Helper T cell immunity in humans with inherited CD4 deficiency.

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαß+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αß T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

Guiding Breathing at the Resonance Frequency with Haptic Sensors Potentiates Cardiac Coherence.

Cardiac coherence is a state achieved when one controls their breathing rate during the so-called resonance frequency breathing. This maneuver allows respiratory-driven vagal modulations of the heart rate to superimpose with sympathetic modulations occurring at 0.1 Hz, thereby maximizing autonomous power in heart-to-brain connections. These stimulations have been shown to improve vagal regulations, which results in obvious benefits for both mental and organic health. Here, we present a device that is able to deliver visual and haptic cues, as well as HRV biofeedback information to guide the user in maintaining a 0.1 Hz breathing frequency. We explored the effectiveness of cardiac coherence in three guidance conditions: visual, haptic and visuo-haptic breathing. Thirty-two healthy students (sixteen males) were divided into three groups that experienced five minutes of either visual, haptic and visuo-haptic guided breathing at 0.1 Hz. The effects of guidance on the (adequate) breathing pattern and heart rate variability (HRV) were analyzed. The interest of introducing haptic breathing to achieve cardiac coherence was shown in the haptic and visuo-haptic groups. Especially, the P0.1 index, which indicates how the autonomous power is 'concentrated' at 0.1 Hz in the PSD spectrum, demonstrated the superiority of combining haptic with visual sensory inputs in potentiating cardiac coherence (0.55 ± 0.20 for visuo-haptic vs. 0.28 ± 0.14 for visual only guidance; p < 0.05) haptic-induced effectiveness could be an asset for a more efficient and time-saving practice, allowing improved health and well-being even under tight time constraints.

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/ß-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/ß immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/ß-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/ß-dependent antiviral immunity.

Diagnostic and Therapeutic Management of Helicobacter pylori Infection in Primary Care: Perspective of Application in France and Narrative Review of the Literature.

BACKGROUND: Helicobacter pylori (Hp) infection affects 30% to 40% of people in industrialized countries. AIM: This study aimed to synthesize knowledge on the diagnostic and therapeutic management of Hp infection in general practice in people under 40 years of age. METHOD: A narrative review of the literature with an inductive content analysis of the articles was performed. RESULTS: The extracted data (22 articles out of 106 included after screening of 965 articles) determined three areas of analysis: indications for screening, methods of screening and diagnosis by non-invasive tests, and treatment modalities. DISCUSSION: Targeted, easily performed screening with noninvasive tests is recommended for patients younger than 45 years of age with no family history of gastric cancer and symptoms of dyspepsia without warning signs. Given their proximity to the general population and their coverage of the territory, general practitioners are ideally positioned. Treatment modalities are well-codified and feasible in primary care. Simplifying the recommendations available to them would optimize the identification of patients at risk and the management of Hp infection. Informing, educating, involving, supporting, and promoting the control of Hp infection in primary care will be future goals. Further research is needed in primary care to evaluate the impact of new procedures on Hp control.

The ups and downs of STAT3 function: too much, too little and human immune dysregulation.

The STAT3 story has almost 30 years of evolving history. First identified in 1994 as a pro-inflammatory transcription factor, Signal Transducer and Activator of Transcription 3 (STAT3) has continued to be revealed as a quintessential pleiotropic signalling module spanning fields including infectious diseases, autoimmunity, vaccine responses, metabolism, and malignancy. In 2007, germline heterozygous dominant-negative loss-of-function variants in STAT3 were discovered as the most common cause for a triad of eczematoid dermatitis with recurrent skin and pulmonary infections, first described in 1966. This finding established that STAT3 plays a critical non-redundant role in immunity against some pathogens, as well as in the connective tissue, dental and musculoskeletal systems. Several years later, in 2014, heterozygous activating gain of function germline STAT3 variants were found to be causal for cases of early-onset multiorgan autoimmunity, thereby underpinning the notion that STAT3 function needed to be regulated to maintain immune homeostasis. As we and others continue to interrogate biochemical and cellular perturbations due to inborn errors in STAT3, we will review our current understanding of STAT3 function, mechanisms of disease pathogenesis, and future directions in this dynamic field.

STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis.

BACKGROUND: Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown. OBJECTIVES: This study sought to delineate unique roles of STAT5 in activation and differentiation of human naive and memory B cells. METHODS: STAT activation was assessed by phospho-flow cytometry cell sorting. Differential gene expression was determined by RNA-sequencing and quantitative PCR. The requirement for STAT5B in B-cell and CD4+ T-cell differentiation was assessed using CRISPR-mediated STAT5B deletion from B-cell lines and investigating primary lymphocytes from individuals with germline STAT5B mutations. RESULTS: IL-21 activated STAT5 and strongly induced SOCS3 in human naive, but not memory, B cells. Deletion of STAT5B in B-cell lines diminished IL-21-mediated SOCS3 induction. PBMCs from STAT5B-null individuals contained expanded populations of immunoglobulin class-switched B cells, CD21loTbet+ B cells, and follicular T helper cells. IL-21 induced greater differentiation of STAT5B-deficient B cells into plasmablasts in vitro than B cells from healthy donors, correlating with higher expression levels of transcription factors promoting plasma cell formation. CONCLUSIONS: These findings reveal novel roles for STAT5B in regulating IL-21-induced human B-cell differentiation. This is achieved by inducing SOCS3 to attenuate IL-21 signaling, and BCL6 to repress class switching and plasma cell generation. Thus, STAT5B is critical for restraining IL-21-mediated B-cell differentiation. These findings provide insights into mechanisms underpinning B-cell responses during primary and subsequent antigen encounter and explain autoimmunity and dysfunctional humoral immunity in STAT5B deficiency.

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance.

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

Remote thermal detection of exfoliation sheet deformation.

A growing body of research indicates that rock slope failures, particularly from exfoliating cliffs, are promoted by rock deformations induced by daily temperature cycles. Although previous research has described how these deformations occur, full three-dimensional monitoring of both the deformations and the associated temperature changes has not yet been performed. Here we use integrated terrestrial laser scanning (TLS) and infrared thermography (IRT) techniques to monitor daily deformations of two granitic exfoliating cliffs in Yosemite National Park (CA, USA). At one cliff, we employed TLS and IRT in conjunction with in situ instrumentation to confirm previously documented behavior of an exfoliated rock sheet, which experiences daily closing and opening of the exfoliation fracture during rock cooling and heating, respectively, with a few hours delay from the minimum and maximum temperatures. The most deformed portion of the sheet coincides with the area where both the fracture aperture and the temperature variations are greatest. With the general deformation and temperature relations established, we then employed IRT at a second cliff, where we remotely detected and identified 11 exfoliation sheets that displayed those general thermal relations. TLS measurements then subsequently confirmed the deformation patterns of these sheets showing that sheets with larger apertures are more likely to display larger thermal-related deformations. Our high-frequency monitoring shows how coupled TLS and IRT allows for remote detection of thermally induced deformations and, importantly, how IRT could potentially be used on its own to identify partially detached exfoliation sheets capable of large-scale deformation. These results offer a new and efficient approach for investigating potential rockfall sources on exfoliating cliffs.

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.

Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity.

Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships among stem cells, progenitors, and mature cells, and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular, and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multilayered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular, and molecular phenotypes, and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B- or T-cells at different stages.

The three-stage rock failure dynamics of the Drus (Mont Blanc massif, France) since the June 2005 large event.

Since the end of the Little Ice Age, the west face of the Drus (Mont Blanc massif, France) has been affected by a retrogressive erosion dynamic marked by large rockfall events. From the 1950s onwards, the rock failure frequency gradually increased until the large rockfall event (292,680 m3) of June 2005, which made the Bonatti Pillar disappear. Aiming to characterize the rock failure activity following this major event, which may be related to permafrost warming, the granitic rock face was scanned each autumn between October 2005 and September 2016 using medium- and long-range terrestrial laser scanners. All the point clouds were successively compared to establish a rockfall source inventory and determine a volume-frequency relationship. Eleven years of monitoring revealed a phase of rock failure activity decay until September 2008, a destabilization phase between September 2008 and November 2011, and a new phase of rock failure activity decay from November 2011 to September 2016. The destabilization phase was marked by three major rockfall events covering a total volume of 61,494 m3, resulting in the progressive collapse of a new pillar located in the northern part of the June 2005 rockfall scar. In the same way as for the Bonatti Pillar, rock failure instability propagated upward with increasing volumes. In addition to these major events, 304 rockfall sources ranging from 0.002 to 476 m3 were detected between 2005 and 2016. The temporal evolution of rock failure activity reveals that after a major event, the number of rockfall sources and the eroded volume both follow a rapid decrease. The rock failure activity is characterized by an exponential decay during the period following the major event and by a power-law decay for the eroded volume. The power law describing the distribution of the source volumes detected between 2005 and 2016 indicates an exponent of 0.48 and an average rock failure activity larger of more than six events larger than 1 m3 per year. Over the 1905-2016 period, a total of 426,611 m3 of rock collapsed from the Drus west face, indicating a very high rock wall retreat rate of 14.4 mm year-1 over a surface of 266,700 m2. Averaged over a time window of 1000 years, the long-term retreat rate derived from the frequency density integration of rock failure volumes is 2.9 mm year-1. Despite difficulty in accessing and monitoring the site, our study demonstrates that long-term surveys of high-elevation rock faces are possible and provide valuable information that helps improve our understanding of landscape evolution in mountainous settings subject to permafrost warming.

Inherited human IFN-γ deficiency underlies mycobacterial disease.

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity due to mutations of 15 genes controlling the production of or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γ receptor 1 (IFN-γR1) and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del), causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss of expression and loss of function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes did not produce IFN-γ, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.

Detection of rock bridges by infrared thermal imaging and modeling.

Characterization of rock discontinuities and rock bridges is required to define stability conditions of fractured rock masses in both natural and engineered environments. Although remote sensing methods for mapping discontinuities have improved in recent years, remote detection of intact rock bridges on cliff faces remains challenging, with their existence typically confirmed only after failure. In steep exfoliating cliffs, such as El Capitan in Yosemite Valley (California, USA), rockfalls mainly occur along cliff-parallel exfoliation joints, with rock bridges playing a key role in the stability of partially detached exfoliation sheets. We employed infrared thermal imaging (i.e., thermography) as a new means of detecting intact rock bridges prior to failure. An infrared thermal panorama of El Capitan revealed cold thermal signatures for the surfaces of two granitic exfoliation sheets, consistent with the expectation that air circulation cools the back of the partially detached sheets. However, we also noted small areas of warm thermal anomalies on these same sheets, even during periods of nocturnal rock cooling. Rock attachment via rock bridges is the likely cause for the warm anomalies in the thermal data. 2-D model simulations of the thermal behavior of one of  the monitored sheets reproduce the observed anomalies and explain the temperature differences detected in the rock bridge area. Based on combined thermal and ground-based lidar imaging, and using geometric and rock fracture mechanics analysis, we are able to quantify the stability of both sheets. Our analysis demonstrates that thermography can remotely detect intact rock bridges and thereby greatly improve rockfall hazard assessment.

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

IRF4 haploinsufficiency in a family with Whipple's disease.

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

A purely quantitative form of partial recessive IFN-γR2 deficiency caused by mutations of the initiation or second codon.

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi-allelic mutations of IFNGR2 can underlie partial or complete forms of IFN-γ receptor 2 (IFN-γR2) deficiency. Patients with partial IFN-γR2 deficiency express a dysfunctional molecule on the cell surface. We studied three patients with MSMD from two unrelated kindreds from Turkey (P1, P2) and India (P3), by whole-exome sequencing. P1 and P2 are homozygous for a mutation of the initiation codon(c.1A>G) of IFNGR2, whereas P3 is homozygous for a mutation of the second codon (c.4delC). Overexpressed mutant alleles produce small amounts of full-length IFN-γR2 resulting in an impaired, but not abolished, response to IFN-γ. Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN-γ, and Epstein Barr virus-transformed B cells had a barely detectable response to IFN-γ. Studies in patients' primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN-γR2 protein of normal molecular weight and function is due to the initiation of translation between the second and ninth non-AUG codons. We thus describe mutations of the first and second codons of IFNGR2, which define a new form of partial recessive IFN-γR2 deficiency. Residual levels of IFN-γ signaling were very low, accounting for the more severe clinical phenotype of these patients with residual expression levels of normally functional surface receptors than of patients with partial recessive IFN-γR2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-γ signaling were higher.

Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.