were observed in 9 patients after rituximab therapy. Rituximab was associated with an 11-fold lower risk of developing lymphoma. KS exacerbation was the most challenging adverse event after rituximab therapy.

An outbreak of rectal lymphogranuloma venereum (LGV) has been reported since 2003 in men who have sex with men, most of them being infected with human immunodeficiency virus. In these patients, unusual clinical presentations such as rectal tumor or intense lymphoproliferation on rectal biopsies may lead to an erroneous diagnosis of aggressive non-Hodgkin lymphoma. Three patients were referred to our center for the management of rectal B-cell non-Hodgkin lymphoma on the basis of a rectal pathologic specimen showing intense lymphoproliferation, the very suspect of lymphoma. Because of anamnesis of anal intercourses and venereal diseases, additional study revealed that all 3 had a positive Chlamydia trachomatispolymerase chain reaction on the rectal biopsy specimen. Rectal LGV was therefore considered and successfully treated with antibiotics. We propose that all patients presenting with a suspected rectal lymphoma should have a careful anamnesis of sexual behavior and a specific detection of C. trachomatisusing polymerase chain reaction analysis on biopsy specimen to rule out the possibility of rectal LGV.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRαβ+ CD4−CD8− T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRαβ+CD4−CD8−T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FASexhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FASmutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.

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.

The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.

Natural killer (NK) cells have been originally defined by their “naturally occurring” effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-γ (IFN-γ) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rβ1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-γ production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rβ1– and IL-12p40–deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56+ effector memory T cells. The susceptibility of IL-12/23 axis–deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56+ T cells in the control of these infections in humans.

Natural killer (NK) cells have been originally defined by their “naturally occurring” effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-γ (IFN-γ) and for their cytotoxic response. In patients with IL12RB1mutations that lead to a complete IL-12Rβ1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-γ production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rβ1– and IL-12p40–deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56+effector memory T cells. The susceptibility of IL-12/23 axis–deficient patients to Mycobacteriumand Salmonellainfections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56+T cells in the control of these infections in humans.

The fact that you can vaccinate a child at 5 years of age and find lymphoid B cells and antibodies specific for this vaccination 70 years later remains an immunologic enigma. It has never been determined how these long-lived memory B cells are maintained and whether they are protected by storage in a special niche. We report that, whereas blood and spleen compartments present similar frequencies of IgG+ cells, antismallpox memory B cells are specifically enriched in the spleen where they account for 0.24% of all IgG+ cells (ie, 10-20 million cells) more than 30 years after vaccination. They represent, in contrast, only 0.07% of circulating IgG+ B cells in blood (ie, 50-100 000 cells). An analysis of patients either splenectomized or rituximab-treated confirmed that the spleen is a major reservoir for long-lived memory B cells. No significant correlation was observed between the abundance of these cells in blood and serum titers of antivaccinia virus antibodies in this study, including in the contrasted cases of B cell– depleting treatments. Altogether, these data provide evidence that in humans, the two arms of B-cell memory—long-lived memory B cells and plasma cells—have specific anatomic distributions—spleen and bone marrow—and homeostatic regulation.

Prognosis of acquired immunodeficiency syndrome (AIDS)–related non-Hodgkin lymphoma has improved since the introduction of highly active antiretroviral therapy. Burkitt lymphomas (BLs) still have poor outcome in patients with bone marrow (BM) or central nervous system (CNS) involvement when treated with standard-dose chemotherapy. We have prospectively evaluated the LMB86 regimen in 63 human immunodeficiency virus (HIV)–infected patients with stage IV (BM and/or CNS involvement) BL consecutively recruited between November 1992 and January 2006. At BL diagnosis, the median CD4 cell count was 239 × 106/L (range, 16-1188 × 106/L). BM and CNS involvement were present in 55 (80%) and 48 (76%) patients, respectively. Forty-four patients (70%) achieved complete response. Seven treatment-related deaths occurred and all patients experienced severe BM toxicity. With a median follow-up of 66 months (range, 6-165 months), 11 patients relapsed. The estimate 2-year overall survival and disease-free survival were 47.1% (95% CI, 34-59.1) and 67.8% (95% CI, 51-80), respectively. We identified 2 poor prognosis factors: low CD4 count and ECOG more than 2. Patients with 0 or 1 factor had good outcome (2-year survival: 60%) contrasting with patients with 2 factors (2-year survival: 12%). We conclude that LMB86 regimen is highly effective in advanced HIV-related BL and should be proposed for patients with CD4 count higher than 200 × 106/L or ECOG of 2 or less.

Complete interleukin-12/interleukin-23 receptor β1 (IL-12Rβ1) deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial disease. The patients described to date lack IL-12Rβ1 at the surface of their natural killer (NK) and T cells due to IL12RB1 mutations, which either interrupt the open reading frame or disrupt protein folding. We describe a patient with a large in-frame deletion of 12165 nucleotides (nt) in IL12RB1, encompassing exons 8 to 13 and resulting in the surface expression of nonfunctional IL-12Rβ1. These 6 exons encode the proximal NH2-terminal half of the extracellular domain downstream from the cytokine-binding domain. Five of 6 monoclonal anti-IL-12Rβ1 antibodies tested recognized the internally truncated chain on the cell surface. However, IL-12 and IL-23 did not bind normally to the patient's IL-12Rβ1-containing respective heterodimeric receptors. As a result, signal transducer and activator of transcription-4 (STAT4) was not phosphorylated and interferon-γ (IFN-γ) production was not induced in the patient's cells upon stimulation with even high doses of IL-12 or IL-23. The functional defect was completely rescued by retrovirus-mediated IL-12Rβ1 gene transfer. Thus, the detection of IL-12Rβ1 on the cell surface does not exclude the possibility of complete IL-12Rβ1 deficiency in patients with mycobacteriosis or salmonellosis. Paradoxically, the largest IL12RB1 mutation detected is associated with the cell surface expression of nonfunctional IL-12Rβ1, defining a novel genetic form of IL-12Rβ1 deficiency. (Blood. 2004;104:2095-2101)

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.

To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-dominant recurrent fever, also known as tumor necrosis factor receptor (TNFR)–associated periodic syndrome (TRAPS), in a French family and to investigate the role of the mutated 55-kd tumor necrosis factor α (TNFα) receptor (TNFR1) in the pathogenesis of the disease. The coding region of TNFR1 was sequenced in 2 individuals with TRAPS (the propositus and her grandfather) and in 3 clinically unaffected relatives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the family members carrying a C30S mutation in TNFR1, and was compared with the levels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The membrane TNFR1 expression was then compared with membrane TNFR2 levels at the surface of peripheral blood mononuclear cells by flow cytometric analysis. The clinical heterogeneity in this French family was investigated by searching polymorphic variants in the TNFα promoter by DNA sequencing. Both the disease course and the clinical presentation in the propositus were highly indicative of TRAPS. MRI study of the segmental inflammatory process in the limbs showed abnormal signals in the muscle and subcutaneous tissue without involvement of adjacent joints or fascia. A novel missense mutation, C30S, in the first extracellular N-terminal cysteine-rich domain (CRD1) of TNFR1 was characterized in the propositus, her affected grandfather, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as the levels of sTNFR1 in serum when the disease was not active were not modified in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, during attacks, sTNFR1 levels remained abnormally low, as compared with the levels in unrelated patients with active adult-onset systemic Still's disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNFα promoter. TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disease. This mutation seems to affect the level of sTNFR1, which did not increase in the propositus during inflammatory attacks.

Two patients with T”B+NK+SCID were shown to have mutations in their IL7Rgenes. This discovery indicates that the defect in IL-7 signaling in XSCID and Jak3-deficient patients is probably responsible for their T-cell defect. Both patients had normal or increased numbers of functional NK cells, confirming that IL-7 is not essential for NK-cell development or function. Both patients had normal numbers of B cells, demonstrating that in humans, IL-7 signaling is not essential for B-cell development; instead other cytokines either are essential or serve a redundant function. The normal B-cell development in JL7R-deficient humans is in contrast to the defective B-cell development in Il7-/-and Il7r-/-mice, and suggests a major difference between humans and mice in B-cell development. As discussed previously, it is speculated that mutations in the IL7gene also may cause T-B+NK+SCID. This article has discussed the range of forms of SCID and has summarized that most patients with SCID have defects related to cytokine signaling (γcdeficiency, Jak3 deficiency, and TL-ZRα deficiency). In the future, it will be interesting to clarify the genetic basis for the remaining undiagnosed forms of SCID and to see how many of these further increase the understanding of cytokine signaling pathways in humans.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

In humans, several grams of IgA are secreted every day in the intestinal lumen. While only one IgA isotype exists in mice, humans secrete IgA1 and IgA2, whose respective relations with the microbiota remain elusive. We compared the binding patterns of both polyclonal IgA subclasses to commensals and glycan arrays and determined the reactivity profile of native human monoclonal IgA antibodies. While most commensals are dually targeted by IgA1 and IgA2 in the small intestine, IgA1+IgA2+ and IgA1−IgA2+ bacteria coexist in the colon lumen, where Bacteroidetes is preferentially targeted by IgA2. We also observed that galactose-α terminated glycans are almost exclusively recognized by IgA2. Although bearing signs of affinity maturation, gut-derived IgA monoclonal antibodies are cross-reactive in the sense that they bind to multiple bacterial targets. Private anticarbohydrate-binding patterns, observed at clonal level as well, could explain these apparently opposing features of IgA, being at the same time cross-reactive and selective in its interactions with the microbiota.

IgA influences bacterial fitness in the intestinal lumen and is only partially compensated for by IgM in selective IgA-deficient patients.

No relevant conflicts of interest to declare.

Context.Congenital neutropenia (CN) is a heterogeneous group of diseases characterized by low neutrophil count, severe bacterial infections, increased risk of leukemic transformation and various extra-hematopoietic organ dysfunctions. Even if 24 different genes have been linked to the etiology of CN, in many patients the genetic causes of CN remain unknown.