Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency.

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-ß and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.

JC Polyomavirus Whole Genome Sequencing at the Single-Molecule Level Reveals Emerging Neurotropic Populations in Progressive Multifocal Leukoencephalopathy.

BACKGROUND: JC polyomavirus (JCV) mostly causes asymptomatic persistent renal infections but may give rise in immunosuppressed patients to neurotropic variants that replicate in the brain, causing progressive multifocal leukoencephalopathy (PML). Rearrangements in the JCV genome regulator noncoding control region (NCCR) and missense mutations in the viral capsid VP1 gene differentiate neurotropic variants from virus excreted in urine. METHODS: To investigate intrahost emergence of JCV neurotropic populations in PML, we deep sequenced JCV whole genome recovered from cerebrospinal fluid (CSF) and urine samples from 32 human immunodeficiency virus (HIV)-infected and non-HIV-infected PML patients at the single-molecule level. RESULTS: JCV strains distributed among 6 of 7 known genotypes. Common patterns of NCCR rearrangements included an initial deletion mostly located in a short 10-nucleotide sequence, followed by duplications/insertions. Multiple NCCR variants present in individual CSF samples shared at least 1 rearrangement, suggesting they stemmed from a unique viral population. NCCR variants independently acquired single or double PML-specific adaptive VP1 mutations. NCCR variants recovered from urine and CSF displayed opposite deletion or duplication patterns in binding sites for transcription factors. CONCLUSIONS: Long-read deep sequencing shed light on emergence of neurotropic JCV populations in PML.

Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis.

Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G>C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-ß in the patients' fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively.

Genetic, Immunological, and Clinical Features of 32 Patients with Autosomal Recessive STAT1 Deficiency.

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.

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

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

Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.

Ambulatory anal self-sampling in MSM living with HIV, an acceptable and reliable screening method.

OBJECTIVES: Anal cancer, usually driven by an oncogenic Human Papillomavirus, remains a leading cause of morbidity in men who have sex with men (MSM) living with HIV, despite combined antiretroviral therapy. Various recommendations advocate to perform regular examination and proctologist-performed samples to anticipate this risk and treat locally before cancer occurrence, an efficient strategy which has the drawback of requiring the proctologist's availability. This study evaluates the acceptability, feasibility, and efficiency of self-performed samples to screen for HPV-infection and HPV-related anal dysplasia among MSM living with HIV followed in Hôtel-Dieu Hospital. METHODS: Between February 2015 and June 2015, MSM living with HIV and referred to the day-care hospital were offered to perform an anal self-sampling for cytologic and virologic evaluation. A self-sampling kit was provided, and a tutorial video was shown. A subset of participants had a proctology appointment after they did the self-sampling, and thus had a clinical examination and an anal swab sampling performed by the proctologist, using the same sampling material. RESULTS: Anal self-sampling was offered to 103 patients, and 100 accepted. Sixty-three samples were interpretable, of which 36 (57%) were normal and 27 (43%) showed abnormal results. Virologic analysis was performed for 60 (95%) interpretable samples: 50/60 (83%) of them were positive for HPV. Among HPV-carrier patients, 42/50 (84%) were infected with at least one HR-HPV. Twenty patients had a proctologist consultation. All clinician-performed samples were interpretable and 14 (70%) self-samples were interpretable. CONCLUSIONS: This study highlights the acceptable accuracy of self-sampling screening method among MSM living with HIV and try out its acceptability and feasibility as a secondary prevention device. Although it cannot replace a proctologist consultation for high risk patients, self-sampling should be studied further as one of the ways of screening for anal cancer among low-risk outpatients.

Usefulness of Plasma SARS-CoV-2 RNA Quantification by Droplet-based Digital PCR to Monitor Treatment Against COVID-19 in a B-cell Lymphoma Patient.

We report the case of an HIV-1-infected patient, treated with anti-CD20 monoclonal antibody for a B-cell lymphoma previously treated by autologous stem cell transplant. He suffered from chronic COVID19 and we monitored by plasma SARS-CoV-2 RNA by highly sensitive droplet-based digital PCR technology (ddPCR). Under tocilizumab therapy and despite a first clinical improvement biologically associated with decreasing inflammatory markers, a slight increase of SARS-CoV-2 RNAaemia quantified by ddPCR was highlighted, confirming the absence of viral efficacy of this treatment and predicting the subsequent observed deterioration. As expected, his complete recovery, finally achieved after COVID-19 convalescent plasmatherapy, strictly paralleled plasma SARS-CoV-2 RNA clearance. With these results, we confirmed the interest of SARS-CoV-2 RNAaemia monitoring by ddPCR in COVID-19 patients, particularly during treatment, and firstly showed that this new and specific biomarker could be helpful to select eligible patient for anti-IL6 receptors therapy considering the variable levels of efficacy recently observed with such therapy.

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-ß and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

Long-Term Immunity to Measles after Allogeneic Hematopoietic Cell Transplantation: Factors Associated with Seroprotection before Revaccination.

Measles can be a life-threatening infection in immunocompromised patients, especially after allogeneic hematopoietic cell transplantation (HCT) because of the corresponding loss of immunity. However, measles vaccines are live-attenuated, which is why measles vaccinations are recommended only in seronegative HCT recipients and in specific conditions. However, little data exist on the rates of seroprotection to measles with the current conditioning regimens and in long-term follow-up. The objectives of this study were to assess measles immunity before considering vaccination in a cohort of allogeneic HCT long-term survivors and to identify the factors associated with seropositivity/seroprotection. One hundred and twenty-six patients who underwent transplantation between 1 and 39 years earlier (median, 9 years) were assessed for measles immunity. Measles IgG titers were determined with an automated chemiluminescent immunoassay. Seropositivity/seroprotection was defined by an IgG titer >16.5 UA/mL. Patients underwent transplantation with a reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning in 46% of cases, mainly for acute leukemia (61%). Seventy-eight of the 126 patients (62%) were seropositive/seroprotected for measles. Among the seropositive patients, the patients who had been vaccinated before transplantation had a lower median IgG titer compared with those who had not (48 UA/mL versus 116 UA/mL). Myeloproliferative disorder, RIC or NMA conditioning, and absence of acute grade ≥II graft-versus-host disease were associated with seropositivity/seroprotection. With a 62% rate of seropositivity/seroprotection for measles at a median of 9 years after transplantation, our findings strongly support a systematic assessment of anti-measles antibody titers to avoid unnecessary vaccination in seroprotected patients.

Predictive Factors of Intraocular Pressure Level Evolution Over Time and Glaucoma Severity in Fuchs' Heterochromic Iridocyclitis.

Purpose: To investigate the clinical and virologic-associated and predictive factors of intraocular pressure (IOP) evolution over time and its severity in Fuchs' heterochromic iridocyclitis (FHC). Methods: Consecutive patients with both clinical FHC and intraocular synthesis of rubella virus (RV)-specific antibodies were included in this study. Specific ocular production of RV antibodies was confirmed using the quotient of serum/aqueous humor ratio of RV IgGs (Crv) and control antiviral IgGs (Cctl), using quantitative serology methods. Epidemiologic, clinical, biological, and virologic data at referral were collected and correlated with IOP values over time, occurrence, and severity of glaucoma. Results: Sixty-eight eyes of 68 patients were included. Mean age at diagnosis was 40.7 ± 11.1 years. Mean follow-up was 4.3 ± 4.3 years. Mean baseline Crv and Cctl values were 12.34 ± 14.67 and 216.70 ± 98.4, respectively. Mean baseline IOP was 17.2 ± 7.2 mm Hg (range, 9-40) and 15.6 ± 5.6 (range, 3-30) 5 years after referral. The predictive factors for pejorative IOP evolution over time and glaucoma severity were male sex (P = 0.03) and decreased Crv (P = 0.04) and presence of iris nodules (P < 0.001) and decreased Cctl (P = 0.02), respectively. Diagnostic delay was associated with increased likelihood of undergoing glaucoma surgery (P = 0.02). Conclusions: Time to diagnosis, male sex, presence of iris nodules at baseline, and decreased Crv and Cctl ratios were associated with increased likelihood of pejorative IOP evolution over time. Given the aggressiveness of glaucoma in FHC, these results provide interesting insight into what category of patients should need the closest screening.

Severe influenza pneumonitis in children with inherited TLR3 deficiency.

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-ß and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

Progressive Multifocal Leukoencephalopathy in Primary Immunodeficiencies.

PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the polyomavirus JC (JCV) in immunocompromised patients. We report a series of patients with primary immune deficiencies (PIDs) who developed PML. METHODS: Retrospective observational study including PID patients with PML. Clinical, immunological, imaging features, and outcome are provided for each patient. RESULTS: Eleven unrelated patients with PIDs developed PML. PIDs were characterized by a wide range of syndromic or genetically defined defects, mostly with combined B and T cell impairment. Genetic diagnosis was made in 7 patients. Before the development of PML, 10 patients had recurrent infections, 7 had autoimmune and/or inflammatory manifestations, and 3 had a history of malignancies. Immunologic investigations showed CD4+ lymphopenia (median 265, range 50-344) in all cases. Six patients received immunosuppressive therapy in the year before PML onset, including prolonged steroid therapy in 3 cases, rituximab in 5 cases, anti-TNF-α therapy, and azathioprine in 1 case each. Despite various treatments, all but 1 patient died after a median of 8 months following PML diagnosis. CONCLUSION: PML is a rare but fatal complication of PIDs. Many cases are secondary to immunosuppressive therapy warranting careful evaluation before initiation subsequent immunosuppression during PIDs.

Cytomegalovirus Anterior Uveitis: Clinical Characteristics and Long-term Outcomes in a French Series.

PURPOSE: To report the characteristics of cytomegalovirus anterior uveitis (CMV AU) and the comparative response to 2 types of antiviral induction treatments. DESIGN: Retrospective, consecutive case series. METHODS: Consecutive immunocompetent patients with polymerase chain reaction-positive CMV AU were included. For each patient, best-corrected visual acuity (BCVA), intraocular pressure (IOP), clinical characteristics at baseline and latest visit, and number of relapses were recorded. All patients received an induction dose of intravenous (IV) ganciclovir or oral valganciclovir and a maintenance dose of oral valganciclovir. RESULTS: Thirty-six eyes of 35 patients were included. Mean age at diagnosis was 55.5 years. Mean follow-up was 4.13 years. Posner-Schlossman and chronic nonspecific AU were observed in 69.4% and 30.6% of cases, respectively. We did not observe any case of Fuchs uveitis or endotheliitis. At baseline, mean BCVA was 20/25 and mean IOP was 29.19 mm Hg. Keratic precipitates and iris atrophy were seen in 91.4% and 25.7% of cases. Induction therapy consisted of oral valganciclovir and IV ganciclovir in 40% and 60% of cases. A total of 94.2% of patients responded to the first line of therapy. Recurrence was reported in 73.5% of cases. Glaucoma surgery was necessary in 25.7% of cases. Early initiation of antiviral therapy (≤700 days) seemed to decrease the recourse to glaucoma surgery. Both IV and oral induction treatments seemed similar in terms of BCVA changes and occurrence of relapses. CONCLUSIONS: Characteristics of CMV AU seem to show specificities in this French cohort. Early initiation of antiviral therapy seems to reduce the severity of glaucoma.

Exploring the role of NCCR variation on JC polyomavirus expression from dual reporter minicircles.

JC virus (JCV), a ubiquitous human polyomavirus, can cause fatal progressive multifocal leukoencephalopathy (PML) in immune compromised patients. The viral genome is composed of two conserved coding regions separated by a highly variable non-coding control region (NCCR). We analyzed the NCCR sequence from 10 PML JCV strains and found new mutations. Remarkably, the NCCR f section was mutated in most cases. We therefore explored the importance of this section in JCV expression in renal (HEK293H) and glioblastoma (U-87MG) cell lines, by adapting the emerging technology of DNA minicircles. Using bidirectional fluorescent reporters, we revealed that impaired NCCR-driven late expression in glioblastoma cells was restored by a short deletion overlapping e and f sections. This study evidenced a relevant link between JCV NCCR polymorphism and cell-type dependent expression. The use of DNA minicircles opens new insights for monitoring the impact of NCCR variation.

Chronic Herpetic Retinitis: Clinical Features and Long-Term Outcomes.

INTRODUCTION: Chronic uveitis treated with immunosuppressive agents may have unfavorable outcomes due to delays in diagnosis. The aim of this study was to review initial data from clinical and ocular assessments and patient outcomes following specific treatments for atypical herpes virus ocular infections. METHODS: The records of four consecutive patients with recurrent uveitis for at least five years treated in our department between 2001 and 2016 were retrospectively reviewed. They had atrophic retinal lesions resulting in an unfavorable outcome with lesion progression and vision loss under immunosuppressive treatment. Varicella zoster virus (1 case) and herpes simplex virus type 2 (3 cases) were detected in ocular samples. RESULTS: Uveitis was granulomatous and bilateral (3 cases) or unilateral (1 case). Immunosuppressive treatments worsened the clinical situation whereas antiherpetic treatments improved the control of intraocular inflammation. CONCLUSION: This description should be added to the broad repertoire of clinical polymorphisms associated with herpes virus infections. Recognizing these cases should be useful due to their sensitivity to antiherpetic treatments.

JC polyomavirus, progressive multifocal leukoencephalopathy.

JC virus (JCV) is an ubiquitous human polyomavirus which causes persistent infections. The biological cycle of JCV in its host is incompletely known. Most infected individuals remain asymptomatic lifelong despite occasional viral urinary shedding. In some cases of immune depression, JCV may reactivate, gain access to the central nervous system, infect and harm glial cells involved in myelin production, leading to a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML). PML cases have recently increased in patients receiving monoclonal antibody therapies - in particular multiple sclerosis patients treated with natalizumab - raising a new interest in the pathophysiology of JCV infection. The tropism of JCV for glial cells has been associated with various mutations and rearrangements in the non-coding control region (NCCR) of JCV genome, a regulator of viral expression. Several hypotheses have taken into account this hypervariability to explain the pathogenesis of JCV infection.

Immunogenicity and Safety of Influenza Vaccine in Inflammatory Bowel Disease Patients Treated or not with Immunomodulators and/or Biologics: A Two-year Prospective Study.

BACKGROUND AND AIMS: Data on the efficacy and safety of seasonal influenza vaccines in patients with inflammatory bowel disease (IBD) remain scarce. The aim of the study was to evaluate the impact of immunosuppressive (IS) therapeutics on serological response to 2-year influenza vaccination in IBD adults. METHODS: A multicentre prospective study performed in 255 IBD adults (18-64 years) receiving the trivalent influenza vaccine in the years 2009-2010 and 2010-2011. Haemagglutination inhibition (HI) titres were assessed before and 3 weeks and 6 months after vaccination. RESULTS: At inclusion, 31 patients were receiving no IS treatment (Group A), 77 were receiving IS treatment without anti-TNF (Group B) and 117 were receiving anti-tumour necrosis factor (TNF) treatment with or without IS treatment (Group C). Three weeks after the first vaccination, rates of seroprotection were 77, 75 and 66% for strain A/H1N12007 (p = 0.35), 77, 68 and 52% for strain A/H3N2 (p = 0.014) and 97, 96 and 95% for strain B (p = 0.99) in Groups A, B and C, respectively. Seroconversion rates for A/H1N12007 (67, 64 and 54%; p = 0.28), A/H3N2 (63, 50 and 41%; p = 0.074) and strain B (63, 76 and 60%; p = 0.078) were not significantly different among treatment groups. At 6 months after vaccination, seroprotection rates were lower in Group C compared with Groups A and B. Comparable results were observed for the second year of vaccination. No impact on Harvey-Bradshaw and Mayo scores was detected. CONCLUSIONS: Influenza vaccine yielded high seroprotection rates in IBD patients. Persistence of seroprotection was lower in patients with anti-TNF treatment. ClinicalTrials.gov, number NCT01022749.

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).