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Background: Reaction threshold and severity in food allergy are difficult to predict, and noninvasive predictors are lacking., Objective: We sought to determine the relationships between pre-challenge levels of peanut (PN)-specific antibodies in saliva and reaction threshold, severity, and organ-specific symptoms during PN allergic reactions., Methods: We measured PN-specific antibody levels in saliva collected from 127 children with suspected PN allergy before double-blind, placebo-controlled PN challenges in which reaction threshold, severity, and symptoms were rigorously characterized. Low threshold (LT) PN allergy was defined as reaction to <300 mg of PN protein cumulatively consumed. A consensus severity grading system was used to grade severity. We analyzed associations between antibody levels and reaction threshold, severity, and organ-specific symptoms., Results: Among the 127 children, those with high pre-challenge saliva PN IgE had higher odds of LT PN allergy (odds ratio [OR] 3.9, 95% CI 1.6-9.5), while those with high saliva PN IgA:PN IgE ratio or PN IgG 4 :PN IgE ratio had lower odds of LT PN allergy (OR 0.3, 95% CI 0.1-0.8; OR 0.4, 95% CI 0.2-0.9). Children with high pre-challenge saliva PN IgG 4 had lower odds of severe PN reactions (OR 0.4, 95% CI 0.2-0.9). Children with high saliva PN IgE had higher odds of respiratory symptoms (OR 8.0, 95% CI 2.2-26.8). Saliva PN IgE modestly correlated with serum PN IgE levels (Pearson r = 0.31, P = .0004). High and low saliva PN IgE levels further distinguished reaction threshold and severity in participants stratified by serum PN IgE, suggesting endotypes., Conclusions: Saliva PN antibodies could aid in noninvasive risk stratification of PN allergy threshold, severity, and organ-specific symptoms., Competing Interests: Disclosure statement This work was supported by National Institutes of Health grants R01AI147028 and U19AI136053. Disclosure of potential conflict of interest: S. Sicherer reports royalty payments from UpToDate and Johns Hopkins University Press; grants to his institution from the National Institute of Allergy and Infectious Diseases, Food Allergy Research & Education, and Pfizer; and personal fees from the American Academy of Allergy, Asthma & Immunology as Deputy Editor of the Journal of Allergy and Clinical Immunology: In Practice, outside of the submitted work. The remaining authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (T FH ) play a central role in humoral immunity, we examined T FH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate T FH , B cell interactions and enhance immunoglobulin production. CVID subjects had decreased T FH17 and increased T FH1 subsets; this was associated with increased transitional B cells and decreased IgG + B and IgD - IgM - CD27 + memory B cells. ICOS expression on CVID CD4 + T cells was also decreased. However, ICOS activation of CD4 + T cells by vopratelimab significantly increased total CVID T FH , T FH2 , cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG + B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of T FH modulation in restoring T FH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2023. Published by Elsevier Inc.)

Objective: The COVID-19 pandemic exacerbated gender disparities in some academic disciplines. This study examined the association of the pandemic with gender authorship disparities in clinical neuropsychology (CN) journals., Method: Author bylines of 1,018 initial manuscript submissions to four major CN journals from March 15 through September 15 of both 2019 and 2020 were coded for binary gender. Additionally, authorship of 40 articles published on pandemic-related topics (COVID-19, teleneuropsychology) across nine CN journals were coded for binary gender., Results: Initial submissions to these four CN journals increased during the pandemic (+27.2%), with comparable increases in total number of authors coded as either women (+23.0%) or men (+25.4%). Neither the average percentage of women on manuscript bylines nor the proportion of women who were lead and/or corresponding authors differed significantly across time. Moreover, the representation of women as authors of pandemic-related articles did not differ from expected frequencies in the field., Conclusions: Findings suggest that representation of women as authors of peer-reviewed manuscript submissions to some CN journals did not change during the initial months of the COVID-19 pandemic. Future studies might examine how risk and protective factors may have influenced individual differences in scientific productivity during the pandemic.

Common variable immunodeficiency (CVID) is characterized by profound primary antibody defects and frequent infections, yet autoimmune/inflammatory complications of unclear origin occur in 50% of individuals and lead to increased mortality. Here, we show that circulating bacterial 16S rDNA belonging to gut commensals was significantly increased in CVID serum (P < 0.0001), especially in patients with inflammatory manifestations (P = 0.0007). Levels of serum bacterial DNA were associated with parameters of systemic immune activation, increased serum IFN-γ, and the lowest numbers of isotype-switched memory B cells. Bacterial DNA was bioactive in vitro and induced robust host IFN-γ responses, especially among patients with CVID with inflammatory manifestations. Patients with X-linked agammaglobulinemia (Bruton tyrosine kinase [BTK] deficiency) also had increased circulating bacterial 16S rDNA but did not exhibit prominent immune activation, suggesting that BTK may be a host modifier, dampening immune responses to microbial translocation. These data reveal a mechanism for chronic immune activation in CVID and potential therapeutic strategies to modify the clinical outcomes of this disease.

Background: Primary antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies. More severe forms of PADs-common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA)-require immunoglobulin replacement therapy (IRT) and may have serious complications. Differentiating severe PAD from milder hypogammaglobulinemia not requiring IRT can involve prolonged evaluations and treatment discontinuation. Severe PAD is defined by plasma cell deficiency, but this requires a biopsy to establish. Serum B-cell maturation antigen (sBCMA) is elevated in multiple myeloma, but levels are reduced among patients with myeloma in remission who have hypogammaglobulinemia., Objective: To measure the sBCMA level in 165 subjects to determine whether it differentiates severe PAD-CVID and XLA-from less severe forms not requiring IRT and those without PAD., Methods: sBCMA, B cells, and tissue plasma cells were measured among subjects with and without PAD, and correlated to clinical and laboratory data., Results: Subjects with an IgG level of less than 600 mg/dL had reduced sBCMA levels compared with subjects with PAD with IgG levels of greater than or equal to 600 mg/dL and controls without PAD. sBCMA level was lower in patients with CVID and XLA compared with patients with IgA or IgG deficiency and controls. sBCMA level correlated with gastrointestinal plasma cells. sBCMA level of less than 15 ng/mL had 97% positive predictive value for CVID or XLA, whereas 25 ng/mL or more had an 88% negative predictive value., Conclusions: sBCMA level is profoundly reduced in patients with severe PAD, including those with CVID and XLA and those with IgG levels of less than 600 mg/dL. sBCMA level measurement has potential to augment clinical evaluation of PAD. Prospective studies are needed to evaluate sBCMA for new PAD diagnosis and determine the necessity of IRT., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Common variable immunodeficiency (CVID) and IgG deficiency are 2 of the more prevalent primary humoral immune defects. The former is defined by consensus with criteria for quantitative and qualitative antibody defects, whereas the latter is used to describe patients with reduced IgG, who commonly have recurrent sinopulmonary infections but do not fulfill CVID criteria. However, these patients are often given this diagnosis., Objective: To compare immunologic findings and clinical manifestations of 2 large cohorts of patients with CVID or IgG deficiency to better delineate differences between these syndromes., Methods: We extracted clinical and laboratory data from electronic medical records of patients at our institution who had received International Classification of Disease codes for either CVID, or IgG deficiency. We gathered immunoglobulin levels, lymphocyte subpopulation counts, and serological vaccine responses. In some patients, we performed flow cytometry to determine percentages of memory and switched-memory B cells. We compiled and statistically compared clinical data related to infectious manifestations, bronchiectasis, autoimmune diseases, infiltrative inflammatory processes, and lymphoid malignancies., Results: In contrast to IgG-deficient patients, we found that patients with CVID had lower IgG levels, greater unresponsiveness to most vaccines, lower percentages of memory and isotype switched-memory B cells, and lower CD4 T-cell counts. Clinically, patients with CVID presented similar rates of sinusitis and pneumonias, but a significantly higher prevalence of bronchiectasis and especially noninfectious complications., Conclusions: CVID and IgG deficiency do not share the same disease spectrum, the former being associated with immunodysregulative manifestations and markers of a more severe immune defect. These data may allow clinicians to distinguish these conditions and the management differences that these patients pose., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and is frequently complicated by interstitial lung disease (ILD) for which etiology is unknown and therapy inadequate., Methods: Medical record review implicated B cell dysregulation in CVID ILD progression. This was further studied in blood and lung samples using culture, cytometry, ELISA, and histology. Eleven CVID ILD patients were treated with rituximab and followed for 18 months., Results: Serum IgM increased in conjunction with ILD progression, a finding that reflected the extent of IgM production within B cell follicles in lung parenchyma. Targeting these pulmonary B cell follicles with rituximab ameliorated CVID ILD, but disease recurred in association with IgM elevation. Searching for a stimulus of this pulmonary B cell hyperplasia, we found B cell-activating factor (BAFF) increased in blood and lungs of progressive and post-rituximab CVID ILD patients and detected elevation of BAFF-producing monocytes in progressive ILD. This elevated BAFF interacts with naive B cells, as they are the predominant subset in progressive CVID ILD, expressing BAFF receptor (BAFF-R) within pulmonary B cell follicles and blood to promote Bcl-2 expression. Antiapoptotic Bcl-2 was linked with exclusion of apoptosis from B cell follicles in CVID ILD and increased survival of naive CVID B cells cultured with BAFF., Conclusion: CVID ILD is driven by pulmonary B cell hyperplasia that is reflected by serum IgM elevation, ameliorated by rituximab, and bolstered by elevated BAFF-mediated apoptosis resistance via BAFF-R., Funding: NIH, Primary Immune Deficiency Treatment Consortium, and Rare Disease Foundation.

We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity.

TACI signals activate B cell proliferation, isotype switch and antibody production in both normal immunity and autoimmune states. In contrast to murine TACI, the human TACI gene undergoes alternative splicing to produce short and long isoforms (TACI-S and TACI-L). In previous studies, we showed that transduction of the short, but not long isoform, into murine B cells or human pre-B cells lacking TACI, caused them to become transcriptional and morphologically identical to plasma cells. These data suggest that the expression of different isoforms in humans provides unique controls on B cell maturation. In these studies we show that TACI-S and TACI-L form complexes in a ligand-independent manner, not dependent on a single extracellular domain. Both TACI isoforms are detectable in the endosomal cellular compartment where they co-localize with MyD88, TRAF6, and the activated 65 kDa form of TLR9, depending on a conserved intracellular TACI sequence. In contrast to TACI-L expressing cells, or cells bearing both isoforms, TACI-S binds ligands BAFF and APRIL with substantially greater affinity and promotes enhanced NF-kB activation. Using isoform-specific monoclonal antibodies, we show that while TACI-L is predominant as a surface receptor surface on human B cells, significantly more TACI-S is noted in the intracellular compartment and also in marginal zone, isotype switched and plasmablast in resting B cells. TACI-S is increased in tonsillar B cells and also in the intracellular compartment of activated peripheral B cells. These data shows that alternative splicing of the human TACI gene leads to two isoforms both of which intersect with MyD88 and TRAF6 and form complexes with TLR9, but the two isoforms have different ligand binding capacities, subcellular locations and activation capabilities.

Background: Common variable immunodeficiency (CVID) is an antibody deficiency treated with immunoglobulin; however, patients can have noninfectious inflammatory conditions that lead to heightened morbidity and mortality., Objectives: Modular analyses of RNA transcripts in whole blood previously identified an upregulation of many interferon-responsive genes. In this study we sought the cell populations leading to this signature., Methods: Lymphoid cells were measured in peripheral blood of 55 patients with CVID (31 with and 24 without inflammatory/autoimmune complications) by using mass cytometry and flow cytometry. Surface markers, cytokines, and transcriptional characteristics of sorted innate lymphoid cells (ILCs) were defined by using quantitative PCR. Gastrointestinal and lung biopsy specimens of subjects with inflammatory disease were stained to seek ILCs in tissues., Results: The linage-negative, CD127(+), CD161(+) lymphoid population containing T-box transcription factor, retinoic acid-related orphan receptor (ROR) γt, IFN-γ, IL-17A, and IL-22, all hallmarks of type 3 innate lymphoid cells, were expanded in the blood of patients with CVID with inflammatory conditions (mean, 3.7% of PBMCs). ILCs contained detectable amounts of the transcription factors inhibitor of DNA binding 2, T-box transcription factor, and RORγt and increased mRNA transcripts for IL-23 receptor (IL-23R) and IL-26, demonstrating inflammatory potential. In gastrointestinal and lung biopsy tissues of patients with CVID, numerous IFN-γ(+)RORγt(+)CD3(-) cells were identified, suggesting a role in these mucosal inflammatory states., Conclusions: An expansion of this highly inflammatory ILC population is a characteristic of patients with CVID with inflammatory disease; ILCs and the interferon signature are markers for the uncontrolled inflammatory state in these patients., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Subjects with common variable immune deficiency may have mutations in transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI). Unlike the murine gene, human TACI undergoes alternative messenger (m)RNA splicing to produce isoforms with 1 or 2 ligand-binding domains. Because both isoforms are found in human B cells, we compared their functions in transduced murine B and human pre-B cells. Although murine cells and pre-B cells transduced with the long TACI isoform retained surface CD19 and immunoglobulin G, cells transduced with the short TACI isoform completely lost these B-cell characteristics. Expression of the short TACI isoform produced intense nuclear factor κB activation, nuclear p65 translocation, and colocalization with myeloid differentiation factor 88 and calcium-modulating cyclophilin ligand. The short TACI-transduced cells became larger and CD138 positive, demonstrated upregulated BLIMP1 and XBP1 mRNA, and acquired the morphology of plasma cells. In contrast, cells bearing the long isoform had significantly less BLIMP1 and XBP1 mRNA and, for human pre-B cells, remained CD138 negative. Although human B cells express both isoforms, the short isoform predominates in CD27(+) B cells, toll-like receptor 9-activated peripheral B cells, and splenic marginal zone B cells. Although the transcriptional controls for alternative splicing of isoforms remain unknown, differential signals via isoforms may control plasma-cell generation in humans., (© 2015 by The American Society of Hematology.)

IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood. Using both a 610 carbohydrate array and enzyme-linked immunosorbent assay, we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T-independent bacterial antigens. Moreover, the quantity of specific IgM correlated with IgM(+)IgD(+)CD27(+) B-cell frequencies. As with mouse marginal zone B cells, human IgM(+)CD27(+) B cells activated by TLR7 or TLR9 agonists produced phosphorylcholine-specific IgM. Further linking splenic IgM(+)IgD(+)CD27(+) B cells with production of T-independent IgM, serum from splenectomized subjects, who also have few IgM(+)IgD(+)CD27(+) B cells, had reduced antibacterial IgM. IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell subset, suggesting a means by which loss of this activation pathway leads to reduced cell numbers. Thus, by bolstering the IgM(+)IgD(+)CD27(+) B-cell subset, IRAK-4 and MyD88 promote optimal T-independent IgM antibody responses against bacteria in humans., (© 2014 by The American Society of Hematology.)

Background: It remains unclear whether interstitial lung disease (ILD) in common variable immunodeficiency (CVID) is a consequence of chronic infection or a manifestation of dysregulated lymphoid proliferation found in those with this condition., Objective: To increase understanding of CVID-associated lung disease by comparing clinical and immunologic associations in those with bronchiectasis, ILD, or no lung disease observed on chest computerized tomography (CT)., Methods: Retrospective review of electronic medical records of 61 patients with CVID was used to identify clinical and laboratory correlates of bronchiectasis, ground glass opacity, and pulmonary nodules on CT scan., Results: Significant clinical and immunologic associations were identified for common CT scan findings in CVID. Bronchiectasis was strongly correlated with a CD4+ T-cell count lower than 700 cells/μL and was associated with a history of pneumonia and older age. Pulmonary nodular disease was correlated with increased CD4+:CD8+ T-cell ratios, a history of autoimmune hemolytic anemia or immune thrombocytopenic purpura, elevated IgM, and younger age. Ground glass opacity had similar clinical and laboratory characteristics as those for nodular lung disease but was associated with elevated monocyte counts and the presence of liver disease., Conclusion: CT findings of bronchiectasis or ILD, including ground glass opacity and extensive pulmonary nodules, were correlated with selected clinical and laboratory characteristics. These results suggest divergent processes of CVID lung disease, with bronchiectasis more strongly associated with infection and T-cell lymphopenia and ILD more strongly linked with autoimmunity and lymphoproliferation., (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Mutations in the gene coding for the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) are found in 8% to 10% of subjects with common variable immunodeficiency (CVID). Although heterozygous mutations may coincide with immunodeficiency in a few families, most mutation-bearing relatives are not hypogammaglobulinemic. Thus, the role of TACI mutations in producing the immune defect remains unclear., Objective: This study examined the expression and function of TACI mutations in healthy heterozygous relatives., Methods: We examined the surface and intracellular expression of TACI protein in EBV-transformed B cells of patients and relatives with mutations in 7 families, binding of a proliferation-inducing ligand, and secretion of IgG and IgA by ligand-activated B cells. We tested whether Toll-like receptor 9 agonists increased TACI expression and whether an agonistic anti-TACI antibody could induce activation-induced cytidine deaminase mRNA in those with mutations., Results: Intracellular and extracellular TACI expression was defective for B cells of all subjects with mutations, including subjects with CVID and relatives. Although Toll-like receptor 9 triggering normally up-regulates B-cell TACI expression, this was defective for all subjects with mutations. Triggering TACI by an agonistic antibody showed loss of activation-induced cytidine deaminase mRNA induction in all mutation-bearing B cells. However, ligand-induced IgG and IgA production was normal for healthy relatives but not for subjects with CVID., Conclusion: Thus, B cells of relatives of subjects with CVID who have mutations in TACI but normal immune globulin levels still have detectable in vitro B-cell defects., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Common variable immune deficiency (CVID) B cells have impaired responses to TLR7 and TLR9 agonists including poor cell proliferation, loss of cytokine production, and failure to produce IgG or IgA. We show that TLR7- or 9-activated B cells from CVID subjects with >0.5% peripheral isotype-switched CD27(+) B cells (group 2) have increased mature Cγ1 and Cγ2 heavy-chain mRNA transcripts compared to subjects who have <0.5% isotype-switched cells (group 1). While TLR-stimulated CVID plasmacytoid dendritic cells for all subjects had impaired IFN-α production, TLR7 or TLR9 stimulation in the presence IFN-α normalized isotype-switched CD27(+) B cells, enhanced activation-induced cytidine deaminase mRNA, and significantly improved IgG production only for group 2 subjects. IFN-α also upregulated TLR7 and TLR9 mRNA expression comparable to normal levels in B cells of group 2 subjects, indicating that the loss of IFN-α could be a significant component of the B-cell defect for these subjects.

Background: Heterozygous deleterious mutations in the gene encoding the tumor necrosis factor receptor superfamily member 13b (TNFRSF13B), or transmembrane activator and CAML interactor (TACI), have been associated with the development of common variable immunodeficiency. Smith-Magenis syndrome (SMS) is a genetic disorder characterized by developmental delay, behavioral disturbances, craniofacial anomalies, and recurrent respiratory tract infections. Eighty percent of subjects have a chromosome 17p11.2 microdeletion, which includes TACI. The remaining subjects have mutations sparing this gene., Objective: We examined TACI protein expression and function in patients with SMS to define the role of TACI haploinsufficiency in B-cell function., Methods: We studied TACI expression and function in a cohort of 29 patients with SMS., Results: In patients with SMS with only 1 TACI allele, we found decreased B-cell extracellular and intracellular expression of TACI, reduced binding of a proliferation-inducing ligand, and decreased TACI-induced expression of activation-induced cytidine deaminase mRNA, but these were normal for cells from patients with SMS and 2 TACI alleles. Impaired upregulation of B-cell surface TACI expression by a Toll-like receptor 9 agonist was also observed in cells from patients with 1 TACI allele. Gene sequence analysis of the remaining TACI allele revealed common polymorphisms, with the exception of 1 patient with an amino acid change of uncertain significance. Patients with SMS with the lowest TACI expression had significantly reduced antibody responses to pneumococcal vaccine serotypes., Discussion: Our findings suggest that haploinsufficiency of the TACI gene results in humoral immune dysfunction, highlighting the role of genomic copy number variants in complex traits., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells., Objective: Because Toll-like receptor (TLR) activation of B cells can initiate and potentially sustain normal B cell functions, we examined functional outcomes of TLR7 and TLR9 signaling in CVID B cells., Methods: TLR7-mediated, TLR7/8-mediated, and TLR9-mediated cell proliferation, isotype switch, and immunoglobulin production by control and CVID B cells or isolated naive and memory B cell subsets were examined. We quantitated TNF-alpha, IL-6, and IL-12 production in response to TLR1-9 ligands and measured IFN-alpha production by TLR7-stimulated PBMCs and isolated plasmacytoid dendritic cells (pDCs). IFN-beta mRNA expression by TLR3-stimulated fibroblasts was assessed., Results: Unlike CD27(+) B cells of controls, TLR7-activated, TLR7/8-activated, or TLR9-activated CVID B cells or isolated CD27(+) B cells did not proliferate, upregulate CD27, or shed surface IgD. TLR-stimulated CVID B cells failed to upregulate activation-induced cytosine deaminase mRNA or produce IgG and IgA. TLR7-stimulated PBMCs and pDCs produced little or no IFN-alpha. Reconstituting IFN-alpha in TLR7-stimulated CVID B-cell cultures facilitated proliferation, CD27 upregulation, and isotype switch. These TLR defects are restricted because CVID PBMCs stimulated with TLR ligands produced normal amounts of TNF-alpha, IL-6, and IL-12; TLR3-mediated expression of IFN-beta by CVID fibroblasts was normal., Conclusion: Defective TLR7 and TLR9 signaling in CVID B cells and pDCs, coupled with deficient IFN-alpha, impairs CVID B cell functions and prevents TLR-mediated augmentation of humoral immunity in vivo.

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired antibody responses, recurrent infections, inflammatory, autoimmune and malignancy-related conditions. We evaluated the relationship between memory B cell phenotype, sex, age at diagnosis, immunologic and clinical conditions in 105 CVID subjects from one medical center. Reduced numbers of switched memory B cells (cutoff

Background: Mutations in the gene coding for transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) have been identified in common variable immunodeficiency (CVID). Mutations coincided with immunodeficiency in families, suggesting dominant inheritance., Objective: Because most subjects with CVID have no immunodeficient family members and heterozygous mutations predominate, the role of TACI mutations in sporadic CVID is unclear., Methods: TACI was sequenced from the genomic DNA of 176 subjects with CVID and family members. B cells of subjects with or without mutations were examined for binding to the ligand, a proliferation inducing ligand (APRIL), and for proliferation and immunoglobulin production after ligand stimulation. Data analysis was performed to assess the clinical relevance of TACI mutations., Results: Heterozygous TACI mutations were found in 13 subjects (7.3%). Six with mutations (46%) had episodes of autoimmune thrombocytopenia, in contrast with 12% of 163 subjects without mutations; splenomegaly and splenectomy were significantly increased (P = .012; P = .001.) B cells of some had impaired binding of APRIL and on culture with this ligand were defective in proliferation and immunoglobulin production; however, this was not different from B cells of subjects without mutations. Eight first-degree relatives from 5 families had the same mutations but were not immune-deficient, and their B cells produced normal amounts of IgG and IgA after APRIL stimulation., Conclusion: Mutations in TACI significantly predispose to autoimmunity and lymphoid hyperplasia in CVID, but additional genetic or environmental factors are required to induce immune deficiency., Clinical Implications: Additional causes of this common immune deficiency syndrome remain to be determined.

Common variable immunodeficiency (CVID) is characterized by low levels of immune globulins and lack of antibody. Mutations in transmembrane activator and calcium-modulating cyclophilin ligand (TACI), are found in 8-10%, associated with autoimmunity and splenomegaly. Some patients with mutations had increased serum levels of TACI. Because of this, and the prevalence of autoimmunity, splenomegaly, and lymphadenopathy, we quantitated levels of TACI ligands, a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF) and TACI in serum of 77 patients. CVID subjects had markedly increased serum levels of BAFF (p<0.0001), APRIL (p<0.0001), and TACI (p=0.001) but there was no relationship between levels and autoimmunity, lymphadenopathy, splenomegaly, B cell numbers, or mutations in TACI. Peripheral blood mononuclear cells of CVID subjects had increased levels of BAFF mRNA. We conclude that increased constitutive production and/or underlying immuno-regulatory or inflammatory conditions lead to enhanced release of ligands; however, the biological result remains unclear.

Common variable immune deficiency (CVID) is a primary immune deficiency characterized by low levels of serum immune globulins, lack of Ab, and reduced numbers of CD27+ memory B cells. Although T, B, and dendritic cell defects have been described, for the great majority, genetic causes have not been identified. In these experiments, we investigated B cell and plasmacytoid dendritic cell activation induced via TLR9, an intracellular recognition receptor that detects DNA-containing CpG motifs from viruses and bacteria. CpG-DNA activates normal B cells by the constitutively expressed TLR9, resulting in cytokine secretion, IgG class switch, immune globulin production, and potentially, the preservation of long-lived memory B cells. We found that CpG-DNA did not up-regulate expression of CD86 on CVID B cells, even when costimulated by the BCR, or induce production of IL-6 or IL-10 as it does for normal B cells. TLR9, found intracytoplasmically and on the surface of oligodeoxynucleotide-activated normal B cells, was deficient in CVID B cells, as was TLR9 mRNA. TLR9 B cell defects were not related to proportions of CD27+ memory B cells. CpG-activated CVID plasmacytoid dendritic cells did not produce IFN-alpha in normal amounts, even though these cells contained abundant intracytoplasmic TLR9. No mutations or polymorphisms of TLR9 were found. These data show that there are broad TLR9 activation defects in CVID which would prevent CpG-DNA-initiated innate immune responses; these defects may lead to impaired responses of plasmacytoid dendritic cells and loss of B cell function.

Common variable immunodeficiency (CVID) is presumed to be a heterogenous group of disorders with potentially separate etiologies. Memory B cell subsets, characterized by CD27 expression, have been suggested as a means to subclassify CVID patients. 53 patients were subdivided based on percentages of switched memory B cells (CD27+IgM-IgD-): 33 were placed in Group I (<0.4% CD27+IgM-IgD- cells/peripheral lymphocytes) and 20 in Group II (>0.4%). The median serum IgG for subjects in Group I was lower at 145 mg/dl vs. 329.5 mg/dl for Group II (P=0.038). Post-pneumococcal vaccine IgG response was tested; the median protective response was 0.5 serotypes for Group I and 3 serotypes for Group II (P=0.041). Autoimmune and granulomatous disease was found in higher rates in Group I. CVID patients with decreased percentages of switched memory B cells have lower levels of serum IgG, less effective pneumococcal vaccine antibody responses, and higher rates of autoimmune and granulomatous disease.

Patients with common variable immune deficiency have reduced serum IgG, IgA, and/or IgM, defective antibody production, and many have cellular abnormalities, including proliferative defects, accelerated T cell apoptosis, and insufficient production of IL-2 and IL-10. Excess monocyte intracellular IL-12 leading to a polarized Th-1-type response which could prevent antibody production has been suggested. Here we found that dendritic cells (DCs) of CVID subjects have a significantly reduced capacity to secrete IL-12, as compared to DCs of normal subjects when cultured with physiologic simulators: LPS (P = 0.0005), TNF-alpha (P = 0.006), or CD40-L fusion protein (P = 0.0004). CVID TNF-alpha or CD40-Ligand matured DCs were also significantly impaired in antigen presentation in mixed lymphocyte culture. Deficient IL-12 production was closely correlated to lymphocyte functions in vitro and to the absolute numbers of CD4 T cells in peripheral blood. While CVID DCs appear morphologically similar to DCs of normal subjects, the lack of IL-12 production and defective antigen presentation demonstrate functional defects. Deficient DC function could lead to attenuated T cell activation and defective immunization, features characteristic of CVID.

In a series of 183 emergency operations in which intraoperative autotransfusion was used, 14 patients received blood contaminated by intestinal contents. Six of the 14 patients died early in the postoperative period, four of whom had received more than 16 liters of blood. Only two of the eight survivors had received comparable amounts of blood (13 and 17.5 liters). All eight received antibiotics upon admission; four had positive blood cultures within 24 hours of operation. Complications included acute tubular necrosis in three patients and bowel obstruction with intra-abdominal abscess in another. One of the patients with acute tubular necrosis died six weeks later; all others recovered. We believe this procedure may be life-saving in some cases.

Poor results in the treatment of lung cancer have led to the development of several techniques designed to obtain tissue for diagnosis and to determine the feasibility of resection. Although mediastinoscopy has obtained great popularity, we have been dissatisfied with it because of the low yield of positive results and the attendant increases in length of operations and hospitalizations. We have modified the old technique of thoracoscopy, using a sterilized sigmoidoscope inserted through an intercostal space with the patient positioned and prepared for thoracotomy. Although most frequently used in patients with lung cancer, this procedure also has been helpful in patients with coin lesions, mediastinal tumors, and penetrating wounds of the chest. Although we agree that mediastinoscopy is useful in selected patients, we believe that thoracoscopy offers a greater number of patients a reliable means of obtaining the proper diagnosis more efficiently.

Barrett esophagus is the term describing the presence of an abnormal columnar epithelium in a portion of the esophagus. We have treated 19 patients within the past three years, representing almost 20% of all our esophageal experience; This one pathologic entity has presented as several different clinical pictures: benign stricture, peptic ulceration of the esophagus, intractable esophagitis, and malignancy. One half the patients were under 50 years old, and most were male. The benign lesions have responded well to surgical therapy. There has been an unusually high incidence of malignancy-26.3%. The reasons for the infrequent diagnosis of Barrett esophagus are confusion with "short esophagus" and failure to biopsy the proper site.

Although interest in intraoperative autotransfusion increased when commercial equipment became available, this technique still is utilized rarely in most hospitals. Our experience began with sporadic use in 1972 and has evolved to regular use at least ten times a month. The machine is operated by a technician, and we heparinize the autotransfusion system (ATS) reservoir. Our series includes 47 patients who had elective vascular operations and 141 who had emergency operations, usually for trauma. In the latter group, seven patients who were autotransfused with blood contaminated by intestinal contents survived near fatal injuries and did not develop complications attributable to the procedure. Morbidity and mortality rates in both groups did not appear to be increased as a result of intraoperative autotransfusion. Controversy over methods of anticoagulation and apprehension about effect on blood are not valid reasons for underutilization of this technique. Although significant administrative commitments are required to implement its use and to treat the coagulopathy that accompanies massive reinfusions, they are justified by the value of intraoperative autotransfusion in most cases in which two or more units of blood would be required ordinarily.