Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency.

BACKGROUND: Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown. METHODS: We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models. RESULTS: We identified rare, X-linked germline mutations in DOCK11 in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated dock11-knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42. CONCLUSIONS: Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).

A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome.

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Expected impact of immunomodulatory agents during pregnancy: A newborn's perspective.

The neonatal immune ontogeny begins during pregnancy to ensure that the neonate is well-suited for perinatal life. It prioritizes Th2/M2 and regulatory responses over Th/M1 activity to avoid excessive inflammatory responses and to ensure immune tolerance and homeostasis. Newborns also present increased Th17/Th22 responses providing effective anti-fungal immunity and mucosal protection. Intrauterine exposure to immune modulatory drugs with the placental transfer may influence the natural course of the fetal immune development. The vertical transfer of both biological therapy and small molecules begins during the first trimester through neonatal Fc receptor or placental diffusion, respectively, reaching its maximum transfer potential during the third trimester of pregnancy. Most of the biological therapy have a prolonged half-life in newborn's blood, being detectable in infants up to 12 months after birth (usually 6-9 months). The use of immunomodulators during pregnancy is gaining global interest. Current evidence mainly reports birth-related outcomes without exhaustive analysis of the on-target side effect on the perinatal immune system ontogeny, the infection risk, or the immune dysregulation. The present review will focus on: (1) the main characteristics of the perinatal immune system to understand its specific features and vulnerabilities to immune modulation; (2) the mechanisms of placental transfer of immunomodulators; and (3) the immune changes reported to date in newborns exposed to immunomodulators with emphasis on the current concerns and gaps in knowledge.

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.

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature.

INTRODUCTION: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. METHODS: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. RESULTS: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. CONCLUSIONS: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

Impact of cytomegalovirus infection prior to hematopoietic stem cell transplantation in children with inborn errors of immunity.

The presence of active viral infections has an impact on the prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT). Nevertheless, the number of reports of cytomegalovirus infection in patients with inborn errors of immunity (IEI) who undergo HSCT is relatively low. To analyze the effect of cytomegalovirus infection acquired prior to curative treatment on patient survival in 123 children with IEI. An observational and retrospective study was performed with patients younger than 18 years diagnosed with IEI who were candidates for HSCT, gene therapy, or thymus transplantation at five hospitals in Spain between 2008 and 2019. We included 123 children, 25 infected by cytomegalovirus prior to undergoing curative treatment (20.3%). At IEI diagnosis, 24 of the patients were already infected, 21 of whom had symptomatic cytomegalovirus disease (87%), while the other three patients developed disease before undergoing curative treatment. The patients with cytomegalovirus infection had higher mortality than those without (p = 0.006). Fourteen patients developed refractory cytomegalovirus infection (56%), all of whom died, while no patients with non-refractory infection died (p = 0.001) All deaths that occurred before curative treatment and three of the five after the treatment were attributed to cytomegalovirus. Patients with refractory cytomegalovirus disease had the highest pre-HSCT mortality rate (64.3%), compared with the non-infected children and those with non-refractory cytomegalovirus disease (10.1%) (p < 0.0001). CONCLUSION: Prevention and prompt control of cytomegalovirus infection, together with early HSCT/gene therapy, are crucial for improving the prognosis in children with IEI. WHAT IS KNOWN: • Cytomegalovirus is the most frequent viral infection in children with inborn errors of immunity who are candidates to hematopoietic stem cell transplantation (HSCT). • Active viral infections at the time of HSCT lead to worse prognosis. WHAT IS NEW: • In children with inborn errors of immunity and indication of HSCT, refractory cytomegalovirus disease is associated with a very high mortality rate, compared with non-infected children and those with non-refractory cytomegalovirus disease. • In patients with novel transplantation indications, the presence and treatment response of CMV infection should be considered to decide the best possible moment for HSCT.

Novel PGM3 compound heterozygous variants with IgE-related dermatitis, lymphopenia, without syndromic features.

BACKGROUND: Phosphoglucomutase-3 (PGM3) deficiency is a congenital disorder of glycosylation (CDG) with hyperimmunoglobulin IgE, atopy, and a variable immunological phenotype; most reported patients display dysmorphic features. The aim of the study was to characterize the genotype and phenotype of individuals with newly identified compound heterozygous variants in the phosphate-binding domain of PGM3 in order to better understand phenotypic differences between these patients and published cases. METHODS: We analyzed PGM3 protein expression, PGM3 enzymatic activity, the presence of other gene variants within the N-glycosylation pathway, and the clinical and immunological manifestations of two affected siblings. RESULTS: Patients belonged to a non-consanguineous family, presenting with atopic dermatitis, elevated levels of IgE, and CD4+ lymphopenia (a more severe phenotype was observed in Patient 2), but lacked dysmorphic features or neurocognitive impairment. Compound heterozygous PGM3 variants were identified, located in the phosphate-binding domain of the enzyme. PGM3 expression was comparable to healthy donors, but L-PHA binding in naïve-CD4+ cells was decreased. Examination of exome sequence identified the presence of one additional candidate variant of unknown significance (VUS) in the N-glycosylation pathway in Patient 2: a variant predicted to have moderate-to-high impact in ALG12. CONCLUSIONS: Our analysis revealed that L-PHA binding is reduced in naïve-CD4+ cells, which is consistent with decreased residual PGM3 enzymatic activity. Other gene variants in the N-glycosylation pathway may modify patient phenotypes in PGM3 deficiency. This study expands the clinical criteria for when PGM3 deficiency should be considered among individuals with hyper-IgE.

Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches.

Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non-invasive infection, mainly due to Candida albicans, in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, the frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow to widen therapeutic options aimed at restoring immunological function. Type I and II Janus kinase-inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered.

Neonatal thymectomy in children-accelerating the immunologic clock?

The thymus is critical for central tolerance and diverse T-lymphocyte repertoire development, to provide lifelong defense against pathogens while maintaining self-tolerance. Peak thymic output occurs in utero, during infancy, and in early childhood, diminishing throughout life. Infants with congenital heart disease requiring sternotomy often undergo thymectomy to clear the surgical field. The long-term effects of early thymectomy are just being appreciated. Many patients remain asymptomatic despite immunologic findings mirroring those of immunosenescence. Few develop increased infection or lymphoreticular malignancy risk. When considering the effects of infant thymectomy, patients with partial DiGeorge syndrome or hypomorphic recombination-activating gene (RAG) mutations may be instructive. These patients are lymphocytopenic, with increased early-onset infection and autoimmunity risk that is not seen in most patients who underwent thymectomy during infancy. The thymic structure of patients with partial DiGeorge syndrome or hypomorphic RAG is abnormal, with disrupted architecture inclining to perturbation of central tolerance. Similar findings may be seen in patients with myasthenia gravis, although disrupted peripheral tolerance may play a greater role in autoimmunity development. In conclusion, thymectomy during infancy may increase future risk of infection or autoimmunity, with premature immunosenescence mediated through disruption of central and peripheral tolerance mechanisms initiated by early cessation or diminution of thymic output. Ideally, some thymic tissue should be preserved at the time of surgery.

Outcome of autoimmune cytopenia after hematopoietic cell transplantation in primary immunodeficiency.

BACKGROUND: Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking. OBJECTIVES: This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab. METHODS: We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018. RESULTS: Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died. CONCLUSIONS: The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Laboratory evaluation of the IFN-γ circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease.

The integrity of the interferon (IFN)-γ circuit is necessary to mount an effective immune response to intra-macrophagic pathogens, especially Mycobacteria. Inherited monogenic defects in this circuit that disrupt the production of, or response to, IFN-γ underlie a primary immunodeficiency known as Mendelian susceptibility to mycobacterial disease (MSMD). Otherwise healthy patients display a selective susceptibility to clinical disease caused by poorly virulent mycobacteria such as BCG (bacille Calmette-Guérin) vaccines and environmental mycobacteria, and more rarely by other intra-macrophagic pathogens, particularly Salmonella and M. tuberculosis. There is high genetic and allelic heterogeneity, with 19 genetic etiologies due to mutations in 10 genes that account for only about half of the patients reported. An efficient laboratory diagnostic approach to suspected MSMD patients is important, because it enables the establishment of specific therapeutic measures that will improve the patient's prognosis and quality of life. Moreover, it is essential to offer genetic counseling to affected families. Herein, we review the various genetic and immunological diagnostic approaches that can be used in concert to reach a molecular and cellular diagnosis in patients with MSMD.

Severe BCG-osis Misdiagnosed as Multidrug-Resistant Tuberculosis in an IL-12Rß1-Deficient Peruvian Girl.

PURPOSE: Mendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient's prognosis. METHODS: We evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rß1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species. RESULTS: We identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rß1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response. CONCLUSIONS: We report the first Peruvian patient with IL-12Rß1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.

Sirolimus as an alternative treatment in patients with granulomatous-lymphocytic lung disease and humoral immunodeficiency with impaired regulatory T cells.

BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success. METHODS: Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs). RESULTS: A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects. CONCLUSIONS: These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.

B Regulatory Cells: Players in Pregnancy and Early Life.

Pregnancy and early infancy represent two very particular immunological states. During pregnancy, the haploidentical fetus and the pregnant women develop tolerance mechanisms to avoid rejection; then, just after birth, the neonatal immune system must modulate the transition from the virtually sterile but haploidentical uterus to a world full of antigens and the rapid microbial colonization of the mucosa. B regulatory (Breg) cells are a recently discovered B cell subset thought to play a pivotal role in different conditions such as chronic infections, autoimmunity, cancer, and transplantation among others in addition to pregnancy. This review focuses on the role of Breg cells in pregnancy and early infancy, two special stages of life in which recent studies have positioned Breg cells as important players.

Evans Syndrome as First Manifestation of Primary Immunodeficiency in Clinical Practice.

BACKGROUND: Evans syndrome (ES) is a rare immune disorder in children, manifested by simultaneous or sequential autoimmune cytopenias (ACs) of unknown cause and having a chronic course with periods of exacerbation and remission. Some primary immunodeficiencies (PIDs) may present with autoimmune manifestations without infections, masking suspicion of them. The PIDs that can typically manifest as ES are autoimmune lymphoproliferative syndrome and common variable immunodeficiency (CVID). MATERIALS AND METHODS: Review of clinical charts and laboratory results of pediatric patients followed-up in the outpatient clinic of PID with a diagnosis of ES and humoral immunodeficiency. RESULTS: Three pediatric patients, a boy and 2 girls, presented with corticosteroid-dependent ES. In the diagnostic approach, autoimmune lymphoproliferative syndrome was ruled out, and during follow-up, patients showed laboratory signs of humoral immune deficiency and were diagnosed with CVID. After initiating the recommended treatment for CVID with AC, patients improved without new exacerbations. CONCLUSIONS: These cases highlight the importance of detection of possible PID in the context of ES and the establishment of CVID treatment to control AC.

The role of albuminuria in the follow-up of HIV-infected pediatric patients.

BACKGROUND: In HIV-infected adults, elevated albumin has been associated with increased inflammatory activity, HIV-related nephropathy, and type 2 diabetes. Data on albuminuria in HIV-infected children are very scarce, and guidelines do not include routine determination of urinary albumin/creatinine ratio in this population. METHODS: We performed a cross-sectional study in a cohort of HIV-infected pediatric patients. Urinary protein/creatinine and albumin/creatinine ratios and hematuria were determined from at least three morning urine samples, and glomerular filtration rate (GFR) was estimated from creatinine levels. Persistent renal damage was defined according to the presence of at least two sequentially abnormal values in one of the parameters. The relationship between renal damage, HIV-related variables, and metabolic comorbidities (dyslipidemia, fat redistribution, glucose intolerance, hypertension) was investigated. RESULTS: Symptom-free renal damage was observed in 13 of 68 patients (19.1%) and mainly consisted of persistent proteinuria (17.6%); glomerular proteinuria was twice as prevalent as tubular proteinuria. GFR were normal in all cases. No relationship between renal markers and HIV-related variables or metabolic comorbidities was observed. CONCLUSIONS: Mild proteinuria affected approximately one fifth of patients in our cohort. The determination of albuminuria allowed the differentiation between glomerular and tubular proteinuria, although no relationship with metabolic comorbidities was observed.

Changes in Treg and Breg cells in a healthy pediatric population.

The interpretation of clinical diagnostic results in suspected inborn errors of immunity, including Tregopathies, is hampered by the lack of age-stratified reference values for regulatory T cells (Treg) in the pediatric population and a consensus on which Treg immunophenotype to use. Regulatory B cells (Breg) are an important component of the regulatory system that have been poorly studied in the pediatric population. We analyzed (1) the correlation between the three immunophenotypic definitions of Treg (CD4+CD25hiCD127low, CD4+CD25hiCD127lowFoxP3+, CD4+CD25hiFoxP3+), and with CD4+CD25hi and (2) the changes in Treg and Breg frequencies and their maturation status with age. We performed peripheral blood immunophenotyping of Treg and Breg (CD19+CD24hiCD38hi) by flow cytometry in 55 healthy pediatric controls. We observed that Treg numbers varied depending on the definition used, and the frequency ranged between 3.3-9.7% for CD4+CD25hiCD127low, 0.07-1.6% for CD4+CD25hiCD127lowFoxP3+, and 0.24-2.83% for CD4+CD25hiFoxP3+. The correlation between the three definitions of Treg was positive for most age ranges, especially between the two intracellular panels and with CD4+CD25hi vs CD4+CD25hiCD127low. Treg and Breg frequencies tended to decline after 7 and 3 years onwards, respectively. Treg's maturation status increased with age, with a decline of naïve Treg and an increase in memory/effector Treg from age 7 onwards. Memory Breg increased progressively from age 3 onwards. In conclusion, the number of Treg frequencies spans a wide range depending on the immunophenotypic definition used despite a good level of correlation exists between them. The decline in numbers and maturation process with age occurs earlier in Breg than in Treg.