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Regulatory T (T reg ) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage-defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that T reg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non-suppressive T reg cells exist in human blood that are otherwise indistinguishable from one another using classical T reg cell markers such as CD25 and FoxP3. Moreover, murine T reg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (T eff ) cells. However, this plasticity can also result in T reg cell lineage instability and acquisition of proinflammatory T eff cell functions. Consequently, these dysfunctional CD4 + FoxP3 + T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human T reg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to T reg cell antigen-specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3 + T reg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human T reg cells, and how abrogating these mechanisms can lead to lineage instability and T reg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer., (© 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

CD4 + regulatory T cells (T reg ) expressing the forkhead box protein 3 (FOXP3) transcription factor (T regs ) are instrumental for the prevention of autoimmune diseases. There is increasing evidence that the human T regulatory population is highly heterogeneous in phenotype and function. Numerous studies conducted in human autoimmune diseases have shown that T reg cells are impaired either in their suppressive function, in number, or both. However, the contribution of the FOXP3 + T reg subpopulations to the development of autoimmunity has not been delineated in detail. Rare genetic disorders that involve deficits in T reg function can be studied to develop a global idea of the impact of partial or complete deficiency in a specific molecular mechanism involved in T reg function. In patients with reduced T reg numbers (but no functional deficiency), the expansion of autologous T reg cells could be a suitable therapeutic approach: either infusion of in-vitro autologous expanded cells, infusion of interleukin (IL)-2/anti-IL-2 complex, or both. T reg biology-based therapies may not be suitable in patients with deficits of T reg function, unless their deficit can be corrected in vivo/in vitro. Finally, it is critical to consider the appropriate stage of autoimmune diseases at which administration of T reg cellular therapy can be most effective. We discuss conflicting data regarding whether T reg cells are more effectual at preventing the initiation of autoimmunity, ameliorating disease progression or curing autoimmunity itself., (© 2019 British Society for Immunology.)

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton's tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP 6 ) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP 6 -mediated Btk regulation is more prominent in IgM + plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling., Competing Interests: The authors declare no conflict of interest.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is one of the inborn errors of immunity, characterized by impaired function of the regulatory T cells. Clinical manifestations of IPEX syndrome are characterized by various autoimmune diseases with autoantibodies. The comprehensive analysis for autoantibodies using human proteome microarrays in the four patients with IPEX syndrome was performed. The numbers of the highly expressed autoantibody showing relative log2 ratios greater than 1 were 1876, 513, 234 and 831 (mean: 864), respectively. Some novel autoantibodies which could explain the phenotypes of patients, adrenal dysfunction, muscular hypotonia, afibrinogenemia, enteropathy and pancytopenia were identified. Various kinds of autoantibodies targeting testis-specific antigens were also identified. Human proteome microarray is a powerful tool to understand the pathophysiology of IPEX syndrome. The larger cohort analysis using this method will provide further understanding of the impaired immune tolerance in humans., (Copyright © 2019. Published by Elsevier Inc.)

Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a devastating autoimmune disease caused by mutations in FoxP3, a transcription factor required for the development and function of regulatory T cells (Treg cells). Allogeneic hematopoietic stem cell transplant (HSCT) can be curative, but suitable donors are often unavailable. Here, we demonstrate a strategy for autologous HSCT and gene therapy utilizing a lentiviral vector (LV) to restore FoxP3 expression under the control of endogenous human FOXP3 regulatory elements. Both murine transplant models and humanized mice engrafted with LV-modified HSCs show high levels of LV expression selective for CD4+CD25+FoxP3+ Treg cells. LV transduction of scurfy (FoxP3 mut ) HSCs restores development of functional FoxP3+ Treg cells that suppress T cell proliferation in vitro and rescue the scurfy autoimmune phenotype in vivo. These findings demonstrate preclinical efficacy for the treatment of IPEX patients by autologous HSC transplant and may provide valuable insights into new cell therapies for autoimmunity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation., (Copyright © 2018. Published by Elsevier Inc.)

Purpose of Review: Conventional gene therapy has been a successful, curative treatment modality for many primary immune deficiencies with significant improvements in the last decade. However, the risk of leukemic transformation with viral-mediated gene addition still remains, and unregulated gene addition is not an option for certain diseases in which the target gene is closely controlled. The recent bloom in genome modification platforms has created the opportunity to site-specifically correct mutated DNA base pairs or insert a corrective cDNA minigene while maintaining gene expression under control of endogenous regulatory elements., Recent Findings: There is an abundance of ongoing research utilizing programmable nucleases to facilitate site-specific gene correction of many primary immune deficiencies including X-linked severe combined immune deficiency, X-linked chronic granulomatous disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome, X-linked agammaglobulinemia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked. In all, these studies have demonstrated the ability to integrate corrective DNA sequences at a precise location in the genome at rates likely to either cure or ameliorate disease., Summary: Gene editing for primary immune deficiency (PID) has advanced to the point to that translation to clinical trials is likely to occur in the next several years. At the current pace of research in DNA repair mechanisms, stem cell biology, and genome-editing technology, targeted genome modification represents the next chapter of gene therapy for PID.

Background: Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear., Objective: We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome., Methods: Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4 + T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6) -/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T-cell counts are measured in Stat6 -/- scurfy mice and scurfy mice., Results: Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4 + T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype., Conclusions: Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper-IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal-dominant hyper-IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy., (© 2018 AABB.)

Background: Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed., Objective: We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology., Methods: We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice)., Results: Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a T H 2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels., Conclusions: These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort., Methods: Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3., Results: Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002)., Conclusion: The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.

Objective: To report on two cases affected with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)., Methods: Two unrelated Chinese infants affected with IPEX were investigated. Case 1 was a 4-month-old boy with neonatal diabetes and severe enteropathy. Case 2 was a 6-day newborn boy with neonatal diabetes and ketoacidosis. DNA samples of the two infants and their parents were sequenced for FOXP3 gene mutations. Suspected mutations were verified among 100 unrelated healthy controls. The function of mutations was predicted with bioinformatics software., Results: Both infants had onset of the disease during neonatal period, and manifested insulin-dependent diabetes mellitus, persistent diarrhea, eczema and malnutrition. In case 1, a novel splice site mutation was identified in intron 9 (c.967+3A>T) of the FOXP3 gene, for which his mother was a carrier. For case 2, a missense mutation (c.1150G>A) was detected in exon 11 of the FOXP3 gene, for which his mother was also a carrier. The IVS9 c.967+3A mutation was not detected among the 100 healthy controls. As predicted with Human Splicing Finder software, the c.967+3A>T mutation may influence the splicing of mRNA and affect the function of protein., Conclusion: Both cases had typical clinical manifestation of the IPEX syndrome, among whom a novel splice site mutation (IVS9 c.967+3A>T) and a missense mutation (c.1150G>A) of the FOXP3 gene were identified. The clinical manifestation of the IPEX syndrome may be variable and the mortality is high. FOXP3 gene sequencing is recommended when insulin-dependent diabetes mellitus is diagnosed during the neonatal period.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tT reg ) cells. tT reg  cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments., (© 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.)

For almost any given human-tropic virus, bacterium, fungus, or parasite, the clinical outcome of primary infection is enormously variable, ranging from asymptomatic to lethal infection. This variability has long been thought to be largely determined by the germline genetics of the human host, and this is increasingly being demonstrated to be the case. The number and diversity of known inborn errors of immunity is continually increasing, and we focus here on autosomal and X-linked recessive traits underlying complete deficiencies of the encoded protein. Schematically, four types of infectious phenotype have been observed in individuals with such deficiencies, each providing information about the redundancy of the corresponding human gene, in terms of host defense in natural conditions. The lack of a protein can confer vulnerability to a broad range of microbes in most, if not all patients, through the disruption of a key immunological component. In such cases, the gene concerned is of low redundancy. However, the lack of a protein may also confer vulnerability to a narrow range of microbes, sometimes a single pathogen, and not necessarily in all patients. In such cases, the gene concerned is highly redundant. Conversely, the deficiency may be apparently neutral, conferring no detectable predisposition to infection in any individual. In such cases, the gene concerned is completely redundant. Finally, the lack of a protein may, paradoxically, be advantageous to the host, conferring resistance to one or more infections. In such cases, the gene is considered to display beneficial redundancy. These findings reflect the current state of evolution of humans and microbes, and should not be considered predictive of redundancy, or of a lack of redundancy, in the distant future. Nevertheless, these observations are of potential interest to present-day biologists testing immunological hypotheses experimentally and physicians managing patients with immunological or infectious conditions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined., Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors., Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed., Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS., Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis., Objective: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID., Methods: A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts., Results: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin β receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations., Conclusions: IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap -/- regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap -/- Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap -/- Treg cells. In addition, Xiap -/- Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap -/- mice. Notably, inflammation-induced reprogramming of Xiap -/- Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap -/- Treg cells confers survival to inflammatory infection in Xiap -/- mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP.

Background: X-linked agammaglobulinaemia (XLA) is a genetic disorder affecting B cell maturation, which is characterised by a low number of B cells, agammaglobulinaemia and increased susceptibility to a variety of bacterial infections. This study was performed to assess T cell subpopulations in a group of children with XLA in association with chronic respiratory disease (CRD)., Methods: Numbers of T cell subpopulations (CD3+, CD4+, CD8+, CD3+DR+, naïve, memory, recent thymic emigrants (RTE), regulatory T cells, follicular T helpers) were measured by eight-colour flow cytometry in 22 XLA patients and 50 controls. BAFF level was measured by ELISA., Results: XLA patients with CRD had a significantly lower percentage of RTE numbers and Tregs, while significantly higher absolute counts of lymphocytes, CD3+, CD8+, CD3+DR+ and CD4+CD45RO+ T cells were detected as compared with healthy controls. In patients with XLA without CRD, the number of follicular T helper cells was altered significantly (percentage and absolute), as compared with healthy controls. Additionally, they had significantly higher counts (percentage and absolute) of CD4+CD45RA+ cells and lower percentage of CD4+CD45RO+ cells in comparison with healthy controls., Conclusions: Our study affords new information concerning CRD and T cell subsets that differentiate or are maintained in the absence of B cells in children with XLA. T cell's homeostasis depends on the presence of chronic respiratory disease that may be caused by the delay in diagnosis., (Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency syndrome characterized by the development of multiple autoimmune disorders in affected individuals. Different forms of renal injury have been reported in IPEX syndrome, and membranous nephropathy (MN) is among the most common glomerulopathies found. However, the exact pathogenesis of MN in this setting has not been elucidated, and it is not clear whether it is part of the clinical spectrum of the disease or secondary to medications, infections or other concomitant insults., Diagnosis/treatment: We describe a child diagnosed with IPEX syndrome shortly after birth who presented with nephrotic syndrome at the age of 11 weeks. Renal biopsy revealed a MN with enhanced immunohistochemical staining for phospholipase A2 receptor (PLA2R)., Conclusion: This is the first report of a PLA2R-positive MN in a patient with IPEX syndrome. We suggest that, in this context, MN results from an autoimmune process against podocytic antigens, namely PLA2R.

Foxp3 controls the development and function of regulatory T (Treg) cells, but it remains elusive how Foxp3 functions in vivo. Here, we established mouse models harboring three unique missense Foxp3 mutations that were identified in patients with the autoimmune disease IPEX. The I363V and R397W mutations were loss-of-function mutations, causing multi-organ inflammation by globally compromising Treg cell physiology. By contrast, the A384T mutation induced a distinctive tissue-restricted inflammation by specifically impairing the ability of Treg cells to compete with pathogenic T cells in certain non-lymphoid tissues. Mechanistically, repressed BATF expression contributed to these A384T effects. At the molecular level, the A384T mutation altered Foxp3 interactions with its specific target genes including Batf by broadening its DNA-binding specificity. Our findings identify BATF as a critical regulator of tissue Treg cells and suggest that sequence-specific perturbations of Foxp3-DNA interactions can influence specific facets of Treg cell physiology and the immunopathologies they regulate., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency.

X-linked agammaglobulinemia (XLA) is a rare genetic disorder, caused by mutations in BTK (Bruton's Tyrosine Kinase) gene. Deep high-throughput RNA sequencing (RNA-Seq) approach was utilized to explore the possible differences in transcriptome profiles of primary monocytes in XLA patients compared with healthy subjects. Our analysis revealed the differences in expression of 1,827 protein-coding genes, 95 annotated long non-coding RNAs (lncRNAs) and 20 novel lincRNAs between XLA patients and healthy subjects. GO and KEGG pathway analysis of differentially expressed (DE) protein-coding genes showed downregulation of several innate immune-related genes and upregulation of oxidative phosphorylation and apoptosis-related genes in XLA patients compared to the healthy subjects. Moreover, the functional prediction analysis of DE lncRNAs revealed their potential role in regulating the monocytes cell cycle and apoptosis in XLA patients. Our results suggested that BTK mutations may contribute to the dysregulation of innate immune system and increase susceptibility to apoptosis in monocytes of XLA patients. This study provides significant finding on the regulation of BTK gene in monocytes and the potential for development of innovative biomarkers and therapeutic monitoring strategies to increase the quality of life in XLA patients.

The lack of BTK in X-linked agammaglobulinemia (XLA) patients does not affect monocytes and polymorphonuclear cells (PMN) phenotype and functions. In this study, we show that XLA patients had an increased frequency of the intermediate monocytes subset and that BTK-deficient monocytes and PMN had a normal expression of receptors involved in the activation and cellular responses. We demonstrate that BTK is not required for migration, phagocytosis and the production of reactive oxygen species (ROS) following engagement of FC gamma receptors (FcγR). XLA monocytes and PMN showed an efficient calcium (Ca2+)-independent activation of oxidative burst, suggesting that oxidative burst is less dependent by Ca2+ mobilization. The phagocytosis was functional and it remained unaltered also after Ca2+ chelation, confirming the independence of phagocytosis on Ca2+ mobilization. Intravenous immunoglobulin (IVIg) infusion exerted an anti-inflammatory effect by reducing the frequency of pro-inflammatory monocytes. In monocytes, the IVIg reduce the oxidative burst and phagocytosis even if these functions remained efficient.

Primary immunodeficiency diseases (PID) are congenital disorders secondary to an impaired immune response. Infections, autoimmune disorders, atopy, and lymphoproliferative syndromes are commonly associated with this disorder., Objective: To present and discuss 3 infants diagnosed with PID., Clinical Cases: The cases are presented of three patients with PID diagnosed during their first admission to a Paediatric Intensive Critical Care Unit. The first patient, a 4-month-old infant affected by a severe pneumonia, and was diagnosed as a Severe Combined Immunodeficiency Disease. The second patient was an 8-month-old infant with Candida lusitaniae mesenteric adenitis, and diagnosed with a Chronic Granulomatous Disease. The last patient, a 6-month-old infant presented with ecthyma gangrenosum and X-linked agammaglobulinaemia., Conclusion: PID should be suspected when an infectious disease does not responde to the appropriate therapy within the expected period. An update of each disease is presented.

This article discusses non-classical forms of inflammatory bowel disease (IBD) mainly occurs in infants and very young children. Defects in every aspect of the immune system, such as neutrophils, T-cell and B-cell lymphocytes, and macrophages are associated with IBD in infants. Also, non lympho-hematopoietic defects with primary defects in enterocytes can also lead to IBD-like manifestations. Clinical vignettes are presented and the genetic origins and possible management strategies are outlined. Early evaluation of these patients is important because identification of underlying immune defects would facilitate the use of better-targeted therapy for the specific genetic defect., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Adipose tissue (AT) macrophages (ATMs) are key players for regulation of AT homeostasis and obesity-related metabolic disorders. However, the phenotypes of human ATMs and regulatory mechanisms of their polarization have not been clearly described. In this study, we investigated human ATMs in both abdominal visceral AT and s.c. AT and proposed an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-glucocorticoid receptor regulatory axis that might dictate M1/M2 polarization in ATMs. The accumulation of CD11c + CD163 + ATMs in both visceral AT and s.c. AT of obese individuals was confirmed at the cellular level and was found to be clearly correlated with body mass index and production of reactive oxygen species. Using our in vitro system where human peripheral blood monocytes (hPBMs) were cocultured with Simpson-Golabi-Behmel syndrome adipocytes, M1/M2 polarization was found to be dependent on 11β-HSD1, an intracellular glucocorticoid reactivating enzyme. Exposure of hPBMs to cortisol-induced expression of CD163 and RU-486, a glucocorticoid receptor antagonist, significantly abrogated CD163 expression through coculture of mature adipocytes with hPBMs. Moreover, 11β-HSD1 was expressed in crown ATMs in obese AT. Importantly, conditioned medium from coculture of adipocytes with hPBMs enhanced proliferation of human breast cancer MCF7 and MDA-MB-231 cells. In summary, the phenotypic switch of ATMs from M2 to mixed M1/M2 phenotype occurred through differentiation of adipocytes in obese individuals, and upregulation of intracellular 11β-HSD1 might play a role in the process., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background: X-linked agammaglobulinemia (XLA) is an X-linked genetic defect in maturation of B lymphocytes that results in the absence of B lymphocytes in the peripheral blood and profound hypogammaglobulinemia. It is caused by a mutation in the BTK gene located on the X chromosome. There are no large series describing XLA from the developing world., Objective: To analyze the clinical features, immunologic and genetic characteristics, and outcomes of 36 patients with XLA diagnosed and managed for a period of 2 decades., Methods: Diagnosis of XLA was made on the basis of presence of BTK gene mutation or marked reduction of B lymphocytes in peripheral blood with a family history of an affected male relative. The diagnosis was confirmed by genetic mutation studies in 28 patients with 25 unique mutations in the BTK gene., Results: There was a significant delay in diagnosis in most of the patients. The mean (SD) delay in the diagnosis was 4.2 (3.5) years. Point mutations were the most common mutations detected, accounting for 68% of all mutations. Deletions and insertions were also seen in a few cases. Four of the mutations are novel mutations that have not been previously reported. Seven of the 36 patients (19%) were dead at the time of analysis in the present cohort. The mean survival was 137 months (95% confidence interval, 13-163 months)., Conclusion: The present study is perhaps the largest series of patients with XLA from any developing country so far., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Bronchiectasis, defined as an abnormal and irreversible dilatation of the bronchi, frequently associated with inflammation, is the most common complication of recurrent infections. Effective pulmonary immunity is necessary to prevent chronic bronchial damage due to bacterial infection. Primary immune deficiencies comprise a heterogeneous group of genetically determined disorders that affect development and/or the function of innate or adaptive immunity. In multiple series reported in literature, common variable immunodeficiency (CVID), X-linked agammaglobulinemia (XLA) and chronic granulomatous disease (CGD) were the most common forms of primary immune deficiencies (PIDs) associated with bronchiectasis (1,15). Despite advances in the molecular knowledge of PIDs during the past two decades, there are many undiagnosed or late diagnosed patients (6,14). We report a case of Bruton's disease late diagnosed, already with bronchiectasis, with an early onset of recurrent respiratory infections.

Background/purpose: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a severe autoimmune disease that is caused by regulatory T cell deficiency due to FOXP3 gene mutations. The long-term outcome can be variable depending on the extent of tissue damage caused by autoimmunity and infections, the use of immunosuppressive treatment or sequela of bone marrow transplantation., Methods: We used immunohistochemical staining to analyze cell types infiltrating the tissue of affected organs from a classic IPEX patient with a splicing mutation (c.736-2A>C) in the FOXP3 gene. Expression of transcription factors that are critical for immune responses including T-bet, GATA-3, RORγt, and FOXP3 were evaluated in various tissue samples. For objective analysis of the distribution of different cell types in tissues, we used an automated microscope-based image acquiring system to assess quantitatively the different cell types by investigating the histopathological changes in the patient's biopsy samples obtained from the intestine and the kidneys before and after treatment., Results: The percentages of cells expressing the T H 2-associated transcription factor GATA3 were higher in the IPEX patient before treatment than in controls, suggesting that T H 2-type cells contribute to the tissue inflammation of the gut and kidneys in IPEX syndrome. Immunosuppressive treatment effectively decreased the number of effector cells in the kidneys and intestine of the IPEX patient., Conclusion: This study provides quantitative evidence that the inflamed intestinal and renal tissues of the IPEX patient contain T H 2-type immune effector cells, which decreased in number after immunosuppressive treatment was initiated and the clinical symptoms had improved., (Copyright © 2015. Published by Elsevier B.V.)

X-linked ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by mutations in the nuclear factor-kappa B essential modulator (NEMO) gene. Here, we report the clinical and genetic features of a XL-EDA-ID patient who developed bacillus Calmette-Guérin infection. Patient lymphocytes failed to degrade IκB-α, and sequencing of NEMO identified the novel mutation c.1238A>C/p.H413P. Furthermore, patient monocyte-derived macrophages ingested Mycobacterium tuberculosis normally, but failed to control the intracellular proliferation of bacilli, a defect which was improved in the presence of interferon-gamma (IFN-γ). This work expands the genetic spectrum of XL-EDA-ID and demonstrates improvement in macrophage function in a NEMO-deficient patient by IFN-γ., (© 2016 Wiley Periodicals, Inc.)

Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIg) is a new immunoglobulin product for replacement therapy in patients with primary antibody deficiencies (PAD). The pre-administration of recombinant human hyaluronidase associated with 10% immunoglobulin allowed the infusion of larger (up to 600 ml) amounts of immunoglobulin at a single infusion site, enabling patients to receive the necessary treatment in a single monthly dose. Here, we report the effectiveness and the tolerability of fSCIg in patients with severe PAD-related comorbidities: refractory autoimmune thrombocytopenia; systemic granulomatous disease; severe enteropathy, and Type I diabetes. We conclude that fSCIg could be a feasible option to improve the adherence to replacement therapy also by patients with severe PAD.

Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-β signaling., Methods and Results: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4 T cells from xIAP mice compared with colitis induced by naïve CD4 T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP or WT Treg cells with naïve WT CD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL-17A-producing CD4 T cells in mice receiving Tregs from xIAP mice., Conclusions: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4 T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.

This open-label multi-centre study evaluated Gammaplex(®) 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3-16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammaplex 5% (at doses of 300-800 mg/kg/infusion) for 12 months, with a 3-month follow-up. The primary efficacy end-point was the incidence of serious acute bacterial infections (SABIs) during the 12-month treatment period. Secondary objectives assessed safety and tolerability. Nineteen males and six females were treated using the same infusion schedule as their prior IVIG treatment (14 and 11 subjects on 21- and 28-day dosing schedules, respectively). Two SABIs of pneumonia were reported, resulting in an annual SABI event rate of 0·09 [upper one-sided 99% confidence interval (CI) = 0·36]. Twenty-one subjects (84%) experienced ≥ 1 infection during the study, with a median infective episode per subject/year of 3·08 (range  = 0-10·4). Sixteen subjects (64%) missed ≥ 1 day of nursery or school because of infection or other illness. All trough immunoglobulin G levels exceeded 7·00 g/l after 15 weeks (mean = 9·69 g/l; range = 7·04-15·35 g/l). Product-related adverse events occurred in 14 subjects (56%); none were serious. Of 368 total infusions, 97 (26%) were associated temporally with an adverse event (≤ 72 h after infusion), regardless of causality. Laboratory test results and adverse-reaction data showed no evidence of product-related haemolysis or thromboembolic events. These data demonstrate that Gammaplex 5% is effective in preventing SABIs and well tolerated in children and adolescents with PID., (© 2016 British Society for Immunology.)

The primary purpose of the immune system is to protect the body from infection. Failure of the immune system can lead to repeated infections. The aim of this review is to discuss primary immune deficiency (PID) and its relationship with bronchiectasis in adults. It examines treatment options for patients with PID and provides practical details of how nurses can empower these patients to reduce their risk of respiratory infections.

Purpose: X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients., Methods: Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing., Results: We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed., Conclusions: This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMTs), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus infection and posttransplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report 2 distinct cases of EBV-related SMT, unique through their coassociated immunosuppressive state or location: the 1st occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation; the 2nd developed in the orbit after heart transplant.

Background: We herein report the first case of X-linked agammaglobulinemia (XLA) that underwent allogeneic stem cell transplantation using reduced intensity conditioning (RIC). We chronologically observed the reconstitution of humoral immunity in this case., Case Presentation: The patient was a 28-year-old Japanese male with XLA who previously had life-threatening infectious episodes and was referred for the possible indication of allogeneic stem cell transplantation. After a thorough discussion within specialists from different backgrounds, we decided to perform allogeneic peripheral stem cell transplantation from his HLA-identical elder brother. Due to the non-malignant nature of XLA, we selected RIC consisting of fludarabine, cyclophosphamide, anti-thymocyte globulin, and 3 Gy of total body irradiation. Neutrophil engraftment was achieved on day 11 with complete donor chimerism. No major complications, except for stage 1 skin graft-versus-host disease, were observed. The patient was discharged on day 75 and has been followed as an outpatient without any infectious episodes for more than 500 days., Conclusions: Regarding immune reconstitution, CD19(+) cells, IgA, and IgM, which were undetectable before allogeneic stem cell transplantation (allo-SCT), started to increase in number 10 days after allo-SCT and continued to increase for more than 1 year. Anti-B antibodies appeared as early as day 10. Total IgG levels decreased after the discontinuation of IgG replacement and spontaneously recovered after day 350. However, most anti-viral IgG titers, except EB virus-virus capsid antigen IgG, disappeared after the discontinuation of IgG replacement. A seasonal vaccination to influenza was performed on day 148, with neither anti-influenza type A nor type B being positive after the vaccination. The transient transfer of allergic immunity to orchard grass was observed. Similar Bruton's tyrosine kinase (BTK) expression levels in monocytes and B-cells were observed between the patient and healthy control. B-cells in the peripheral blood (PB) of the patient on day 279 showed sufficient proliferation after a CD40L and IL-21 or CD40L and CpG stimulation. Effective immunoglobulin production and class switching were also observed after a CD40L and IL-21 or CpG stimulation. Signal joint kappa-deleting recombination excision circles (sjKRECs) became positive 16 days post-SCT, increased to 6300 copies/μg DNA at 42 days, and were maintained at a high level thereafter. The recovery of T-cell receptor excision circles (TRECs) was slow, but became detectable 1 year post-hematopoietic stem cell transplantation (HSCT).

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic autoimmune disease characterized by early-onset life-threatening multisystemic autoimmunity. This rare hereditary disorder is caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor, which plays a key role in the differentiation and function of CD4(+)CD25(+) natural regulatory T cells (Tregs), essential for the establishment and maintenance of natural tolerance. We identified a novel mutation in the FOXP3 gene affecting the Phe367 residue of the protein (F367V) in a family with three male siblings affected by IPEX. Two other mutations affecting the FOXP3 Phe367 residue (F367L and F367C) have been described previously. This unique situation of three mutations affecting the same residue in FOXP3 led us to study the molecular impact of these mutations on the structure of FOXP3 protein. Structure analysis showed that Phe367 is involved in a rich interaction network related to both monomer and dimer structure stabilization, and is crucial for FOXP3 regulatory activity. The relevance of this location is confirmed by the results of SIFT and PolyPhen-2 pathogenicity predictions for F367V mutation. In summary, as assessment of the pathogenicity of a novel mutation is crucial to achieve a proper molecular diagnosis, we analysed the impact of mutations affecting the Phe367 residue using a combined approach that provides a mechanistic view of their pathogenic effect., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Since the original identification of Bruton's tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease.

We present a 22-month-old boy with X-linked agammaglobulinemia masked by normal immunoglobulin levels and vaccine seroconversion. Diagnosis was made after strong clinical suspicion of immune deficiency led to identification of markedly reduced B-cell numbers and confirmation with identification of a novel Bruton tyrosine kinase gene mutation. He was commenced on replacement immunoglobulin therapy with excellent clinical improvement. This case highlights the variability of phenotypic presentation and apparent disunity between routine immunologic investigations and severe disease in X-linked agammaglobulinemia, necessitating clinical acumen to make the diagnosis., (Copyright © 2015 by the American Academy of Pediatrics.)