Novel SLC5A6 mutations lead to B lymphocyte maturation defects with metabolic abnormality rescuable by biotin replenishment.

We characterized a family diagnosed with immunodeficiency disease presenting with low immunoglobulin levels and skin dyskeratosis. Exome sequencing revealed compound heterozygous missense variants in SLC5A6, the gene encoding a cellular sodium-dependent multivitamin transporter (SMVT) responsible for transporting vitamins, including biotin (vitamin B7). We showed that the biotin deficiency was caused by the SLC5A6 variants resulting in defective B cell differentiation and antibody deficiency. Altered cellular metabolic profiles, including aberrant mitochondrial respiration and reliance on glycolysis, may underlie the failure in plasma cell maturation. Replenishment of biotin improved plasma cell maturation and recovered the antibody producing activity in the patient and in a CRISPR-Cas9 gene-edited mouse model bearing a patient-specific SLC5A6 variant. Our results demonstrate the critical role of metabolic reprogramming in the maturation of plasma cells and nominate SLC5A6 as a causative gene for immunodeficiency that may be treated by biotin replenishment.

Postnatal corticosteroid treatment as a risk factor for false positivity in severe combined immunodeficiency newborn screening.

From 2011, 37 children were referred to a hospital due to low levels of T cell receptor excision circles (TRECs) from newborn screening. Among them, three children were immunologically characterized and followed up to show that postnatal corticosteroid usage may be among the causes of false positivity in TRECs screening.

Innate Immune Responses of Vaccinees Determine Early Neutralizing Antibody Production After ChAdOx1nCoV-19 Vaccination.

Background: Innate immunity, armed with pattern recognition receptors including Toll-like receptors (TLR), is critical for immune cell activation and the connection to anti-microbial adaptive immunity. However, information regarding the impact of age on the innate immunity in response to SARS-CoV2 adenovirus vector vaccines and its association with specific immune responses remains scarce. Methods: Fifteen subjects between 25-35 years (the young group) and five subjects between 60-70 years (the older adult group) were enrolled before ChAdOx1 nCoV-19 (AZD1222) vaccination. We determined activation markers and cytokine production of monocyte, natural killer (NK) cells and B cells ex vivo stimulated with TLR agonist (poly (I:C) for TLR3; LPS for TLR4; imiquimod for TLR7; CpG for TLR9) before vaccination and 3-5 days after each jab with flow cytometry. Anti-SARS-CoV2 neutralization antibody titers (surrogate virus neutralization tests, sVNTs) were measured using serum collected 2 months after the first jab and one month after full vaccination. Results: The older adult vaccinees had weaker vaccine-induced sVNTs than young vaccinees after 1st jab (47.2±19.3% vs. 21.2±22.2%, p value<0.05), but this difference became insignificant after the 2nd jab. Imiquimod, LPS and CpG strongly induced CD86 expression in IgD+CD27- naïve and IgD-CD27+ memory B cells in the young group. In contrast, only the IgD+ CD27- naïve B cells responded to these TLR agonists in the older adult group. Imiquimode strongly induced the CD86 expression in CD14+ monocytes in the young group but not in the older adult group. After vaccination, the young group had significantly higher IFN-γ expression in CD3- CD56dim NK cells after the 1st jab, whilst the older adult group had significantly higher IFN-γ and granzyme B expression in CD56bright NK cells after the 2nd jab (all p value <0.05). The IFN-γ expression in CD56dim and CD56bright NK cells after the first vaccination and CD86 expression in CD14+ monocyte and IgD-CD27-double-negative B cells after LPS and imiquimod stimulation correlated with vaccine-induced antibody responses. Conclusions: The innate immune responses after the first vaccination correlated with the neutralizing antibody production. Older people may have defective innate immune responses by TLR stimulation and weak or delayed innate immune activation profile after vaccination compared with young people.

NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities.

Immune-mediated arthritis is an important chronic inflammatory disease of joints causing debilitating morbidity in affected patients. The mechanisms underlying immune-mediated arthritis have been intensively investigated, however the cellular and molecular factors contributing to the joint inflammation in different redox conditions have not been clearly elucidated. Previous research showed that phagocyte-produced reactive oxygen species (ROS) plays an anti-inflammatory role in K/BxN serum-transfer arthritis and NOX2-deficient mice tend to have more severe arthritis. Although many leukocytes play critical roles in the development of immune-mediated arthritis, the role of neutrophils, which are the main producers of ROS in inflammation, is still controversial. We hence assessed the immunomodulatory function of neutrophils from arthritic joints of NOX2-deficient and wild type mice in this study. We found more neutrophils accumulation in NOX2-deficient inflamed joints. RNA-sequencing and quantitative PCR revealed significantly increased expression of acute inflammation genes including IL1b, Cxcl2, Cxcl3, Cxcl10 and Mmp3 in activated neutrophils from the inflamed joints of NOX2-deficient mice. Moreover, gene set enrichment analysis (GSEA) showed enriched gene signatures in type I and II IFN responses, IL-6-JAK-STAT3 signaling pathway and TNF-α signaling pathway via NF-κB in NOX2-deficient neutrophils. In addition, we found that NOX2-deficient neutrophils expressed lower levels of PD-L1 and were less suppressive than WT neutrophils. Moreover, treatment of PD-L1-Fc decreased cytokine expression and ameliorated the severity of inflammatory arthritis. Our results suggest that NOX2-derived ROS is critical for regulating the function and gene expression in arthritic neutrophils. Both the strong pro-inflammatory and weakened anti-inflammatory functions of neutrophils due to abnormal redox regulation may be targets of treatment for immune-mediated arthritis.

How mycobacteria take advantage of the weakness in human immune system in the modern world.

Tuberculosis (TB) infection remains a global health threat in recent decades partly due to a marked increase in the number of susceptible patients, including those with diabetes mellitus (DM) and who receive biologics. Immunity in TB infection is complex as Mycobacterium tuberculosis (MTB) is a highly adaptive pathogen and may evade the immune defense through various ways. Recent advances in TB immunity have revealed that granulomatous inflammation in TB infection is highly dynamic and the early influx of neutrophils may lead to excessive inflammation and pulmonary cavitation, which provide niches for MTB not only to survive but also to spread to other sites. Furthermore, reactive oxygen species have been found to play a crucial role among pathogenesis of TB infection in diabetics (DM-TB) through regulating inflammasome activation and the production of IL-1ß, which in turn modulates the inflammatory network in TB infection, leading to dysfunctional inflammatory responses and tissue remodeling. To understand the exact immunological mechanisms underlying TB infection hence is essential for developing novel adjunctive host-directed therapy (HDT) aiming to alleviate excessive inflammation and tissue destruction and, at the same time, enhance the efficacy of currently available choices of anti-mycobacterial agents. Here we reviewed current epidemiological challenges of global TB control, novel immunological mechanisms underlying dysregulated inflammation in TB infection, especially in DM-TB, and some potential applications of adjunctive HDT in TB treatment.

Increased ILC3s associated with higher levels of IL-1ß aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase.

The role of redox regulation in immune-mediated arthritis has been previously described. However, the relationship between innate immune cells, including innate lymphoid cells (ILCs) and phagocyte-derived ROS, in this process remains unclear. Here, we characterize ILCs and measure the IL-1 family cytokines along with other cytokines relevant to ILC functions and development in serum-induced arthritic joints in wild type and phagocytic NADPH oxidase (NOX2)-deficient Ncf1-/- mice. We found more severe serum-induced joint inflammation and increased NCR+ ILC3s in inflamed joints of Ncf1-/- mice. Furthermore, in vitro stimulation with IL-1ß on Tbet+ ILC1s from joints facilitated their differentiation into ROR-γt+ ILC3s. Moreover, treatment with IL-1 antagonists effectively lowered the proportions of NCR+ ILC3s and IL-17A producing ILC3s in Ncf1-/- arthritic mice and ameliorated the joint inflammation. These results suggest that NOX2 is an essential regulator of ILC transdifferentiation and may mediate this process in a redox-dependent manner through IL-1ß production in the inflammatory joint. Our findings shed important light on the role of ILCs in the initiation and progression in tissue inflammation and delineate a novel innate immune cell-mediated pathogenic mechanism through which redox regulation may determine the direction of immune responses in joints.

Targeted Delivery of Curcumin Rescues Endoplasmic Reticulum-Retained Mutant NOX2 Protein and Avoids Leukocyte Apoptosis.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by defects in the leukocyte NADP oxidase. We previously reported that sarcoplasmic/endoplasmic reticulum calcium pump (SERCA) inhibitors could be used to rescue mutant H338Y-gp91phox protein of a particular type of CGD with a CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T mutation on a Cybb knockout background and investigated the therapeutic effects of ER-targeted delivery of the SERCA inhibitor, curcumin, with poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs). We found that PLGA encapsulation improved the efficacy of curcumin as a SERCA inhibitor to induce ER calcium release. ER-targeting curcumin-loaded PLGA NPs reduced and delayed extracellular calcium entry and protected the cells from mitochondrial damage and apoptosis. In vivo studies showed that ER-targeting curcumin-loaded PLGA NPs treatment enhanced neutrophil gp91phox expression, ROS production and peritoneal bacterial clearance ability of the CybbC1024T transgenic Cybb -/- mice. Our findings indicate that ER-targeted delivery of curcumin not only rescues ER-retained H338Y-gp91phox protein, and hence leukocyte function, but also enhances the bioavailability and reduces cytotoxicity. Modulation of ER function by using organelle-targeted NPs may be a promising strategy to improve the therapeutic potential of curcumin as a treatment for CGD.

Magnetism-tuning strategies for graphene oxide based on magnetic oligoacene oxide patches model.

Graphene oxide (GO) has wide application potential owing to its 2D structure and diverse modification sites for various targeted uses. The introduction of magnetism into GO structures has further advanced the controllability of the application of GO materials. Herein, the concept of modular design and modeling was applied to tune the magnetism of GO. To obtain desirable magnetic properties, diradical-structured GO patches were formed by the introduction of two functional groups to break the Kekule structure of the benzene ring. In these diradical GO patches, the energy of the triplet state was lower than those of the open-shell broken-symmetry singlet state and closed-shell singlet state. To create such multi-radical patches, a practical approach is to determine a substantial spatial separation of the α and ß spin densities in the molecule. Thus, systematic design strategies and tests were evaluated. The first strategy was extending the distance between the distribution center of the α and ß spin densities; the second was controlling the delocalization directions of the α and ß electrons; the third was controlling the delocalization extension of the α and ß electrons by oxidative modification, and finally introducing multi-radical structures into the molecular system and controlling the position of each radical. Herein, successful molecular models with a large magnetic coupling constant (∼3600 cm-1) were obtained. This study paves the way to explore ferromagnetic MGO guided by theoretical study, which may become reality soon.

Mycobacterial infection induces higher interleukin-1ß and dysregulated lung inflammation in mice with defective leukocyte NADPH oxidase.

Granulomatous inflammation causes severe tissue damage in mycobacterial infection while redox status was reported to be crucial in the granulomatous inflammation. Here, we used a NADPH oxidase 2 (NOX2)-deficient mice (Ncf1-/-) to investigate the role of leukocyte-produced reactive oxygen species (ROS) in mycobacterium-induced granulomatous inflammation. We found poorly controlled mycobacterial proliferation, significant body weight loss, and a high mortality rate after M. marinum infection in Ncf1-/- mice. Moreover, we noticed loose and neutrophilic granulomas and higher levels of interleukin (IL)-1ß and neutrophil chemokines in Ncf1-/- mice when compared with those in wild type mice. The lack of ROS led to reduced production of IL-1ß in macrophages, whereas neutrophil elastase (NE), an abundant product of neutrophils, may potentially exert increased inflammasome-independent protease activity and lead to higher IL-1ß production. Moreover, we showed that the abundant NE and IL-1ß were present in the caseous granulomatous inflammation of human TB infection. Importantly, blocking of IL-1ß with either a specific antibody or a recombinant IL-1 receptor ameliorated the pulmonary inflammation. These findings revealed a novel role of ROS in the early pathogenesis of neutrophilic granulomatous inflammation and suggested a potential role of IL-1 blocking in the treatment of mycobacterial infection in the lung.

Magnetofluorescent Carbon Dots Derived from Crab Shell for Targeted Dual-Modality Bioimaging and Drug Delivery.

We propose a one-pot microwave-assisted pyrolysis method for fabrication of magnetofluorescent carbon quantum dots (MFCQDs), using a combination of waste crab shell and three different transition-metal ions, Gd3+, Mn2+, and Eu3+, referred to as Gd@CQDs, Mn@CQDs, and Eu@CQDs, respectively. Chitin from waste crab shell acted not only as a carbon source but also as a chelating ligand to form complexes with transition-metal ions. Gd@CQDs exhibited a high r1 relaxivity of 4.78 mM-1·s-1 and a low r2/r1 ratio of 1.33, suggesting that they show excellent potential as a T1 contrast agent. Mn@CQDs and Eu@CQDs showed high r2 relaxivity values of 140.7 and 28.32 mM-1·s-1, respectively, suggesting their potential for use as T2 contrast agents. Further conjugation of Gd@CQDs with folic acid (FA) enabled specific targeting to folate receptor-positive HeLa cells, as confirmed via in vitro magnetic resonance and fluorescence imaging. Doxorubicin (DOX) was selected as a model drug for conjugation with FA-Gd@CQDs. The as-prepared nanocomposites showed significantly higher cytotoxicity toward HeLa cells than free DOX. No apparent cytotoxicity was observed in vivo (zebrafish embryos) or in vitro (cell viability), suggesting that MFCQDs show potential for development as diagnostic probes or theranostic agents.

Redox Regulation of Pro-IL-1ß Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice.

AIMS: To elucidate the role of reactive oxygen species (ROS) in arthritis and to identify targets of arthritis treatment in conditions with different levels of oxidant stress. RESULTS: Through establishing an arthritis model by injecting arthritogenic serum into wild-type and NADPH oxidase 2 (NOX2)-deficient mice, we found that arthritis had a neutrophilic infiltrate and was more severe in Ncf1(-/-) mice, a mouse strain lacking the expression of the NCF1/p47(phox) component of NOX2. The levels of interleukin-1ß (IL-1ß) and IL-6 in inflamed joints were higher in Ncf1(-/-) than in controls. Antagonists of tumor necrosis factor-α (TNFα) and IL-1ß were equally effective in suppressing arthritis in wild-type mice, while IL-1ß blockade was more effective than TNFα blockade in Ncf1(-/-) mice. A treatment of caspase inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a cathepsin inhibitor alone, suppressed arthritic severity in the wild-type mice, while a treatment of cathepsin inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a caspase inhibitor alone, were effective in treating Ncf1(-/-) mice. Consistently, cathepsin B was found to proteolytically process pro-IL-1ß to its active form and this activity was suppressed by ROS. INNOVATION: This novel mechanism of a redox-mediated immune regulation of arthritis through leukocyte-produced ROS is important for devising an optimal treatment for patients with different levels of tissue ROS. CONCLUSION: Our results suggest that ROS act as a negative feedback to constrain IL-1ß-mediated inflammation, accounting for the more severe arthritis in the absence of NOX2.

Application of paramagnetic graphene quantum dots as a platform for simultaneous dual-modality bioimaging and tumor-targeted drug delivery.

Here, we report the development of a multifunctional nanocarrier consisting of paramagnetic graphene quantum dots (GQDs), folate, and doxorubicin (Dox), used as delivery vehicles, a targeting ligand, and a chemotherapeutic drug, respectively. The paramagnetic GQDs, named folate-GdGQDs, were successfully prepared by covalently conjugating diethylenetriaminepentaacetic acid gadolinium and folic acid onto the surface of GQDs. The resultant folate-GdGQDs, which showed a longitudinal relaxivity r1 of 11.49 mM-1 s-1, greatly enhanced the brightness of the T1-weighted magnetic resonance (MR) images, indicating their potential for use as positive contrast agents for MR imaging (MRI). The feasibility of utilizing the folate-GdGQDs with strong luminescence emissions for targeted imaging of HeLa cells was also evaluated. An in vitro cell (HeLa and HepG2 cells) viability assay and in vivo evaluation of toxicity to the embryonic development of zebrafish showed that these folate-GdGQDs exhibited negligible cytotoxicity and excellent biocompatibility within the given range of concentrations. More importantly, strong therapeutic activity was achieved by loading Dox onto the surfaces of folate-GdGQDs through π-π stacking and hydrophobic interactions, leading to the formation of folate-GdGQD/Dox multifunctional nanocarriers. Approximately 80% of the loaded Dox was released from the folate-GdGQD/Dox nanocarriers under mild acidic conditions (pH 5.0), whereas only 20% of Dox was released at pH 7.0 after 48 h. Furthermore, these multifunctional nanocarriers could efficiently induce an inhibitory effect on HeLa cells, as confirmed by an in vitro cytotoxicity assay. The combined flow cytometry analysis and confocal laser scanning microscopic observation showed that these nanocarriers were efficiently taken up by the cancer cells overexpressing folate receptors. Taken together, these results suggested that the multifunctional nanocarriers could be used as promising targeted drug delivery vehicles for the diagnosis and image-guided chemotherapy of various cancers.

Increased resistin may suppress reactive oxygen species production and inflammasome activation in type 2 diabetic patients with pulmonary tuberculosis infection.

Although it has been known for decades that patients with type 2 diabetes mellitus (DM) are more susceptible to severe tuberculosis (TB) infection, the underlying immunological mechanisms remain unclear. Resistin, a protein produced by immune cells in humans, causes insulin resistance and has been implicated in inhibiting reactive oxygen species (ROS) production in leukocytes. Recent studies suggested that IL-1ß production in patients with Mycobacteria tuberculosis infection correlates with inflammasome activation which may be regulated by ROS production in the immune cells. By investigating the level of resistin in different patient groups, we found that serum resistin levels were significantly higher in severe TB and DM-only groups when compared with mild TB cases and healthy controls. Moreover, elevation of serum resistin correlated with impairment of ROS production of neutrophils in patients with both DM and TB. In human macrophages, exogenous resistin inhibits the production of ROS which are important in the mycobacterium-induced inflammasome activation. Moreover, macrophages with defective ROS production had poor IL-1ß production and ineffective control of mycobacteria growth. Our results suggest that increased resistin in severe TB and DM patients may suppress the mycobacterium-induced inflammasome activation through inhibiting ROS production by leukocytes.

Impact of molecular diagnosis on treating Mendelian susceptibility to mycobacterial diseases.

BACKGROUND/OBJECTIVE: The IL-12-IFN-γ axis is critical for immune defense against mycobacterial infections. Inherited mutations that affect normal activation of this self-amplifying cytokine reaction lead to increased chances of mycobacterial infections, known as Mendelian susceptibility to mycobacterial diseases (MSMD). Delayed diagnosis and difficulty in identifying pathogenic mycobacteria hinder proper treatment of patients, so the aim of this study was to facilitate the diagnosis of mycobacterial infections in MSMD patients using an oligonucleotide array method. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from three MSMD patients in the same family. A series of immunologic studies, including testing for cytokine secretion after leukocyte stimulation, cell-surface marker analysis, and cDNA sequencing, were then performed. An oligonucleotide array was used to rapidly identify pathogens. RESULTS: Cytokine secretion testing showed normal IFN-γ secretion after IL-12 stimulation but low IL-12 secretion after IFN-γ stimulation, which indicates a defect in the IFN-γ receptor or its intracellular signaling. Cell-surface receptor analysis showed IFN-γ receptor 1 overexpression, suggesting an autosomal dominant IFN-γ receptor 1 deficiency. cDNA sequencing identified the IFNGR1 818del4 mutation in three members of the family with known MSMD, and an oligonucleotide array identified Mycobacterium tuberculosis complex and Mycobacterium abscessus as pathogens. CONCLUSIONS: Patients with suspected MSMD should undergo molecular diagnosis of the primary immunodeficiency. Oligonucleotide array methods may be a tool for rapid identification of pathogens and for guiding antimicrobial treatment in immunodeficient patients.

Effect of type 2 diabetes mellitus on the clinical severity and treatment outcome in patients with pulmonary tuberculosis: a potential role in the emergence of multidrug-resistance.

BACKGROUND/PURPOSE: A globally increasing trend of type 2 diabetes mellitus (DM), the rising prevalence of tuberculosis (TB) in many countries, and the emergence of multidrug-resistant TB (MDR-TB) in recent years pose a serious challenge for TB control. METHODS: We investigated pulmonary tuberculosis patients with and without type 2 DM (DMTB and TB, respectively) treated at the Chest Hospital, Taiwan, between November 2004 and October 2005. RESULTS: One hundred and ninety-two new patients (60 DMTB, 132 TB) were regularly treated for a full course (≥ 6 months) and prospectively followed for more than 1 year. The DMTB patients had more severe infections (far-advanced: 45.0%vs. 22.7%, p < 0.01), higher mycobacterial loads (sputum smear: 2.9 ± 1.3(+)vs. 1.9 ± 1.7(+), p < 0.01), higher treatment failure rates (17%vs. 2%, p < 0.01), and longer delayed clearance of mycobacteria than did the TB patients (2.5 ± 3.0 months vs. 1.6 ± 1.4 months, p < 0.01). After one year, three DMTB patients and one TB patient had MDR-TB (5.0%vs. 0.8%, p = 0.056). Bacterial genotyping revealed that the proportion of mycobacterial strains was not significantly different in DMTB and TB patients (Beijing strain: 46.7%vs. 40.6%, Non-Beijing strain: 53.3%vs. 59.4%, p = 0.632). CONCLUSION: DMTB patients have more severe TB infections, which require longer treatment and are more likely to develop MDR-TB than are patients with TB alone.

Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation.

BACKGROUND: Isocyanates are low-molecular-weight compounds noted for inducing occupational and environmental asthma. Isocyanate-induced lung disease, an oxidant stress-dependent pulmonary inflammation, is the leading cause of occupational asthma. OBJECTIVES: To address the role of leukocyte-produced oxidants in airway inflammation induced by toluene diisocyanate (TDI), and to elucidate the role of leukocyte nicotinamide adenine dinucleotide phosphate-reduced (NADPH) oxidase in pathogenesis by TDI. METHODS: Wild-type mice and NADPH oxidase-deficient mice (neutrophil cytosolic factor 1 mutant, Ncf1(-/-)) were intranasally injected, challenged with inhalatory TDI, and then investigated for lung inflammation. RESULTS: Cell infiltration in lung tissue and leukocytes in bronchoalveolar lavage, airway reactivity to a methacholine challenge, and TDI-induced inflammatory cytokine expression and nuclear factor activation in the lung tissue were all markedly lower in Ncf1(-/-) mice. Wild-type mice treated with blocking antibodies against CD4 and IL-17 showed markedly lower TDI-induced airway hyperresponsiveness. CONCLUSION: Leukocyte NADPH oxidase is an essential regulator in TDI-induced airway inflammation through redox modification of immune responses.

Thapsigargin and flavin adenine dinucleotide ex vivo treatment rescues trafficking-defective gp91phox in chronic granulomatous disease leukocytes.

Mutations in leukocyte NADPH oxidase genes lead to defective respiratory burst in leukocytes and cause chronic granulomatous diseases (CGD) in humans. The most common form of CGD is caused by mutations in the membrane-bound oxidase component gp91phox, which is encoded by the CYBB gene on the X chromosome. We previously reported on a patient with a CYBB mutation (H338Y) that prevents the intracellular trafficking and expression of gp91phox on leukocytes. The capacity of the leukocytes to produce reactive oxygen species (ROS) was rescued by treatment with thapsigargin and flavin adenine dinucleotide (FAD). The increase in ROS production was not due to the increase in cytoplasmic calcium induced by thapsigargin because the treatment of calcium ionophore did not have the same effect. Protein and cellular analyses on leukocytes and cells transfected with GFP-tagged gp91phox mutant showed that treated cells expressed more Endo H-resistant gp91phox protein on the cell surface and are more effective in killing bacteria. Thapsigargin- and FAD-treated CGD leukocytes had enhanced activity in protecting mice from Staphylococcus-induced peritoneal abscess formation in a mouse model of CGD. These results indicate that thapsigargin-FAD ex vivo treatment is effective in rescuing the ROS-producing activity of leukocytes in selected CGD patients.

Systemic Mycobacterium kansasii infection mimicking peripheral T-cell lymphoma.

Nontuberculous mycobacteria are opportunistic pathogens which predominantly infect the immunocompromised host. The clinical and pathologic diagnosis of mycobacterial infection is generally not difficult. However, it may mimic malignancy on account of the clinical manifestations or the morphology of atypical lymphocytes with epithelioid histiocytes. The latter can be found in some types of lymphomas, especially T-cell lymphoma. This report describes two immunocompetent patients with systemic Mycobacterium kansasii infection presenting with fever, systemic lymphadenopathy, and osteolytic bone lesions. The microscopic features of these two cases were similar and were characterized by effacement of the nodal architecture by lymphocytic infiltrates and small aggregates of epithelioid histiocytes throughout. These lymphocytes showed mild atypia and expressed predominantly CD3. Bone marrow was also involved in the same process in one case and T-cell lymphoma with lymphoepithelioid features was the initial impression. However, further studies reported germline arrangements of T-cell receptor genes, presence of acid-fast bacilli, and recovery of M. kansasii in culture. At follow-up, the lymphadenopathy was seen to have disappeared during antimycobacterial treatment. This report describes two infectious cases with small aggregates of epithelioid histiocytes and atypical lymphocytes mimicking peripheral T-cell lymphoma; and such cases may become more common as the number of immunosuppressed hosts is increasing worldwide. We have reviewed the literature and summarized useful morphologic criteria for differentiation.