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INTRODUCTION: In X-linked agammaglobulinemia (XLA), the diversity of BTK variants complicates the study of genotype-phenotype correlations. Since BTK negatively regulates toll-like receptors (TLRs), we investigated if distinct BTK mutation types selectively modulate TLR pathways, affecting disease expression. METHODS: Using reverse transcription-quantitative polymerase chain reaction, we quantified ten TLR signaling-related genes in XLA patients with missense (n = 3) and nonsense (n = 5) BTK mutations and healthy controls (n = 17). RESULTS: BTK, IRAK2, PIK3R4, REL, TFRC, and UBE2N were predominantly downregulated, while RIPK2, TLR3, TLR10, and TLR6 showed variable regulation. The missense XLA group exhibited significant downregulation of IRAK2, PIK3R4, REL, and TFRC and upregulation of TLR3 and/or TLR6. CONCLUSION: Hypo-expression of TLR3, TLR6, and TLR10 may increase susceptibility to infections, while hyper-expression might contribute to chronic inflammatory conditions like arthritis or inflammatory bowel disease. Our findings shed light on the important inflammatory component characteristic of some XLA patients, even under optimal therapeutic conditions.

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OBJECTIVES: Immunoglobulin A deficiency (IgAD) is a common disease with an unknown genetic defect, characterized by the decreased or absent IgA with other isotypes normal, normal subclasses, and specific antibodies. Patients with this disorder represent a spectrum of clinical manifestations including infections, autoimmune disorders, malignancy, and allergic diseases. The current study aimed to evaluate their prevalence and categorized them. METHODS: We searched PubMed, Web of Science, and Scopus databases to find eligible studies from the earliest available date to January 2022 with standard keywords. Pooled estimates of clinical manifestations prevalence and the corresponding 95% confidence intervals were calculated using random-effects models. RESULTS: The most prevalent clinical manifestations belonged to infection (64.8%) followed by allergic diseases (26.16%) and autoimmunity (22.0%), respectively. In selective IgA deficiency patients as the largest group of IgAD in current study, celiac disease (6.57%), Inflammatory bowel disease (4.01%), and rheumatoid arthritis (3.80%) were the most prevalent autoimmunity. Meanwhile, the most frequent infection was respiratory tract infection, fungal infection, and gastrointestinal infection at 50.74%, 18.48%, and 15.79%, respectively. In addition, the pooled prevalence of asthma, allergic rhinitis, and allergic conjunctivitis were 19.06%, 15.46%, and 11.68%, respectively which were reported as the most widespread allergic diseases. CONCLUSIONS: Our results showed that apart from undiagnosed IgAD patients, IgAD patients represent a wide range of clinical manifestations. Infection, allergy, and autoimmunity are the most common clinical manifestations. The concurrent presence of IgA and IgG subtypes deficiency could be associated with increased susceptibility to infection. Considering the probability of developing new clinical complications during follow-up, periodic assessments of IgAD patients should be inspected.

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BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

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Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The 10-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcomes.

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STAT3 is a cytokine-signaling transcription factor critical for gene regulation. Gain-of-function (GOF) mutations in STAT3 are associated with lymphoproliferation, autoimmune cytopenias, increased susceptibility to infection, early-onset solid-organ autoimmunity, short stature, and eczema. We studied the JAK/STAT signaling pathway gene expression and the cytokine profile in two families carrying STAT3-GOF variants to shed light on the STAT3-GOF-associated variable expressivity, including the identification of disease markers. Considering 92 target genes, KIT and IL2RA were downregulated only in patients with high clinical penetrance, while CXCL8 was markedly downregulated for all of them. Unlike previous studies, SOCS3-a STAT3 inhibitor-was not upregulated in patients. In addition, low levels of IL-2 and a reduced numbers of Tregs cells were strikingly prevalent in patients. This study shows a disruptive role of STAT3-GOF variants in the regulatory axis activities CXCL8/STAT3, KIT/STAT3, IL2/CD25/Treg, which, by slightly different mechanisms, underlie the broad clinical spectrum seen in the studied patients. In addition, we suggest the investigation of CXCL8 as a biomarker for identifying STAT3-GOF mutation.

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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.

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BACKGROUND: Thrombocytopenia can occur in different circumstances during childhood and although immune thrombocytopenia is its most frequent cause, it is important to consider other conditions, especially when there is a persistent or recurrent low platelet count. We report two cases of intermittent thrombocytopenia, previously misdiagnosed as immune thrombocytopenia. CASES PRESENTATION: Both cases described were boys who presented with an intermittent pattern of thrombocytopenia, with a persistently low mean platelet volume. In both patients, peripheral blood smear revealed small platelets and flow cytometry showed low expression of Wiskott-Aldrich syndrome protein (WASP) in leucocytes. Molecular analysis of the first case identified a mutation in exon 2 of the gene coding for WASP, leading to a p.Thr45Met amino acid change and confirming the diagnosis of X-linked thrombocytopenia. In the second case, a novel missense mutation in exon 2 of the gene coding for WASP was detected, which resulted in a p.Pro58Leu amino acid change. CONCLUSION: These two rare presentations of thrombocytopenia highlight the importance of evaluating the peripheral blood smear in the presence of recurrent or persistent thrombocytopenia and show that failing to do so can lead to misdiagnoses. Since thrombocytopenia may be found in pediatric outpatient clinic, increased awareness among general pediatricians will help to improve the differential diagnosis of this condition.

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Most cases of autoimmune lymphoproliferative syndrome (ALPS) have an inherited genetic defect involving apoptosis-related genes of the FAS pathway. MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs playing a role in the control of gene expression. This is the first report on miRNAs in ALPS patients. We studied a mother and son carrying the same FAS cell surface death receptor (FAS) mutation, but with only the son manifesting the signs and symptoms of ALPS-FAS. The aim was to analyse, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the peripheral blood mononuclear cells (PBMC) relative expression of miR-146a and miR-21, including their passenger strands and respective targets (FAS and FASLG). In comparison with healthy matched control individuals, miR-21-3p was over-expressed significantly (P = 0·0313) in the son, with no significant change in the expression of miR-146a, miR-146a-3p and miR-21. In contrast, the mother had a slight under-expression of the miR-146a pair and miR-21-3p (P = 0·0625). Regarding the miRNA targets, FAS was up-regulated markedly for the mother (P = 0·0078), but down-regulated for the son (P = 0·0625), while FASLG did not have any significant alteration. Taken together, our finding clearly suggests a role of the miR-146a/FAS axis in ALPS-FAS variable expressivity in which FAS haploinsufficiency seems to be compensated only in the mother who had the miR-146a pair down-regulated. As only the son had the major clinical manifestations of ALPS-FAS, miR-21-3p should be investigated as playing a critical role in ALPS physiopathology, including the development of lymphoma.

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Mutations in the Bruton agammaglobulinemia tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA). Unfolded or misfolded proteins can trigger stress pathways in the endoplasmic reticulum (ER), known as unfolded protein response (UPR). The aim was to clarify the involvement of UPR in XLA pathophysiology. By reverse transcription-quantitative PCR, we evaluated the expression of BTK and 12 UPR-related genes in eight patients. Moreover, we assessed the BTK protein expression and pattern in the patients' monocytes by flow cytometry and fluorescence immunocytochemistry. We found a reduced BTK expression in patients with stop codon mutations (P < 0.02). However, missense mutations did not affect BTK expression. Flow cytometry showed a reduction of BTK in patients which was corroborated by an absent or nonfunctional protein synthesis revealed by immunocytochemistry. In contrast with the other UPR-related genes, X-box binding protein 1 (XBP1) was markedly upregulated in the patients (P < 0.01), suggesting Toll-like receptor (TLR) activation since BTK directly interacts with TLRs as a negative regulator and XBP1 can be activated in direct response to TLR ligation. Different BTK mutations can be identified by the BTK expression. Inasmuch as UPR-related genes were downregulated or unaltered in patients, we speculate the involvement of the TLRs-XBP1 axis in the XLA pathophysiology. Such data could be the basis for further studies of this novel pathomechanism concerning XLA.

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Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

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INTRODUCTION: Adherence, which is crucial to the success of antiretroviral therapy (HAART), is currently a major challenge in the care of children and adolescents living with HIV/AIDS. OBJECTIVE: To evaluate the prevalence of nonadherence to HAART using complementary instruments in a cohort of children and adolescents with HIV/AIDS followed in a reference service in Campinas, Brazil. METHODS: The level of adherence of 108 patients and caregivers was evaluated by an adapted standardized questionnaire and pharmacy dispensing records (PDR). Non-adherence was defined as a drug intake lower than 95% (on 24-hour or seven-day questionnaires), or as an interval of 38 days or more for pharmacy refills. The association between adherence and clinical, immunological, virological, and psychosocial characteristics was assessed by multivariate analysis. RESULTS: Non-adherence prevalence varied from 11.1% (non-adherent in three instruments), 15.8% (24-hour self-report), 27.8% (seven-day self-report), 45.4% (PDR), and 56.3% (at least one of the outcomes). 24-hour and seven-day self-reports, when compared to PDR, showed low sensitivity (29% and 43%, respectively) but high specificity (95% and 85%, respectively). In multivariate analysis, medication intolerance, difficulty of administration by caregiver, HAART intake by the patient, lower socioeconomical class, lack of virological control, missed appointments in the past six months, and lack of religious practice by caregiver were significantly associated with non-adherence. CONCLUSION: A high prevalence of HAART non-adherence was observed in the study population, and PDR was the most sensitive of the tested instruments. The instruments employed were complementary in the identification of non-adherence.

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Apocynin is widely used as an inhibitor of the NADPH oxidase. Since myeloperoxidase (MPO) has been considered as essential for the mechanism of action of apocynin, here we used cells with different levels of MPO and compared their sensitivity to apocynin. HL-60 cells were differentiated with DMSO or IFN γ /TNF α and compared with peripheral mononuclear (PBMC) and polymorphonuclear cells (PMN). The relative MPO activity was PBMC = HL60 DMSO < HL60 IFN γ < PMN. Apocynin inhibited the intracellular reactive oxygen species production by PMN (80%) and IFN γ /TNF α -differentiated HL-60 cells (45%) but showed a minor effect in PBMC and DMSO differentiated HL-60 cells (20%). The addition of azide decreased the efficiency of apocynin in PMN and the addition of peroxidase increased the inhibition in PBMC. We also determined the gene expression of the components gp91phox, p47phox, p22phox and p67phox in the resting cells. Apocynin did not change gp91phox, p47phox or p22phox gene expression in nonstimulated PBMC, HL60 DMSO, HL60 IFN γ /TNF α , and PMN and has a subtle increase in p67phox in HL60 IFN γ /TNF α . The results from this work suggest that a rational search for better inhibitors of NADPH oxidase in leukocytes should include a correlation with their affinity as substrates for MPO.

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Little is known about the vaccine protective response for infants born from HIV-infected mothers. We evaluated the antibody response to hepatitis B, tetanus, and diphtheria vaccine in vertically HIV-exposed uninfected infants and compared them to those of control infants not exposed to the virus. The quantitative determination of specific neutralizing antibodies against hepatitis B, diphtheria, and tetanus were performed blindly on serum samples. The results showed that 6.7% of the HIV-exposed uninfected individuals were nonresponders to hepatitis B vaccine (anti-HBs titer, <10 mIU/ml), and 64.4% were very good responders (anti-HBs titer, ≥1,000 mIU/ml), whereas only 3.6% of the nonexposed infants were nonresponders (χ(2)=10.93; 1 df). The HIV-exposed uninfected infants showed protective titers for diphtheria and tetanus but lower geometric mean anti-tetanus titers compared to those of the HIV-unexposed infants. Our data point to the necessity of evaluating vaccine immune responses in these children and reinforced that alterations in lymphocyte numbers and functions reported for newborns from HIV-infected mothers interfere with the vaccine response.

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