ORCID Profile
0000-0002-9953-9959
Current Organisations
Sydney Local Health District
,
University of Otago Dunedin School of Medicine
,
Royal Australasian College of Physicians
,
Royal College of Pathologists of Australasia
,
University of Sydney
,
University of Sydney Concord Clinical School
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Publications
The double misfortune: time to improve off‐label immune intervention
Publisher: Wiley
Date: 08-2013
DOI: 10.1111/IMJ.12214
Safe and effective use of chromatographically purified intravenous immunoglobulin despite profound anti‐IgA sensitization
Publisher: Wiley
Date: 20-05-2001
Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance
Publisher: Elsevier BV
Date: 04-2014
Distinct roles for interleukin‐12p40 and tumour necrosis factor in resistance to oral candidiasis defined by gene‐targeting
Publisher: Wiley
Date: 06-07-2006
Re: Atopy and Risk of Non-Hodgkin lymphoma
Publisher: Oxford University Press (OUP)
Date: 11-09-2007
DOI: 10.1093/JNCI/DJM114
Molecular Pathogenesis of EBV Susceptibility in XLP as Revealed by Analysis of Female Carriers with Heterozygous Expression of SAP
Publisher: Public Library of Science (PLoS)
Date: 11-2011
Induction intravenous cyclophosphamide followed by maintenance oral immunosuppression in refractory myasthenia gravis
Publisher: Wiley
Date: 18-06-2015
DOI: 10.1002/MUS.24536
Abstract: Myasthenia gravis (MG) can be refractory to conventional immunotherapy. We report on the efficacy and durability of intravenous (IV) remission-induction cyclophosphamide (CYC) followed by oral immunosuppression in refractory MG. We identified 8 patients from our medical records with moderate or severe refractory MG who were treated with 6 cycles of IV CYC (0.75 g/m(2) ) every 4 weeks followed by oral immunosuppression. Six patients improved within 3 months of treatment. Four patients remained in clinical remission (mean follow-up 31 months). Two patients responded partially, and 1 patient relapsed after 11 months. Two patients were non-responders. CYC was well tolerated. Acetylcholine receptor antibody levels remained below pretreatment levels in patients in clinical remission. The leukocyte nadir was lower in CYC responders. Remission-induction IV CYC followed by oral immunosuppression is a rapid, effective, and durable treatment for refractory MG. Adding a post-CYC immunosuppressant may account for low relapse rates compared with other published series.
B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans
Publisher: Rockefeller University Press
Date: 04-01-2010
DOI: 10.1084/JEM.20091706
Abstract: Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Expansion of somatically reverted memory CD8 + T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus
Publisher: Rockefeller University Press
Date: 09-04-2012
DOI: 10.1084/JEM.20112391
Abstract: Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8+ T cell subset, displayed a CD45RA−CCR7− effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8+ SAP+ T cells, but not SAP− cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.
Severe spongiform aortic stenosis in monozygotic twins with anti-phospholipid syndrome related to systemic lupus erythematosus
Publisher: Oxford University Press (OUP)
Date: 04-2003
Autoimmunity in primary antibody deficiency is associated with protein tyrosine phosphatase nonreceptor type 22 (PTPN22)
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.JACI.2012.06.023
Abstract: The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22 R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5% T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P=.0014 odds ratio, 3.64 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21low B cells. The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD.
Critical Points of Tumor Necrosis Factor Action in Central Nervous System Autoimmune Inflammation Defined by Gene Targeting
Publisher: Rockefeller University Press
Date: 03-11-1997
Abstract: Tumor necrosis factor (TNF)–dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35–55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF−/− mice. However, in the TNF−/− mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF−/− and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF−/− mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF−/− mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.
Managing the risks of immunosuppression
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2011
Distinguishing Susac’s syndrome from multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 30-12-2014
DOI: 10.1007/S00415-014-7628-9
Abstract: Susac's syndrome is considered a rare differential diagnosis in the work-up of suspected multiple sclerosis. Over the last decade or so, significant advances in our understanding of Susac's syndrome mean that it can now be readily distinguished from multiple sclerosis in the majority of cases with a careful history and close attention to MR imaging. Supporting investigations such as CSF examination, fluorescein angiogram, visual field perimetry and audiology often yield important clues. In milder cases, however, diagnostic uncertainty can exist, and forme frustes of the disease are recognised. In this article, we discuss the clinical features of Susac's syndrome with emphasis on the findings and investigations that help to differentiate it from MS.
Secreted lymphotoxin-α is essential for the control of an intracellular bacterial infection
Publisher: Rockefeller University Press
Date: 15-01-2001
Abstract: Although the essential role of tumor necrosis factor (TNF) in the control of intracellular bac-terial infection is well established, it is uncertain whether the related cytokines lymphotoxin-α (LTα3) and lymphotoxin-β (LTβ) have independent roles in this process. Using C57Bl/6 mice in which the genes for these cytokines have been disrupted, we have examined the relative contribution of secreted LTα3 and membrane-bound LTβ in the host response to aerosol Mycobacterium tuberculosis infection. To overcome the lack of peripheral lymph nodes in LTα−/− and LTβ−/− mice, bone marrow chimeric mice were constructed. LTα−/− chimeras, which lack both secreted LTα3 and membrane-bound LTβ (LTα1β2 and LTα2β1), were highly susceptible and succumbed 5 wk after infection. LTβ−/− chimeras, which lack only the membrane-bound LTβ, controlled the infection in a comparable manner to wild-type (WT) chimeric mice. T cell responses to mycobacterial antigens and macrophage responses in LTα−/− chimeras were equivalent to those of WT chimeras, but in LTα−/− chimeras, granuloma formation was abnormal. LTα−/− chimeras recruited normal numbers of T cells into their lungs, but the lymphocytes were restricted to perivascular and peribronchial areas and were not colocated with macrophages in granulomas. Therefore, LTα3 is essential for the control of pulmonary tuberculosis, and its critical role lies not in the activation of T cells and macrophages per se but in the local organization of the granulomatous response.
Lymphotoxin α/β and Tumor Necrosis Factor Are Required for Stromal Cell Expression of Homing Chemokines in B and T Cell Areas of the Spleen
Publisher: Rockefeller University Press
Date: 18-01-1999
Abstract: Mice deficient in the cytokines tumor necrosis factor (TNF) or lymphotoxin (LT) α/β lack polarized B cell follicles in the spleen. Deficiency in CXC chemokine receptor 5 (CXCR5), a receptor for B lymphocyte chemoattractant (BLC), also causes loss of splenic follicles. Here we report that BLC expression by follicular stromal cells is defective in TNF-, TNF receptor 1 (TNFR1)-, LTα- and LTβ-deficient mice. Treatment of adult mice with antagonists of LTα1β2 also leads to decreased BLC expression. These findings indicate that LTα1β2 and TNF have a role upstream of BLC/CXCR5 in the process of follicle formation. In addition to disrupted follicles, LT-deficient animals have disorganized T zones. Expression of the T cell attractant, secondary lymphoid tissue chemokine (SLC), by T zone stromal cells is found to be markedly depressed in LTα-, and LTβ-deficient mice. Expression of the SLC-related chemokine, Epstein Barr virus–induced molecule 1 ligand chemokine (ELC), is also reduced. Exploring the basis for the reduced SLC expression led to identification of further disruptions in T zone stromal cells. Together these findings indicate that LTα1β2 and TNF are required for the development and function of B and T zone stromal cells that make chemokines necessary for lymphocyte compartmentalization in the spleen.
Increased Thymic B Cells but Maintenance of Thymic Structure, T Cell Differentiation and Negative Selection in Lymphotoxin-α and TNF Gene-Targeted Mice
Publisher: Hindawi Limited
Date: 2000
DOI: 10.1155/2000/13492
Abstract: TNF, lymphotoxin (LT) and their receptors are expressed constitutively in the thymus. It remains unclear whether these cytokines play a role in normal thymic structure or function. We have investigated thymocyte differentiation, selection and thymic organogenesis in gene targeted mice lacking LTα, TNF, or both (TNF/LTα -/- ). The thymus was normal in TNF/LTα -/- mice with regard to cell yields and stromal architecture. Detailed analysis of αβ and γδ T cell-lineage thymocyte subsets revealed no abnormalities, implying that neither TNF nor LT play an essential role in T cell differentiation or positive selection. The number and distribution of thymic CD11c + dendritic cells was also normal in the absence of both TNF and LTα. A three-fold increase in B cell numbers was observed consistently in the TNF/LTα -/- thymus. This phenotype was due entirely to the LTα deficiency and associated with changes in the hemopoietic compartment, rather than the thymic stromal compartment of LTα -/- mice. Finally, specific Vβ8 + T cell deletion within the thymus following intrathymic injection of staphylococcal enterotoxin B (SEB) was TNF/LT independent. Thus, despite the presence of these cytokines and their receptors in the normal thymus, there appears no essential role for either TNF or LT in development of organ structure or for those processes associated with T cell repertoire selection.
Tuberculosis and Treatment with Infliximab
Publisher: Massachusetts Medical Society
Date: 21-02-2002
Dermal Enhancement: Bacterial Products on Intact Skin Induce and Augment Organ-Specific Autoimmune Disease
Publisher: The American Association of Immunologists
Date: 2004
DOI: 10.4049/JIMMUNOL.172.1.302
Abstract: The skin is both an essential barrier for host defense and an important organ of immunity. In this study, we show that the application of cholera toxin to intact mouse skin induces and enhances autoimmune diseases affecting organs at distant anatomic sites, whereas its administration by the mucosal route has been reported to have the opposite effect. First, the CNS autoantigen myelin oligodendrocyte glycoprotein 35–55, when applied repeatedly with cholera toxin to the intact skin of healthy C57BL/6 mice, induced relapsing paralysis with demyelinating immunopathologic features similar to multiple sclerosis. Second, the application of cholera toxin in the absence of autoantigen exacerbated the severity of conventional experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein in CFA. Third, the application of cholera toxin to the intact skin of NOD/Lt mice, with or without insulin B peptide 9–23, exacerbated insulitis and T lymphocyte-derived IFN-γ and IL-4 production in the islets of Langerhans, resulting in an increased incidence and rate of onset of autoimmune diabetes. The data presented in this study highlight the different outcomes of adjuvant administration by different routes. Because dermal application of cholera toxin, and other bacterial products with similar adjuvant activities, is being developed as a clinical vaccination strategy, these data raise the possibility that it could precipitate autoimmune disease in genetically susceptible humans.
Myeloperoxidase‐antineutrophil cytoplasmic antibody seroconversion and fulminant vasculitis in Scl‐70‐positive scleroderma
Publisher: Wiley
Date: 22-02-2007
Tumefactive demyelination following treatment for relapsing multiple sclerosis with alemtuzumab
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-02-2017
Tubulo‐interstitial nephritis and uveitis (TINU) syndrome in an adult
Publisher: Wiley
Date: 02-1993
DOI: 10.1111/J.1445-5994.1993.TB00542.X
Abstract: Mild cognitive impairment (MCI) is defined as the symptomatic pre-dementia phase on the continuum of cognitive decline. Early recognition and application of potential interventions could prevent or delay the progression to dementia. The Rowland Universal Dementia Assessment Scale (RUDAS) shows good performance in the screening of dementia but has limited data regarding its diagnostic properties in the screening of MCI. The objectives of this study were to assess the psychometric properties of the Thai version of the RUDAS (RUDAS-Thai) in the screening of MCI, identify associated factors for the RUDAS performance, and determine the optimal cutoff point in detecting MCI. This was a cross-sectional study conducted from January 2020 to March 2021. Older patients at the outpatient clinic of an internal medicine department at a tertiary care hospital in Thailand were examined. Baseline data were collected, and the RUDAS-Thai was administered to each patient. Afterward, a geriatrician assessed each patient for MCI. A total of 150 patients were included, of whom 42 cases (28%) had MCI. The overall performance of the test using an area under the receiver operating characteristic curve (AUC) was 0.82 (95% confidence interval 0.75-0.89). At the optimal cutoff point of 25/30, the AUC was 0.76 with sensitivity and specificity of 76.2 and 75%, respectively. The educational level affected the test performance according to regression analysis. For patients with years of education ≤6 and >6, the optimal cutoff points were 25/30 and 26/30, respectively. The RUDAS-Thai performed well in differentiating patients with MCI from normal cognition however, it was affected by educational level. A score of 25/30 or lower for persons with ≤6 years of education or 26/30 or lower for persons with higher than 6 years of education is the optimal cutoff point for indication of developing MCI.
Muckle–Wells Cryopyrinopathy: Complex Phenotyping and Response to Therapy in a New Multiplex Kindred
Publisher: Springer Science and Business Media LLC
Date: 23-10-2013
DOI: 10.1007/S10753-013-9752-6
Abstract: Muckle-Wells syndrome (MWS) is a member of the cryopyrin-associated periodic syndrome family of auto-inflammatory diseases, originally described as a triad of urticaria, sensorineural deafness and amyloidosis. IL-1 blockade is a proven therapy for MWS. The clinical, laboratory and genotypic characteristics of a novel kindred of five in iduals with Muckle-Wells syndrome are described. Response to IL-1 blockade therapy in the proband was evaluated. All five affected family members experienced symptoms of multi-organ inflammation. Lead time between symptom onset and diagnosis was approximately 30 years in the proband. Fever was not a universal feature in all affected family members. Anti-IL-1 therapy in the proband resulted in improvements in patient-reported symptoms, inflammatory markers, auditory acuity and reversal of her infertility. Muckle-Wells syndrome is a rare, multisystem, auto-inflammatory syndrome. Delay in diagnosis prevents effective treatment. We propose reversal of infertility to be among the potential benefits of IL-1 inhibition in this disease.
Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency?
Publisher: American Society of Hematology
Date: 26-08-2010
DOI: 10.1182/BLOOD-2010-03-272351
Abstract: Analysis of cancer risk in primary immune deficiency (PID) offers insight into the relationship between immune function and cancer. Data on Australian patients (n = 1132) notified voluntarily to the Australasian Society of Clinical Immunology and Allergy PID Registry (1990-2008) were linked with national death and cancer registries. Person-years of follow-up commenced from up to 15 years before registration on the PID Registry or January 1982, the inception of national cancer registration. Site-specific, 5-year age-, sex-, calendar year–, and state-standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs) were calculated for all cancers except nonmelanocytic skin cancer. During an average of 16 person-years follow-up, a 1.6-fold excess relative risk of cancer was observed (n = 58 SIR 1.60, 95% CI 1.22-2.07) for all PID combined. Relative risk was increased for non-Hodgkin lymphoma (n = 16 SIR 8.82, 95% CI 5.04-14.30), leukemia (n = 4 SIR 5.36, 95% CI 1.46-13.73), and stomach cancer (n = 3 SIR 6.10, 95% CI 1.26-17.84). Excess cancer risk was observed for predominantly antibody deficiencies and other well-defined immunodeficiency syndromes. Results suggest that predominantly antibody deficiencies may be associated with a narrower range of solid cancers than immunodeficiency characterized by predominantly T-cell deficiency, such as iatrogenic and HIV-related immunodeficiency, although this requires confirmation in larger cohorts.
Gene targeting technology and advances in the pathophysiology of inflammation
Publisher: Elsevier BV
Date: 2002
DOI: 10.1080/003130201201111230
Abstract: Gene targeting ('knock-out') technology is now widely used in the basic science of all disciplines of pathology and particularly auto-immune and inflammatory disease. Gene targeting is the wilful introduction of precise mutations into the genome of an animal, usually a mouse, affecting the function of a single gene or genes. The phenotyping of knockout mice provides whole animal data on the functions of in idual genes in pathophysiological settings, and frequently provides the basis for novel therapeutic strategies. 'Knock-ins', the Cre-LoxP system and conditional knockouts are important new advances. This paper serves as an introduction to the methodology and draws on ex les of major advances in inflammation research provided by the targeting of cytokines, in particular the tumour necrosis factor family of ligands.
Systemic strongyloidiasis complicating HIV: a promising response to ivermectin
Publisher: SAGE Publications
Date: 07-1996
Virus-related Merkel cell carcinoma complicating fingolimod treatment for multiple sclerosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-11-2016
The corpus callosum in the diagnosis of multiple sclerosis and other CNS demyelinating and inflammatory diseases
Publisher: BMJ
Date: 09-04-2015
Abstract: Lesions in the corpus callosum (CC) are important radiological clues to the diagnosis of multiple sclerosis (MS), but may also occur in other neuroinflammatory and non-neuroinflammatory conditions. In this article, we discuss the radiological features of lesions within the CC in MS and other central nervous system inflammatory and acquired demyelinating diseases. An understanding of the appearance and location of lesions in the CC is important not only for accurate diagnosis and treatment of these various conditions, but as it also provides insights into pathogenesis.
A systematic checklist approach to immunosuppression risk management: An audit of practice at two clinical neuroimmunology centers
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JNEUROIM.2017.08.009
Abstract: There is no consensus approach to safety screening for immune intervention in clinical neuroimmunology. An immunosuppression risk evaluation checklist was used as an audit tool to assess real-world immunosuppression risk management and formulate recommendations for quality improvements in patient safety. Ninety-nine patients from two centres with 27 non-MS diagnoses were included. An average of 1.9 comorbidities with the potential to adversely impact morbidity and mortality associated with immunosuppression were identified. Diabetes and smoking were the most common, however a range of rarer but potentially life-threatening co-morbid disorders in the context of immunosuppression were identified. Inadequate documentation of risk mitigation tasks was common at 40.1% of total tasks across both cohorts. A routine, systematic immunosuppression checklist approach should be considered to improve immunosuppression risk management in clinical neuroimmunology practice.
Membrane lymphotoxin contributes to anti-leishmanial immunity by controlling structural integrity of lymphoid organs
Publisher: Wiley
Date: 07-2002
DOI: 10.1002/1521-4141(200207)32:7<1993::AID-IMMU1993>3.0.CO;2-F
Primary Immunodeficiency Diseases in Australia and New Zealand
Publisher: Springer Science and Business Media LLC
Date: 22-06-2007
DOI: 10.1007/S10875-007-9105-Z
Abstract: Despite rapid developments in the science of primary immunodeficiency diseases (PID), population characteristics and the burden of disease are poorly characterized. Aggregated data on PID via patient registries are a key component of the public health response. The web-enabled Australasian Society of Clinical Immunology and Allergy PID Register was designed and implemented to address gaps in knowledge of PID. The register provided a cumulative, cross-sectional survey of PID patients in Australia and New Zealand via an online, single time point, center-based, voluntarily recalled, and patient-consented questionnaire. Eighty-eight centers reported 1,209 patients across 56 separate PID syndromes. The study prevalence (cases per 100,000 population) was 5.6 for Australia, 12.4 for the state of South Australia, and 4.9 for Australia and New Zealand combined. Predominately antibody deficiency syndromes accounted for 77% of patients. Common variable immunodeficiency was the most common diagnosis. Patients were geographically dispersed with 80% of centers reporting caseloads of less than 20 patients. Potentially preventable complications of disease were common. Immunoglobulin replacement therapy was used in 30 conditions with 26.5% of the total recipients having antibody deficiency disorders with normal serum IgG. PID in Australia and New Zealand are prevalent, clinically erse, geographically dispersed, and are characterized by high rates of potentially preventable morbidity and resource utilization. A public health focus on PID is required, including strategies to correct disparities in access to care, improve molecular diagnostics and reduce preventable complications of disease. Further studies in antibody deficiency syndromes with normal serum IgG are required.
International experience of pregnancy outcomes in auto-inflammatory syndromes treated with Interleukin-1 inhibitors
Publisher: Springer Science and Business Media LLC
Date: 28-09-2015
Generation of splenic follicular structure and B cell movement in tumor necrosis factor-deficient mice
Publisher: Rockefeller University Press
Date: 19-10-1998
Abstract: Secondary lymphoid tissue organogenesis requires tumor necrosis factor (TNF) and lymphotoxin α (LTα). The role of TNF in B cell positioning and formation of follicular structure was studied by comparing the location of newly produced naive recirculating and antigen-stimulated B cells in TNF−/− and TNF/LTα−/− mice. By creating radiation bone marrow chimeras from wild-type and TNF−/− mice, formation of normal splenic B cell follicles was shown to depend on TNF production by radiation-sensitive cells of hemopoietic origin. Reciprocal adoptive transfers of mature B cells between wild-type and knockout mice indicated that normal follicular tropism of recirculating naive B cells occurs independently of TNF derived from the recipient spleen. Moreover, soluble TNF receptor–IgG fusion protein administered in vivo failed to prevent B cell localization to the follicle or the germinal center reaction. Normal T zone tropism was observed when antigen-stimulated B cells were transferred into TNF−/− recipients, but not into TNF/LTα−/− recipients. This result appeared to account for the defect in isotype switching observed in intact TNF/LTα−/− mice because TNF/LTα−/− B cells, when stimulated in vitro, switched isotypes normally. Thus, TNF is necessary for creating the permissive environment for B cell movement and function, but is not itself responsible for these processes.
Oral amoxicillin-associated anaphylaxis, 1 year after negative penicillin testing and oral amoxicillin challenge
Publisher: Elsevier BV
Date: 07-2016
Challenging Cytokine Redundancy: Inflammatory Cell Movement and Clinical Course of Experimental Autoimmune Encephalomyelitis Are Normal in Lymphotoxin-deficient, but Not Tumor Necrosis Factor–deficien
Publisher: Rockefeller University Press
Date: 04-05-1998
Abstract: Lymphotoxin (LT) is widely regarded as a proinflammatory cytokine with activities equivalent to tumor necrosis factor (TNF). The contribution of LT to experimental autoimmune encephalomyelitis (EAE) was examined using TNF/LTα−/− mice, TNF−/− mice, and a new LTα−/− line described here. All mice were generated directly in the C57BL/6 strain and used for the preparation of radiation bone marrow chimeras to reconstitute peripheral lymphoid organs and restore immunocompetence. This approach overcame the problems related to the lack of lymph nodes that results from LTα gene targeting. We show here that when LT is absent but TNF is present, EAE progresses normally. In contrast, when TNF is absent but LT is present, EAE is delayed in onset and inflammatory leukocytes fail to move normally into the central nervous system parenchyma, even at the peak of disease. In the absence of both cytokines, the clinical and histological picture is identical to that seen when TNF alone is deficient, including demyelination. Furthermore, the therapeutic inhibition of TNF and LTα with soluble TNF receptor in unmanipulated wild-type or TNF−/− mice exactly reproduces these outcomes. We conclude from these studies that TNF and LT are functionally distinct cytokines in vivo, and despite sharing common receptors, show no redundancy of function nor mutual compensation.
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