The Association between Childhood Overweight and Reflux Esophagitis

Background. In adults, it has been shown that obesity is associated with gastroesophageal reflux disease (GERD) and GERD-related complications. There are sparse pediatric data demonstrating associations between childhood overweight and GERD. Objective. To investigate the association between childhood overweight and RE. Methods. We performed a retrospective chart review of 230 children (M : F = 114  : 116) who underwent esophagogastroduodenoscopy (EGD) with biopsies between January 2000 and April 2006. Patient demographics, weight, height, clinical indications for the procedure, the prevalence of BMI classification groups, the prevalence of RE and usage of anti-reflux medications were reviewed. For these analyses, the overweight group was defined to include subjects with BMI≥ 85th percentile. The normal weight group was defined to include subjects with BMI 5th to 85th percentile. Results. Among the 230 subjects, 67 (29.1%) had BMI percentiles above the 85th percentile for age and gender. The prevalence of RE in the overweight group did not differ significantly from that in the normal weight group (23.9% versus 24.5%, resp.). Overweight subjects taking anti-reflux medications clearly demonstrated a higher prevalence of biopsy-proven RE compared to overweight subjects not taking anti-reflux medications (34.1% versus 7.7%, P = .009). Conclusions. There was no significant difference in the prevalence of biopsy-proven RE in the overweight group compared to the normal weight group. However, the prevalence of RE was significantly higher in overweight subjects on anti-reflux medications compared to overweight subjects not taking anti-reflux medications. This finding emphasizes the importance of early recognition and treatment of GERD for the overweight pediatric patients with symptoms in conjunction with weight loss program for this population to reduce long-term morbidities associated with GERD

Hypogammaglobulinemia with Facial Edema

Knight and colleagues discuss the diagnosis and management of a 35-year-old man with a past history of recurrent cellulitis and otitis media and a two-year history of facial swelling

Bruton's Tyrosine Kinase Is Essential for Human B Cell Tolerance

Most polyreactive and antinuclear antibodies are removed from the human antibody repertoire during B cell development. To elucidate how B cell receptor (BCR) signaling may regulate human B cell tolerance, we tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients suffering from X-linked agammaglobulinemia (XLA). These patients carry mutations in the Bruton's tyrosine kinase (BTK) gene that encode an essential BCR signaling component. We find that in the absence of Btk, peripheral B cells show a distinct antibody repertoire consistent with extensive secondary V(D)J recombination. Nevertheless, XLA B cells are enriched in autoreactive clones. Our results demonstrate that Btk is essential in regulating thresholds for human B cell tolerance

Association of Secondary Amyloidosis with Common Variable Immune Deficiency and Tuberculosis

This paper describes the first case of common variable immunodeficiency (CVID) and AA amyloidosis. A recently treated tuberculosis, and chronic inflammation induced by frequent respiratory tract infections, were thought to be responsible for the amyloidosis. No other reason for this condition could be detected. Although T cell dysfunction in some CVID patients has been reported, pulmonary tuberculosis is quite rare with this condition. Bacterial or viral agents or evidence in favour of intestinal tuberculosis, which would explain this patient's recurrent diarrhea, were not found. In this case, the response of the attacks of diarrhea to metranidazole and the histologic observation of extensive intestinal amyloid deposition, which is known to decrease intestinal motility, made us conclude that the diarrhea was associated with bacterial overgrowth. In this report, we discuss the association of CVID and tuberculosis to secondary amyloidosis and recurrent diarrhea

Evaluation of Lymphoproliferative Disease and Increased Risk of Lymphoma in Activated Phosphoinositide 3 Kinase Delta Syndrome: A Case Report With Discussion

Activated phosphoionositide-3 kinase delta syndrome (APDS) is a rare disorder caused by activating mutations in phosphoionositide 3-kinase delta (PI3Kδ). This syndrome usually presents in childhood with recurrent sinopulmonary infections and immune deficiency as is seen in the case discussed in this report. Patients with APDS also experience other complications including lymphoid hyperplasia, autoimmunity, increased susceptibility to herpes viruses, especially Epstein-Barr virus and cytomegalovirus, and an increased incidence of B-cell lymphoma. The clinical implications for lymphoid hyperplasia and lymphoma are profound and frequently, it is challenging to distinguish between the two. This case report is of a young girl with a mutation in PIK3CD, the gene encoding the catalytic subunit of PI3Kδ, who presents with asymmetrical cervical lymphadenopathy and parotid swelling. After little improvement in lymphadenopathy on antibiotics, an excisional biopsy of a cervical lymph node was obtained which was initially concerning for lymphoma. This case recounts the clinical decisions made to evaluate this lymphadenopathy and concern for malignancy due to the increased incidence of B-cell lymphoma in this population. It was concluded after careful evaluation of her lymph node histology and cytometry, bone marrow biopsy, and CSF studies that her findings were consistent with lymphoid hyperplasia and not lymphoma and she was treated with rituximab. This case highlights the many comorbidities present in patients with this disease and the current treatments for complications in patients with APDS, including new targeted therapies

Naturally occurring mutation affecting the MyD88-binding site of TNFRSF13B impairs triggering of class switch recombination

Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) were previously found to be associated with hypogammaglobulinemia in humans. It has been shown that proliferation inducing ligand (APRIL) elicits class switch recombination (CSR) by inducing recruitment ofMyD88 to a TACI highly conserved cytoplasmic domain (THC). We have identified a patient with hypogammaglobulinemia carrying a missense mutation (S231R) predicted to affect the THC. Aiming to evaluate the relevance of this novel mutation of TACI in CSR induction, we tested the ability of TACI, TLR9, or/and CD40 ligands to trigger CSR in naive B cells and B-cell lines carrying S231R. IgG secretion was impaired when triggered by TACI or/and TLR9 ligands on S231R-naive B cells. Likewise, these stimuli induced less expression of activation-induced cytidine deaminase, I(γ)1-C(μ), and I(γ)1-C(μ), while induction by optimal CD40 stimulation was indistinguishable from controls. These cells also showed an impaired cooperation between TACI and TLR9 pathways, as well as a lack of APRIL-mediated enhancement of CD40 activation in suboptimal conditions. Finally, after APRIL ligation, S231R-mutated TACI failed to colocalize withMyD88. Collectively, these results highlight the requirement of an intact MyD88-binding site in TACI to trigger CSR.Fil: Almejún, María Belén. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cols, Montserrat. Mount Sinai School of Medicine. Department of Medicine; Estados UnidosFil: Zelazko, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Oleastro, Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Cerutti, Andrea. Mount Sinai School of Medicine. Department of Medicine; Estados UnidosFil: Oppezzo, Pablo. Instituto Pasteur. Unidad de Proteínas Recombinantes; UruguayFil: Cunningham Rundles, Charlotte. Mount Sinai School of Medicine. Department of Medicine; Estados UnidosFil: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentin

Effect of Probiotic Bacteria on Microbial Host Defense, Growth, and Immune Function in Human Immunodeficiency Virus Type-1 Infection

The hypothesis that probiotic administration protects the gut surface and could delay progression of Human Immunodeficiency Virus type1 (HIV-1) infection to the Acquired Immunodeficiency Syndrome (AIDS) was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV-1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria which upregulate Treg activation have shown promise in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections, and immune activation contributes to nutritional deficiencies that have lasting consequences especially in the HIV-1 infected child. While effective anti-retroviral therapy (ART) has enhanced survival, wasting is still an independent predictor of survival and a major presenting symptom. Congenital exposure to HIV-1 is a risk factor for growth delay in both infected and non-infected infants. Nutritional intervention after 6 months of age appears to be largely ineffective. A meta analysis of randomized, controlled clinical trials of infant formulae supplemented with Bifidobacterium lactis showed that weight gain was significantly greater in infants who received B. lactis compared to formula alone. Pilot studies have shown that probiotic bacteria given as a supplement have improved growth and protected against loss of CD4+ T cells. The recognition that normal bacterial flora prime neonatal immune response and that abnormal flora have a profound impact on metabolism has generated insight into potential mechanisms of gut dysfunction in many settings including HIV-1 infection. As discussed here, current and emerging studies support the concept that probiotic bacteria can provide specific benefit in HIV-1 infection. Probiotic bacteria have proven active against bacterial vaginosis in HIV-1 positive women and have enhanced growth in infants with congenital HIV-1 infection. Probiotic bacteria may stabilize CD4+ T cell numbers in HIV-1 infected children and are likely to have protective effects against inflammation and chronic immune activation of the gastrointestinal immune system

CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance

Hyper-IgM (HIGM) syndromes are primary immunodeficiencies characterized by defects of class switch recombination and somatic hypermutation. HIGM patients who carry mutations in the CD40-ligand (CD40L) gene expressed by CD4+ T cells suffer from recurrent infections and often develop autoimmune disorders. To investigate the impact of CD40L–CD40 interactions on human B cell tolerance, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from three CD40L-deficient patients. Antibody characteristics and reactivity from CD40L-deficient new emigrant B cells were similar to those from healthy donors, suggesting that CD40L–CD40 interactions do not regulate central B cell tolerance. In contrast, mature naive B cells from CD40L-deficient patients expressed a high proportion of autoreactive antibodies, including antinuclear antibodies. Thus, CD40L–CD40 interactions are essential for peripheral B cell tolerance. In addition, a patient with the bare lymphocyte syndrome who could not express MHC class II molecules failed to counterselect autoreactive mature naive B cells, suggesting that peripheral B cell tolerance also depends on major histocompatibility complex (MHC) class II–T cell receptor (TCR) interactions. The decreased frequency of MHC class II–restricted CD4+ regulatory T cells in CD40L-deficient patients suggests that these T cells may mediate peripheral B cell tolerance through CD40L–CD40 and MHC class II–TCR interactions

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases