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Nguyen VT, Van LH, Thwaites G, Thuong NTT, Oanh PKN, Thu DDA, Dung NT, Quynh VTX, Dinh NTT, Nghia HDT. Fatal Mycobacterium avium meningitis in an HIV-negative Vietnamese man: a case report. J Med Case Rep 2025; 19:227. [PMID: 40375297 PMCID: PMC12079899 DOI: 10.1186/s13256-025-05273-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 04/24/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Nontuberculous mycobacteria are environmental mycobacteria that rarely cause human disease, especially in the central nervous system. Central nervous system infection by Mycobacterium avium complex, the most common pathogen among nontuberculous mycobacteria species, is rare and seldom reported, even in those with advanced human immunodeficiency virus infection. We describe a case of Mycobacterium avium complex meningitis with cerebral hemorrhage in an human immunodeficiency virus uninfected man in Vietnam. CASE PRESENTATION A 56-year-old Vietnamese man with hypertension was hospitalized with a 5-day history of headache, dizziness, low-grade fever, and unresponsive to 5 days of oral antibiotics. A brain magnetic resonance imaging, performed on day 12, showed hydrocephalus and lacunar infarct. The patient did not improve with 8 days of empirical treatment with ceftriaxone, vancomycin, dexamethasone, and meropenem, and was transferred to a referral hospital for tropical diseases. At the second hospital admission, a cerebrospinal fluid analysis showed a white cell count of 22,518 cells/μL with 81% neutrophils, protein 1.72 g/L, and glucose 0.85 mmol/L. Acid-fast bacilli smear of the cerebrospinal fluid was positive. Molecular testing of the cerebrospinal fluid was negative on GeneXpert Ultra testing, while the line probe assay was positive for Mycobacterium avium. Blood cultures at two sites, cerebrospinal fluid cultures for bacteria and fungi, and human immunodeficiency virus Ag/Ab test were negative. The patient was continuously administered meropenem with the addition of azithromycin, rifampin, and ethambutol. Then, 1 day after nontuberculous mycobacteria treatment, he developed right-sided hemiplegia, and brain computed tomography showed a hemorrhage in the parietal area, adjacent to the left lateral ventricle, and left lateral intraventricular hemorrhage shifts the midline to the right. He was transferred to the third referral general hospital and died 22 days after the onset of symptoms. CONCLUSION Nontuberculous mycobacteria-central nervous system infection might mimic unresponsive pyogenic bacterial meningitis. A rapid and accurate diagnosis is essential for initiating appropriate therapy for this deadly disease.
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Affiliation(s)
- Van Thanh Nguyen
- Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, 700000, Vietnam
| | - Le Hong Van
- Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, 700000, Vietnam.
| | - Guy Thwaites
- Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, 700000, Vietnam
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LG, UK
| | - Nguyen Thuy Thuong Thuong
- Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, 700000, Vietnam
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LG, UK
| | | | - Do Dang Anh Thu
- Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, 700000, Vietnam
| | | | | | | | - Ho Dang Trung Nghia
- Hospital for Tropical Diseases, Ho Chi Minh City, 700000, Vietnam.
- Infectious Diseases Department, Pham Ngoc Thach Medical University, Ho Chi Minh City, 700000, Vietnam.
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He H, Cai L, Lin Y, Zheng F, Liao W, Xue X, Pan W. Advances in the understanding of talaromycosis in HIV-negative patients (especially in children and patients with hematological malignancies): A comprehensive review. Med Mycol 2024; 62:myae094. [PMID: 39289007 DOI: 10.1093/mmy/myae094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/19/2024] [Accepted: 09/11/2024] [Indexed: 09/19/2024] Open
Abstract
Talaromyces marneffei (T. marneffei) stands out as the sole thermobiphasic fungus pathogenic to mammals, including humans, within the fungal community encompassing Ascomycota, Eurotium, Eurotiumles, Fungiaceae, and Cyanobacteria. Thriving as a saprophytic fungus in its natural habitat, it transitions into a pathogenic yeast phase at the mammalian physiological temperature of 37°C. Historically, talaromycosis has been predominantly associated with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), classified among the three primary opportunistic infections linked with AIDS, alongside tuberculosis and cryptococcosis. As advancements are made in HIV/AIDS treatment and control measures, the incidence of talaromycosis co-infection with HIV is declining annually, whereas the population of non-HIV-infected talaromycosis patients is steadily increasing. These patients exhibit diverse risk factors such as various types of immunodeficiency, malignant tumors, autoimmune diseases, and organ transplantation, among others. Yet, a limited number of retrospective studies have centered on the clinical characteristics and risk factors of HIV-negative talaromycosis patients, especially in children and patients with hematological malignancies, resulting in an inadequate understanding of this patient cohort. Consequently, we conducted a comprehensive review encompassing the epidemiology, pathogenesis, risk factors, clinical manifestations, diagnosis, treatment, and prognosis of HIV-negative talaromycosis patients, concluding with a prospectus of the disease's frontier research direction. The aim is to enhance comprehension, leading to advancements in the diagnosis and treatment rates for these patients, ultimately improving their prognosis.
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Affiliation(s)
- Haiyang He
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Liuyang Cai
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yusong Lin
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fangwei Zheng
- Department of Dermatology, Linping District Traditional Chinese Medicine Hospital, Hangzhou 311103, China
| | - Wanqing Liao
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xiaochun Xue
- Department of Pharmacy, No. 905 Hospital of PLA Navy, Shanghai 200052, China
| | - Weihua Pan
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
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3
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Cheng A, Holland SM. Anti-cytokine autoantibodies: mechanistic insights and disease associations. Nat Rev Immunol 2024; 24:161-177. [PMID: 37726402 DOI: 10.1038/s41577-023-00933-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2023] [Indexed: 09/21/2023]
Abstract
Anti-cytokine autoantibodies (ACAAs) are increasingly recognized as modulating disease severity in infection, inflammation and autoimmunity. By reducing or augmenting cytokine signalling pathways or by altering the half-life of cytokines in the circulation, ACAAs can be either pathogenic or disease ameliorating. The origins of ACAAs remain unclear. Here, we focus on the most common ACAAs in the context of disease groups with similar characteristics. We review the emerging genetic and environmental factors that are thought to drive their production. We also describe how the profiling of ACAAs should be considered for the early diagnosis, active monitoring, treatment or sub-phenotyping of diseases. Finally, we discuss how understanding the biology of naturally occurring ACAAs can guide therapeutic strategies.
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Affiliation(s)
- Aristine Cheng
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Division of Infectious Diseases, Department of Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Steven M Holland
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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4
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Zheng JH, Wu D, Guo XY. Intracranial infection accompanied sweet’s syndrome in a patient with anti-interferon-γ autoantibodies: A case report. World J Clin Cases 2023; 11:7926-7934. [DOI: 10.12998/wjcc.v11.i32.7926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/23/2023] [Accepted: 11/09/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND Several reports of adult-onset immunodeficiency syndrome have been associated with anti-interferon-gamma (IFN-γ) autoantibodies (AIGAs). However, it is rare to find AIGAs with intracranial infections.
CASE SUMMARY In this case study, we report a case of an AIGAs with intracranial infection and hand rashes considered Sweet’s syndrome. The patient presented to our hospital with a persistent cough, a fever that had been going on for 6 mo, and a rash that had been going on for a week. The patient started losing consciousness gradually on the fourth day after admission, with neck stiffness and weakened limb muscles. The upper lobe of the left lung had a high-density mass with no atypia and a few inflammatory cells in the interstitium. Brain magnetic resonance imaging and cerebrospinal fluid suggest intracranial infection. The pathology of the skin damage on the right upper extremity revealed an infectious lesion that was susceptible to Sweet’s disease. It has an anti-IFN-γ autoantibody titer of 1:2500. She was given empirical anti-non-tuberculous mycobacterial and antifungal treatments. The patient had no fever, obvious cough, headache, or rash on the hand. She got out of bed and took care of herself following hospitalization and discharge with medicine.
CONCLUSION Adults with severe and recurrent infections of several organs should be considered for AIGAs if no other known risk factors exist. AIGAs are susceptible to subsequent intracranial infections and Sweet’s syndrome.
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Affiliation(s)
- Jun-Hui Zheng
- General Internal Medicine, Affiliated Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Dan Wu
- Department of Intensive Care Unit, Affiliated Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Yun Guo
- General Internal Medicine, Affiliated Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Gray PE, David C. Inborn Errors of Immunity and Autoimmune Disease. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1602-1622. [PMID: 37119983 DOI: 10.1016/j.jaip.2023.04.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/01/2023] [Accepted: 04/21/2023] [Indexed: 05/01/2023]
Abstract
Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.
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Affiliation(s)
- Paul Edgar Gray
- Sydney Children's Hospital, Randwick, NSW, Australia; Western Sydney University, Penrith, NSW, Australia.
| | - Clementine David
- Sydney Children's Hospital, Randwick, NSW, Australia; The School of Women's & Children's Health, University of New South Wales, Randwick, NSW, Australia
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6
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Qiu Y, Fang G, Ye F, Zeng W, Tang M, Wei X, Yang J, Li Z, Zhang J. Pathogen spectrum and immunotherapy in patients with anti-IFN-γ autoantibodies: A multicenter retrospective study and systematic review. Front Immunol 2022; 13:1051673. [PMID: 36569827 PMCID: PMC9772057 DOI: 10.3389/fimmu.2022.1051673] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Background Anti-interferon-γ autoantibody (AIGA) positivity is an emerging immunodeficiency syndrome closely associated with intracellular infection in individuals without human immunodeficiency virus (HIV). However, the information on epidemiology, pathogen spectrum, and immunotherapy among these patients lack a systematic description of large data. Methods This systematic literature review and multicenter retrospective study aimed to describe the pathogen spectrum and review treatment strategies among patients with AIGA positivity. Results We included 810 HIV-negative patients with AIGA positivity infected with one or more intracellular pathogens. Excluding four teenagers, all the patients were adults. The most common pathogen was nontuberculous mycobacteria (NTM) (676/810, 83.5%). A total of 765 NTM isolates were identified in 676 patients with NTM, including 342 (44.7%) rapid-grower mycobacteria, 273 (35.7%) slow-grower mycobacteria, and 150 (19.6%) unidentified NTM subtype. Even with long-term and intensive antimicrobial treatments, 42.6% of patients with AIGA positivity had recurrence and/or persistent infection. Sixty-seven patients underwent immunoregulatory or immunosuppressive therapy, and most (60) achieved remission. The most common treatment strategy was rituximab (27/67, 40.3%) and cyclophosphamide (22/67, 32.8%), followed by cyclophosphamide combined with glucocorticoids (8/67, 11.9%). Conclusions Intracellular pathogen was the most common infection in patients with AIGA positivity. The predominant infection phenotypes were NTM, varicella-zoster virus, Talaromyces marneffei, and Salmonella spp., with or without other opportunistic infections. AIGA immunotherapy, including rituximab or cyclophosphamide, has yielded good preliminary results in some cases.
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Affiliation(s)
- Ye Qiu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China,Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China,Department of General medicine, The Cancer Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Gaoneng Fang
- Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China,Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Feng Ye
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wen Zeng
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Mengxin Tang
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xuan Wei
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jinglu Yang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhengtu Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,*Correspondence: Jianquan Zhang, ; Zhengtu Li,
| | - Jianquan Zhang
- Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China,*Correspondence: Jianquan Zhang, ; Zhengtu Li,
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7
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IFNγ Regulates NAD+ Metabolism to Promote the Respiratory Burst in Human Monocytes. Blood Adv 2022; 6:3821-3834. [PMID: 35500221 DOI: 10.1182/bloodadvances.2021005776] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 04/12/2022] [Indexed: 11/20/2022] Open
Abstract
IFNγ is an essential and pleiotropic activator of human monocytes, but little is known about the changes in cellular metabolism required for IFNγ-induced activation. We sought to elucidate the mechanisms by which IFNγ reprograms monocyte metabolism to support its immunologic activities. We found that IFNγ increased oxygen consumption rates (OCR) in monocytes, indicative of reactive oxygen species generation by both mitochondria and NADPH oxidase. Transcriptional profiling revealed that this oxidative phenotype was driven by IFNγ-induced reprogramming of NAD+ metabolism, which is dependent on nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage to generate NADH and NADPH for oxidation by mitochondrial complex I and NADPH oxidase, respectively. Consistent with this pathway, monocytes from patients with gain-of-function mutations in STAT1 demonstrated higher than normal OCR. Whereas chemical or genetic disruption of mitochondrial complex I (rotenone treatment or Leigh Syndrome patient monocytes) or NADPH oxidase (DPI treatment or chronic granulomatous disease (CGD) patient monocytes) reduced OCR. Interestingly, inhibition of NAMPT in healthy monocytes completely abrogated the IFNγ-induced oxygen consumption, comparable to levels observed in CGD monocytes. These data identify an IFNγ-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for IFNγ activation of human monocytes.
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8
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Gray PE, Bartlett AW, Tangye SG. Severe COVID-19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals. Clin Transl Immunology 2022; 11:e1365. [PMID: 35444807 PMCID: PMC9013505 DOI: 10.1002/cti2.1365] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 01/08/2023] Open
Abstract
Since the emergence of the COVID-19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre-existing comorbidities, that predispose some people to severe disease, while many other SARS-CoV-2-infected individuals experience mild, if any, consequences. One explanation for intra-individual differences in susceptibility to severe COVID-19 may be that a growing percentage of otherwise healthy people have a pre-existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS-CoV-2 infection. Germline genetic defects have been identified in individuals with life-threatening COVID-19 that compromise local type I interferon (IFN)-mediated innate immune responses to SARS-CoV-2. Remarkably, these variants - which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines - may account for between 3% and 5% of severe COVID-19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN-α, IFN-ω) have been detected in patients' serum prior to infection with SARS-CoV-2 and were found to cause c. 20% of severe COVID-19 in the above 70s and 20% of total COVID-19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID-19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN-α or IFN-β, and may facilitate better management of social distancing, vaccination and early post-exposure prophylaxis.
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Affiliation(s)
- Paul E Gray
- Department of Immunology and Infectious Diseases Sydney Children's Hospital Randwick NSW Australia.,School of Women's and Children's Health University of New South Wales Randwick NSW Australia
| | - Adam W Bartlett
- Department of Immunology and Infectious Diseases Sydney Children's Hospital Randwick NSW Australia.,School of Women's and Children's Health University of New South Wales Randwick NSW Australia
| | - Stuart G Tangye
- Garvan Institute of Medical Research Darlinghurst NSW Australia.,St Vincent's Clinical School UNSW Sydney Randwick NSW Australia
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9
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Knight V. Immunodeficiency and Autoantibodies to Cytokines. J Appl Lab Med 2022; 7:151-164. [PMID: 34996092 DOI: 10.1093/jalm/jfab139] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022]
Abstract
BACKGROUND Anti-cytokine autoantibodies (AAbs) associated with an infectious phenotype are now included along with anti-complement AAbs and somatic pathogenic gene variants as a distinct category termed 'phenocopies of primary immunodeficiencies' in the classification of inborn errors of immunity. Anti-cytokine AAbs target specific cytokine pathways, leading to inordinate susceptibility to specific organisms, generally in the setting of immunocompetence. CONTENT Anti-cytokine AAbs are detected in the majority of healthy individuals and may play a regulatory role in limiting exaggerated responses to cytokines. While it is not well understood why some individuals with anti-cytokine AAbs develop increased susceptibility to organisms of low pathogenicity and others do not, it is likely that genetics and environment play a role. To date, AAbs to interferon gamma (IFNγ), interferon alpha (IFNα), interleukins-17 and 22 (IL-17/IL-22), interleukin-6 and granulocyte macrophage colony stimulating factor (GM-CSF) and their association with increased susceptibility to nontuberculous mycobacteria and other intracellular organisms, viral infections, Candida albicans, Staphylococcus aureus and other pyogenic organisms, and fungal infections respectively, have been described. The clinical phenotype of these patients is very similar to that of individuals with pathogenic gene variants in the specific cytokine pathway that the autoantibody targets, hence the term 'phenocopy.' Recognition of anti-cytokine AAbs as a distinct cause of immunodeficiency or immune dysregulation is important for appropriate management of such patients. SUMMARY Understanding the roles that anti-cytokine AAbs play in health and disease continues to be a fascinating area of research. Evaluating generally immunocompetent individuals who present with chronic, treatment refractory, or unusual infections for anti-cytokine AAbs is critical as it may direct therapy and disease management.
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Affiliation(s)
- Vijaya Knight
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.,Children's Hospital, Colorado, Aurora, CO, USA
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10
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Cheng A, Holland SM. Anticytokine autoantibodies: Autoimmunity trespassing on antimicrobial immunity. J Allergy Clin Immunol 2022; 149:24-28. [PMID: 34998474 PMCID: PMC9034745 DOI: 10.1016/j.jaci.2021.11.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 11/20/2021] [Accepted: 11/20/2021] [Indexed: 01/03/2023]
Abstract
Anticytokine autoantibodies can cause immunodeficiency or dysregulate immune responses. They may phenocopy genetically defined primary immunodeficiencies. We review current anti-type 1 and anti-type 2 interferon; anti-IL-12/23, anti-IL-17, and anti-GM-CSF autoantibodies; HLA associations; disease associations; and mechanistically based treatment options. Suspecting the presence of these autoantibodies in patients and identifying them at the onset of symptoms should ameliorate disease and improve outcomes.
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Affiliation(s)
- Aristine Cheng
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA,Division of Infectious Diseases, Department of Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Steven M. Holland
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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11
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Boisson-Dupuis S, Bustamante J. Mycobacterial diseases in patients with inborn errors of immunity. Curr Opin Immunol 2021; 72:262-271. [PMID: 34315005 DOI: 10.1016/j.coi.2021.07.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/03/2021] [Accepted: 07/01/2021] [Indexed: 12/17/2022]
Abstract
Clinical disease caused by the agent of tuberculosis, Mycobacterium tuberculosis, and by less virulent mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria, can result from inborn errors of immunity (IEIs). IEIs underlie more than 450 conditions, each associated with an impairment of the development and/or function of hematopoietic and/or non-hematopoietic cells involved in host defense. Only a minority of IEIs confer predisposition to mycobacterial disease. The IEIs underlying susceptibility to bona fide tuberculosis are less well delineated than those responsible for susceptibility to less virulent mycobacteria. However, all these IEIs share a defining feature: the impairment of immunity mediated by interferon gamma (IFN-γ). More profound IFN-γ deficiency is associated with a greater vulnerability to weakly virulent mycobacteria, whereas more selective IFN-γ deficiency is associated with a more selective predisposition to mycobacterial disease. We review here recent progress in the study of IEIs underlying mycobacterial diseases.
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Affiliation(s)
- Stéphanie Boisson-Dupuis
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, EU, France; University of Paris, Imagine Institute, Paris, EU, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
| | - Jacinta Bustamante
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, EU, France; University of Paris, Imagine Institute, Paris, EU, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, EU, France.
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12
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Hong GH, Ortega-Villa AM, Hunsberger S, Chetchotisakd P, Anunnatsiri S, Mootsikapun P, Rosen LB, Zerbe CS, Holland SM. Natural History and Evolution of Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome in Thailand and the United States. Clin Infect Dis 2021; 71:53-62. [PMID: 31429907 DOI: 10.1093/cid/ciz786] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/18/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood. METHODS Data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples. RESULTS Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001). CONCLUSIONS Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.
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Affiliation(s)
- Gloria H Hong
- Laboratory of Clinical Immunology and Microbiology, Bethesda, Maryland, USA
| | - Ana M Ortega-Villa
- Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Sally Hunsberger
- Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | | | | | | | - Lindsey B Rosen
- Laboratory of Clinical Immunology and Microbiology, Bethesda, Maryland, USA
| | - Christa S Zerbe
- Laboratory of Clinical Immunology and Microbiology, Bethesda, Maryland, USA
| | - Steven M Holland
- Laboratory of Clinical Immunology and Microbiology, Bethesda, Maryland, USA
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Chawansuntati K, Rattanathammethee K, Wipasa J. Minireview: Insights into anti-interferon-γ autoantibodies. Exp Biol Med (Maywood) 2021; 246:790-795. [PMID: 33430618 DOI: 10.1177/1535370220981579] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The association between the presence of anti-interferon-γ autoantibodies and the onset of immunodeficiency with intracellular infections has been clearly established. No standard regimen to control the production of these pathogenic autoantibodies, apart from antimicrobial therapy to eliminate infections, contributes to the medical burden of this syndrome, which sometimes has a fatal outcome. In this review, we summarize the findings on anti-interferon-γ autoantibodies to facilitate further research and to provide guidance for treatment strategies.
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Affiliation(s)
| | | | - Jiraprapa Wipasa
- Research Institute for Health Sciences, 26682Chiang Mai University, Chiang Mai 50200, Thailand
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14
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Incorrect diagnoses in patients with neutralizing anti-interferon-gamma-autoantibodies. Clin Microbiol Infect 2020; 26:1684.e1-1684.e6. [DOI: 10.1016/j.cmi.2020.02.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 02/17/2020] [Accepted: 02/21/2020] [Indexed: 12/22/2022]
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Autoantibodies against cytokines: phenocopies of primary immunodeficiencies? Hum Genet 2020; 139:783-794. [PMID: 32419033 PMCID: PMC7272486 DOI: 10.1007/s00439-020-02180-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 05/05/2020] [Indexed: 01/04/2023]
Abstract
Anti-cytokine autoantibodies may cause immunodeficiency and have been recently recognized as ‘autoimmune phenocopies of primary immunodeficiencies’ and are found in particular, but not exclusively in adult patients. By blocking the cytokine’s biological function, patients with anti-cytokine autoantibodies may present with a similar clinical phenotype as the related inborn genetic disorders. So far, autoantibodies to interferon (IFN)-γ, GM-CSF, to a group of TH-17 cytokines and to IL-6 have been found to be causative or closely associated with susceptibility to infection. This review compares infectious diseases associated with anti-cytokine autoantibodies with primary immunodeficiencies affecting similar cytokines or related pathways.
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Su SS, Zhang SN, Ye JR, Xu LN, Lin PC, Xu HY, Wu Q, Li YP. Disseminated Talaromyces marneffei And Mycobacterium avium Infection Accompanied Sweet's Syndrome In A Patient With Anti-Interferon-γ Autoantibodies: A Case Report. Infect Drug Resist 2019; 12:3189-3195. [PMID: 31632104 PMCID: PMC6791407 DOI: 10.2147/idr.s218836] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 09/18/2019] [Indexed: 12/22/2022] Open
Abstract
Background Patients with high-titer anti-IFN-γ autoantibodies present disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections. Due to its rare occurrence and non-specific symptoms, this syndrome is difficult to diagnose during early disease stages. Here, we report a case with high-concentrations of serum anti-IFN-γ autoantibodies who presented with disseminated Talaromyces marneffei and NTM disease accompanied Sweet’s syndrome. Case presentation A 62-year-old Chinese woman with no previous history was admitted to our hospital in August 2016 due to intermittent fever for 2 years, left chest wall redness, and swelling for 3 months. During hospitalization, the patient was confirmed with disseminated T. marneffei and successfully treated with antifungal therapy. In July 2017, upon second admission, Mycobacterium avium intracellular (MAC) pulmonary infection was established after positive cultures from the right lung tissue. The patient failed treatment after 1 month of anti-NTM therapy due to side effects. In May 2018, she was confirmed as having disseminated MAC disease accompanied by hand rashes, which was considered as Sweet’s syndrome. High-level anti-IFN-γ antibodies in the patient serum were detected upon comparison with normal controls (2.85-fold increase). Following anti-NTM therapy, both symptoms and pulmonary infiltration gradually improved, and joint destruction and lymphadenitis remained. Conclusions Patients with anti-interferon-γ autoantibodies should be considered for severe, recurrent infections in adults in the absence of other known risk factors. Sweet’s syndrome is a common skin manifestation of the syndrome.
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Affiliation(s)
- Shan-Shan Su
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
| | - Sheng-Nan Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
| | - Jun-Ru Ye
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
| | - Ling-Na Xu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
| | - Peng-Cheng Lin
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
| | - Han-Yan Xu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
| | - Qing Wu
- The Center of Laboratory and Diagnosis, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
| | - Yu-Ping Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People's Republic of China
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Merkel PA, Lebo T, Knight V. Functional Analysis of Anti-cytokine Autoantibodies Using Flow Cytometry. Front Immunol 2019; 10:1517. [PMID: 31354706 PMCID: PMC6640114 DOI: 10.3389/fimmu.2019.01517] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 06/18/2019] [Indexed: 12/23/2022] Open
Abstract
Autoantibodies to cytokines are increasingly being detected in association with immunodeficient, autoimmune and immune dysregulated states. Presence of these autoantibodies in an otherwise healthy individual may result in a unique phenotype characterized by predisposition to infection with specific organisms. The ability to detect these autoantibodies is of importance as it may direct treatment toward a combination of anti-microbial agents and immunomodulatory therapies that decrease autoantibody levels, thereby releasing the immune system from autoantibody-mediated inhibition. Ligand binding assays such as ELISA or bead multiplex assays have been used to detect these antibodies. However, not all anti-cytokine autoantibodies have demonstrable function in vitro and therefore their clinical significance is unclear. Assays that evaluate the functionality of anti-cytokine autoantibodies can supplement such ligand binding assays and add valuable functional information that, when viewed in the context of the clinical phenotype, may guide the use of adjunctive immunomodulatory therapy. This mini review provides an overview of anti-cytokine autoantibodies identified to date and their clinical associations. It also describes the use of flow cytometry for the functional analysis of anti-IFNγ and anti-GM-CSF autoantibodies.
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Affiliation(s)
- Patricia A Merkel
- Section of Allergy and Immunology, Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, United States
| | - Terri Lebo
- Advanced Diagnostic Laboratories, National Jewish Health, Denver, CO, United States
| | - Vijaya Knight
- Section of Allergy and Immunology, Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, United States
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Juvenile-Onset Immunodeficiency Secondary to Anti-Interferon-Gamma Autoantibodies. J Clin Immunol 2019; 39:512-518. [PMID: 31177358 DOI: 10.1007/s10875-019-00652-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 05/27/2019] [Indexed: 10/26/2022]
Abstract
Immunodeficiency secondary to anti-interferon-gamma (anti-IFN-γ) autoantibodies was first described in 2004 as an acquired defect in the IFN-γ pathway leading to susceptibility to multiple opportunistic infections, including dimorphic fungi, parasites, and bacteria, especially tuberculosis and non-tuberculous mycobacterium (NTM) species. It has so far only been described in adult patients. We present 2 cases of disseminated NTM infections in otherwise immunocompetent children. A 16-year-old girl with Sweet's syndrome-like neutrophilic dermatosis developed recurrent fever and cervical lymphadenitis secondary to Mycobacterium abscessus. A 10-year-old boy with a history of prolonged fever, aseptic meningitis, aortitis, and arteritis in multiple blood vessels developed thoracic vertebral osteomyelitis secondary to Mycobacterium avium complex. Both patients were found to have positive serum neutralizing anti-IFNγ autoantibodies. Testing for anti-IFNγ autoantibodies should be considered in otherwise healthy immunocompetent hosts with recurrent or disseminated NTM infection. This represents a phenocopy of primary immunodeficiency which has been recently described only in adults. We report the first two cases of this phenomenon to affect children.
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Refractory Mycobacterium avium Complex Pneumonia and Anti-Interferon-γ Autoantibodies. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2019. [DOI: 10.1097/ipc.0000000000000698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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20
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Gupta S, Browne SK. Autoantibody-Mediated Phenocopies of Primary Immunodeficiency Diseases. Clin Immunol 2019. [DOI: 10.1016/b978-0-7020-6896-6.00040-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Intravenous Cyclophosphamide Therapy for Anti-IFN-Gamma Autoantibody-Associated Mycobacterium abscessus Infection. J Immunol Res 2018; 2018:6473629. [PMID: 30687765 PMCID: PMC6330823 DOI: 10.1155/2018/6473629] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 11/07/2018] [Indexed: 01/08/2023] Open
Abstract
Introduction Anti-interferon-gamma (IFN-γ) autoantibodies are increasingly recognized as a cause of adult-onset immunodeficiency (AOID) worldwide. These patients are susceptible to various intracellular pathogens especially nontuberculous mycobacteria. Most of the patients have a refractory clinical course. Herein, we report the use of immunotherapy with pulse intravenous cyclophosphamide (IVCY) in patients who had progressive, refractory Mycobacterium abscessus infection. Method We included patients, seen at Srinagarind Hospital, Thailand, infected with M. abscessus, who had received ≥3 courses of parenteral antibiotics within the last 12 months and who received pulse IVCY with a tapering dose of prednisolone. Results There were 8 AOID patients who met the criteria and received pulse IVCY between January 2011 and December 2015. One patient was lost to follow-up after 5 courses of IVCY: he had died at home 3 months later. Five patients had favorable outcomes: 2 were able to discontinue NTM therapy, and 3 had stable disease and were on NTM treatment without hospitalization for parenteral antibiotics. Two patients relapsed and needed hospitalization. The IFN-γ Ab titers among the 7 patients were significantly decreased during treatment, and the median initial antibody titer started at 200,000 and then decreased to 5,000 after 2 years of treatment (P < 0.0001). The antibody titer reduction among responsive vs. nonresponsive patient was significantly different after 6 months of treatment: the median antibody titer was 5,000 and 100,000, respectively (P = 0.0467). Conclusion IVCY therapy might be an alternative treatment for AOID patients infected with M. abscessus and refractory to antimycobacterial therapy.
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22
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Wipasa J, Chaiwarith R, Chawansuntati K, Praparattanapan J, Rattanathammethee K, Supparatpinyo K. Characterization of anti-interferon-γ antibodies in HIV-negative immunodeficient patients infected with unusual intracellular microorganisms. Exp Biol Med (Maywood) 2018; 243:621-626. [PMID: 29512397 DOI: 10.1177/1535370218764086] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
A major characteristic of immunodeficiency associated with life-threatening intracellular infection in adults is the presence of anti-interferon-γ antibodies. Although little is known about the mechanism underlying this syndrome, it is believed that the antibodies inhibit the activity of downstream signaling pathway of interferon-γ. In this study, the characteristics of these antibodies in patients who presented, or have a history of, intracellular infection and were positive to anti-interferon-γ antibodies were investigated. The antibodies exhibited mainly the IgG1 and the IgG4 subtypes and recognized the C-terminal of the interferon-γ linear epitope containing the KRKR motif, which is required for the biological activity of interferon-γ. The antibodies bound to recombinant interferon-γ with significantly lower avidity than antibodies to a recall antigen, tetanus toxoid, suggesting that the antibodies might have not undergone affinity maturation. The data from this study may provide fundamental information to better understand the properties of anti-interferon-γ antibodies, which can be useful for future studies. Impact statement An increase in the number of immunodeficient patients related to autoantibodies to interferon (IFN)-γ has been observed particularly in East Asian adults. These patients are often presented with opportunistic infections caused by intracellular pathogens, including non-tuberculous mycobacteria (NTM), Cryptococcus neoformans, Penicillium marneffei (now called Talaromyces marneffei), and non-typhoidal Salmonella spp. The mortality rate for this syndrome is relatively high with 32% patients dying at the median time of 25 months after diagnosis. Characterization of these autoantibodies may promote better understanding of the syndrome, an emerging health problem affecting East Asia populations and impeding their welfare and economic development.
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Affiliation(s)
- Jiraprapa Wipasa
- 1 Research Institute for Health Sciences, 26682 Chiang Mai University , Chiang Mai 50202, Thailand
| | - Romanee Chaiwarith
- 2 Department of Internal Medicine, 26682 Chiang Mai University , Chiang Mai 50202, Thailand
| | - Kriangkrai Chawansuntati
- 1 Research Institute for Health Sciences, 26682 Chiang Mai University , Chiang Mai 50202, Thailand
| | | | | | - Khuanchai Supparatpinyo
- 1 Research Institute for Health Sciences, 26682 Chiang Mai University , Chiang Mai 50202, Thailand.,2 Department of Internal Medicine, 26682 Chiang Mai University , Chiang Mai 50202, Thailand
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van de Vosse E, van Wengen A, van der Meide WF, Visser LG, van Dissel JT. A 38-year-old woman with necrotising cervical lymphadenitis due to Histoplasma capsulatum. Infection 2017; 45:917-920. [PMID: 28822097 PMCID: PMC5696445 DOI: 10.1007/s15010-017-1060-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 08/11/2017] [Indexed: 12/11/2022]
Abstract
Case presentation We analysed a 38-year-old woman with disseminated histoplasmosis for primary immunodeficiency. Her blood showed no IFN-γ response while her peripheral blood mononuclear cells (PBMCs) did. We identified IFN-γ autoantibodies of the IgG class in her serum. Conclusion IFN-γ autoantibodies leading to infections were so far mainly detected in people from Asian descent, where it was found to be associated with certain HLA types. This may be the first patient of African descent, and without the typical HLA types that predispose to this problem, that produces IFN-γ autoantibodies.
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Affiliation(s)
- Esther van de Vosse
- Department of Infectious Diseases, Leiden University Medical Center, Room C5-42, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
| | - Annelies van Wengen
- Department of Infectious Diseases, Leiden University Medical Center, Room C5-42, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | | | - Leo G Visser
- Department of Infectious Diseases, Leiden University Medical Center, Room C5-42, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Jaap T van Dissel
- Department of Infectious Diseases, Leiden University Medical Center, Room C5-42, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
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Abstract
PURPOSE OF REVIEW Concise overview of the field of anticytokine autoantibodies with a focus on recent developments. RECENT FINDINGS Advances in particular in the analysis of autoantibodies to IFNγ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and type I IFN are presented. The target epitope for anti-IFNγ autoantibodies has been found to have high homology to a protein from Aspergillus suggesting molecular mimicry as a mechanism of breaking self-tolerance. A treatment strategy using a recombinant, epitope-depleted version of IFNγ is suggested. Autoantibodies to GM-CSF are associated with disseminated Crytococcus and Nocardia infections thus expanding the spectrum of associated diseases beyond pulmonary alveolar proteinosis. Detailed analysis of anti-GM-CSF autoantibody clones derived from pulmonary alveolar proteinosis patients show evidence of high somatic mutation suggesting T cell-dependent affinity maturation; full GM-CSF neutralization is achieved by synergistic binding of antibodies targeting various distinct noncross-reactive epitopes and leading to antigen sequestration and Fc-mediated clearance. Single mAbs in contrast may lead to higher GM-CSF bioavailability. Anti type I IFN-specific autoantibodies derived from autoimmune polyglandular syndrome type I patients are of extreme high affinity and negatively correlate with the incidence of type I diabetes and may be thus considered to be protective. Hypomorphic severe combined immune deficiency may be associated with complex anticytokine patterns and the emergence of anti type I IFN autoantibodies correlates with severe viral infection histories. SUMMARY Anticytokine autoantibodies may cause susceptibility to infections. In autoimmune/autoinflammatory conditions, anticytokine autoantibodies may be protective or promote disease.
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25
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Wu UI, Chuang YC, Sheng WH, Sun HY, Jhong YT, Wang JY, Chang SC, Wang JT, Chen YC. Use of QuantiFERON-TB Gold In-tube assay in screening for neutralizing anti-interferon-γ autoantibodies in patients with disseminated nontuberculous mycobacterial infection. Clin Microbiol Infect 2017; 24:159-165. [PMID: 28694201 DOI: 10.1016/j.cmi.2017.06.029] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 06/27/2017] [Accepted: 06/29/2017] [Indexed: 11/18/2022]
Abstract
OBJECTIVE Anti-interferon- γ (IFN-γ) autoantibodies (anti-IFN-γ Abs) have been increasingly recognized as an important cause of disseminated nontuberculous mycobacterial (DNTM) infection, and identification of this immunodeficiency impacts clinical management. However, the protean disease manifestations and inaccessibility to diagnostic tests in clinical settings hamper its early diagnosis. Here, we sought to determine whether QuantiFERON-TB Gold In-tube (QFT-GIT), a commercialized IFN-γ release assay, could be used to screen for neutralizing anti-IFN-γ Abs among previously healthy adults with DNTM infection. METHODS Non-HIV patients with DNTM infection were prospectively enrolled for the QFT-GIT assays. We measured their plasma concentration of anti-IFN-γ Abs and their neutralizing capacity through enzyme-linked immunosorbent assay and flow cytometry. We then analysed the correlation between QFT-GIT results and the presence of neutralizing anti-IFN-γ Abs among patients with and without previously recognized immunosuppression, respectively. RESULTS Irrespective of the autoantibody concentration or disease activity, all patients with neutralizing anti-IFN-γ Abs (100%, 30/30) had indeterminate QFT-GIT results because of extremely low or undetectable IFN-γ levels in the mitogen tubes. None of the four DNTM patients who were previously healthy and tested negative of anti-IFN-γ Abs had an indeterminate QFT-GIT result, and their IFN-γ levels in the mitogen tube were significantly higher than those of the patients with anti-IFN-γ Abs (8.28 IU/mL vs. 0.05 IU/mL, p 0.001). CONCLUSION An indeterminate QFT-GIT result because of undetectable or extremely low IFN-γ level in the mitogen tube suggests the presence of neutralizing anti-IFN-γ Abs in a previously healthy patient with DNTM infection.
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Affiliation(s)
- U-I Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Y-C Chuang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - W-H Sheng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - H-Y Sun
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Y-T Jhong
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - J-Y Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - S-C Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - J-T Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| | - Y-C Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
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Hase I, Morimoto K, Sakagami T, Ishii Y, van Ingen J. Patient ethnicity and causative species determine the manifestations of anti-interferon-gamma autoantibody-associated nontuberculous mycobacterial disease: a review. Diagn Microbiol Infect Dis 2017. [PMID: 28633901 DOI: 10.1016/j.diagmicrobio.2017.05.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Nontuberculous mycobacteria (NTM) infections involving anti-interferon-gamma (IFN-γ)-neutralizing autoantibodies have been described in previously immunocompetent adults. To investigate the factors underlying various disease manifestations, we reviewed 35 articles published between January 2004 and November 2016 and identified 111 NTM patients with anti-IFN-γ autoantibodies. Rapidly growing mycobacteria (RGM) accounted for 53% of the isolated species. RGM were predominant among the NTM species isolated from Thai (73%), Chinese (58%) and Filipino (56%) patients, whereas M. avium complex (MAC) was predominant among Japanese (58%) and non-Asian (80%) patients. The commonly involved organs included the lymph nodes (79%), bones/joints (34%) and lungs (32%). Compared with the patients with MAC, the patients with RGM had a higher incidence of lymph node lesions (P<0.05) and a lower incidence of bone/joint (P<0.01), lung (P<0.01), soft tissue (P<0.01), bronchus (P<0.01) and muscle (P<0.05) lesions. Clinical manifestations of NTM disease with anti-IFN-γ-neutralizing autoantibodies differ across ethnicities and NTM species.
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Affiliation(s)
- Isano Hase
- Department of Respiratory Medicine, National Hospital Organization Utsunomiya Hospital, 2160 Shimo-Okamoto, Utsunomiya-shi, Tochigi, 329-1193, Japan; Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.
| | - Kozo Morimoto
- Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose-shi, Tokyo, 204-0022, Japan
| | - Takuro Sakagami
- Department of Respiratory Medicine and Infectious Disease, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata-shi, Niigata, 951-8510, Japan
| | - Yoshiki Ishii
- Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
| | - Jakko van Ingen
- Department of Medical Microbiology, Radboud University Medical Center, P.O. Box 9101, 6500HB, Nijmegen, The Netherlands
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Johnson J, Driscoll M, Cohen M, Adler DG. Mycobacterium avium-Intracellulare Complex (MAC) Producing a Periportal Pseudotumor in a Patient With HIV and a Normal CD4 Count. ACG Case Rep J 2016; 3:e92. [PMID: 27807554 PMCID: PMC5062663 DOI: 10.14309/crj.2016.65] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/10/2016] [Indexed: 11/24/2022] Open
Abstract
Mycobacterium avium-intracellulare complex (MAC) is an opportunistic infection typically associated with profound immunosuppression, such as AIDS. The presentation of disseminated MAC can be subtle and mimic systemic symptoms associated with lymphoma; abdominal pseudotumor is an exceptionally rare presentation. In the era of highly active anti-retroviral therapy (HAART), opportunistic infections are increasingly rare, and secondary prophylaxis for MAC may be discontinued after adequate therapy and immune reconstitution. Recurrence of disseminated MAC after adequate therapy may be due to macrolide resistance, but with an adequate CD4 T-cell count and undetectable HIV viral load, recurrence raises questions of more subtle immune dysregulation.
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Affiliation(s)
- Jessica Johnson
- Department of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT
| | - Meghan Driscoll
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT
| | - Michael Cohen
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT
| | - Douglas G. Adler
- Department of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT
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Lim MS, Bermingham N, O'Broin C, Khalil A, Keohane C, Lim C. Isolated Cerebellar Spindle Cell Pseudotumor Caused by Mycobacterium Avium-Intracellulare Complex in a Patient without AIDS. World Neurosurg 2016; 90:703.e1-703.e3. [PMID: 26926796 DOI: 10.1016/j.wneu.2016.02.082] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 02/17/2016] [Accepted: 02/18/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND Spindle cell pseudotumors are formed by histiocytes in response to infection by Mycobacterium avium-intracellulare complex (MAC) and are rare in patients without AIDS. CASE DESCRIPTION A 66-year-old man presented with neck pain, ataxia, and a history of sarcoidosis. A cerebellar lesion was identified on magnetic resonance imaging and surgically excised. Histopathology revealed this to be a spindle cell pseudotumor and MAC was isolated by bacterial culture of cerebrospinal fluid. Hematology revealed cluster of differentiation 4 lymphocytopenia but human immunodeficiency virus serology was negative. The patient was commenced on antimicrobial treatment that included a macrolide and remained well at 1 year follow-up. CONCLUSIONS This rare presentation of isolated intracranial MAC was treated with surgical excision and antimicrobials with a good outcome.
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Affiliation(s)
- Ming-Sheng Lim
- Department of Neurosurgery, Cork University Hospital, Cork, Ireland.
| | - Niamh Bermingham
- Department of Neuropathology, Cork University Hospital, Cork, Ireland
| | - Cathal O'Broin
- Department of Infectious Diseases, Cork University Hospital, Cork, Ireland
| | - Ayman Khalil
- Department of Neurosurgery, Cork University Hospital, Cork, Ireland
| | - Catherine Keohane
- Department of Neuropathology, Cork University Hospital, Cork, Ireland
| | - Chris Lim
- Department of Neurosurgery, Cork University Hospital, Cork, Ireland
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Knight V, Merkel PA, O'Sullivan MD. Anticytokine Autoantibodies: Association with Infection and Immune Dysregulation. Antibodies (Basel) 2016; 5:E3. [PMID: 31557985 PMCID: PMC6698860 DOI: 10.3390/antib5010003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 12/15/2015] [Accepted: 01/05/2016] [Indexed: 12/14/2022] Open
Abstract
The association of autoantibodies to cytokines with immune deficiency, autoimmunity and/or immune dysregulation is increasingly being recognized. For example, autoantibodies to interferon gamma have been found to be associated with chronic, treatment refractory infections with intracellular organisms such as mycobacteria, autoantibodies to interleukin 17 with chronic mucocutaneous candidiasis, and anti-interferon alpha autoantibodies with systemic lupus erythematosus. While low titer autoantibodies to these and other cytokines may be detected in normal individuals, patients with infectious or autoimmune manifestations tend to have high titer autoantibodies that may block or potentiate the function of the respective cytokine. Recognition of these autoantibodies is important because it may direct treatment toward a combination of adjunctive immunotherapy to modulate the autoantibody level while continuing with appropriate anti-microbial therapy. This review focuses on the anti-cytokine autoantibodies documented to date, their autoimmune, immune dysregulation and infectious disease associations, methods for detection of these antibodies and potential treatment options.
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Affiliation(s)
- Vijaya Knight
- Division of Pathology, Department of Medicine, National Jewish Health, Denver, CO 80015, USA.
- National Jewish Health Advanced Diagnostic Laboratories, National Jewish Health, Denver, CO 80015, USA.
| | - Patricia A Merkel
- Division of Pathology, Department of Medicine, National Jewish Health, Denver, CO 80015, USA.
| | - Michael D O'Sullivan
- Immunology Department, PathWest Laboratory Medicine WA, Perth 6009, Australia.
- School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Australia.
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Ku CL, Lin CH, Chang SW, Chu CC, Chan JFW, Kong XF, Lee CH, Rosen EA, Ding JY, Lee WI, Bustamante J, Witte T, Shih HP, Kuo CY, Chetchotisakd P, Kiertiburanakul S, Suputtamongkol Y, Yuen KY, Casanova JL, Holland SM, Doffinger R, Browne SK, Chi CY. Anti-IFN-γ autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia. J Allergy Clin Immunol 2015; 137:945-8.e8. [PMID: 26522403 DOI: 10.1016/j.jaci.2015.09.018] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 09/18/2015] [Accepted: 09/23/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Cheng-Lung Ku
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
| | - Chia-Hao Lin
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Su-Wei Chang
- Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Chen-Chung Chu
- Immunogenetics Laboratory, Medical Research Department, Mackay Memorial Hospital, Taipei, Taiwan
| | - Jasper F W Chan
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, The University of Hong Kong Queen Mary Hospital, Hong Kong, China
| | - Xiao-Fei Kong
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Chen-Hsiang Lee
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Emily A Rosen
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Jing-Ya Ding
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Wen-I Lee
- Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jacinta Bustamante
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
| | - Torsten Witte
- Clinic for Immunology and Rheumatology, Medical School of Hanover, Hanover, Germany
| | - Han-Po Shih
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Chen-Yen Kuo
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | | | | | - Yupin Suputtamongkol
- Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kwok-Yung Yuen
- State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, The University of Hong Kong Queen Mary Hospital, Hong Kong, China
| | - Jean-Laurent Casanova
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; Howard Hughes Medical Institute, New York, NY; Pediatric Immuno-Hematology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
| | - Steven M Holland
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Rainer Doffinger
- Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom; National Institute for Health Research, Cambridge Biomedical Research Center, Cambridge, United Kingdom
| | - Sarah K Browne
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Chih-Yu Chi
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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Chowdhary M, Narsinghani U, Kumar RA. Intracranial abscess due to Mycobacterium avium complex in an immunocompetent host: a case report. BMC Infect Dis 2015. [PMID: 26201464 PMCID: PMC4511996 DOI: 10.1186/s12879-015-1026-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background Mycobacterium avium complex (MAC) is a ubiquitous pathogen, widely distributed in the environment including water, soil and animals. It is an uncommonly encountered clinical pathogen; primarily causing pulmonary infections in patients with underlying lung disease or disseminated disease in immunocompromised hosts. Sporadically, extra-pulmonary infections have been documented including involvement of the liver, spleen, skin, soft tissue and lymph nodes. Central nervous system (CNS) infections due to MAC are exceedingly rare and carry a poor prognosis. Additionally, such infections are largely reported in patients infected with HIV. Herein we report the first case of intracranial abscess due to MAC in an immunocompetent man with a normal CD4 count and negative HIV status. Case presentation A previously healthy 40-year-old male presented to us with progressively worsening CNS symptoms. The patient’s presentation was uncharacteristic of MAC infection in immunocompetent hosts, as he developed subacute, progressive symptoms that included severe frontal headaches, left eyelid swelling, blurry vision, and diplopia, without any pulmonary or systemic manifestations. Neuroimaging revealed multiple ring-enhancing lesions, which required neurosurgical intervention. MAC was the only pathogen that grew from intraoperative tissue cultures. The patient was subsequently treated with a 12-month regimen consisting of Clarithromycin, Ethambutol, and Rifampin, with successful clinical resolution. Conclusion Our findings indicate that it is important to consider rare infections such as MAC in immunocompetent patients, regardless of atypical symptoms. Despite the severity of this infection, with timely diagnosis effective treatment is available.
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Affiliation(s)
- Mudit Chowdhary
- Department of Internal Medicine, Mercer University School of Medicine, 707 Pine Street, Macon, GA, 31201, USA.
| | - Umesh Narsinghani
- Department of Pediatrics, Mercer University School of Medicine, Macon, GA, USA.
| | - Ritu A Kumar
- Department of Internal Medicine, Mercer University School of Medicine, 707 Pine Street, Macon, GA, 31201, USA. .,Department of Infectious Diseases, Mercer University School of Medicine, Macon, GA, USA.
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Endobronchial lesions caused by nontuberculous mycobacteria in apparently healthy pediatric patients. Pediatr Infect Dis J 2015; 34:532-5. [PMID: 25478650 DOI: 10.1097/inf.0000000000000606] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Pulmonary disease caused by nontuberculous mycobacteria in healthy children is rare, and its pathogenesis is unknown in most cases and standardized treatment is lacking. Here, we report various endobronchial manifestations in 5 patients including hitherto undescribed diffuse tracheobronchial granulomas in 2 patients. Bronchoscopic debulking was performed in all patients and tuberculostatic treatment in 4. All patients including 1 without tuberculostatic treatment showed remission.
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Hanitsch LG, Löbel M, Müller-Redetzky H, Schürmann M, Suttorp N, Unterwalder N, Mönnich U, Meisel C, Wittke K, Volk HD, Scheibenbogen C, Kölsch U. Late-Onset Disseminated Mycobacterium avium intracellulare Complex Infection (MAC), Cerebral Toxoplasmosis and Salmonella Sepsis in a German Caucasian Patient with Unusual Anti-Interferon-Gamma IgG1 Autoantibodies. J Clin Immunol 2015; 35:361-5. [PMID: 25875701 DOI: 10.1007/s10875-015-0161-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 03/31/2015] [Indexed: 11/24/2022]
Abstract
PURPOSE Since we described for the first time a patient with IgG4 autoantibodies to IFN-γ more than 10 years ago, many patients with IFN-γ IgG4 autoantibodies have been described, mostly in Mongolian/ Asian patients with a particular HLA background and in association with disseminated nontuberculous mycobacterial infections. Very recently, the first Caucasian US patient was reported and we now present the case of a 65-year old Caucasian woman with severe disseminated Mycobacterium avium infection, cerebral toxoplasmosis and salmonella sepsis who was tested positive for IFN-γ deficiency due to unusual anti-IFN-γ IgG1 autoantibodies. METHODS IFN-γ production after ex vivo ConA stimulation of the patient's whole blood and isolated peripheral blood mononuclear cells was assessed. Anti-human IFN-γ antibodies were measured by Ig/Ig-subclass-specific ELISA. In vitro physiologic relevance and blocking capacity of IFN-γ-stimulation by patient's serum was analysed by flow cytometric assessment of cytokine-induced phosphorylation of pSTAT1(Y701). RESULTS Severely impaired IFN-γ production in the patient's whole blood but normal production in peripheral blood mononuclear cells in the absence of autologous serum was observed. High titre anti-IFN-γ antibodies of the IgG1 subclass could be demonstrated in the patient's serum by ELISA. Further, the addition of patient's serum to IFN-γ-stimulated immune cells showed inhibition of STAT1 phosphorylation. CONCLUSIONS IFN-γ autoantibodies of any IgG-isotype should be considered in patients with severe opportunistic infections independent of age at onset and ethnicity.
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Affiliation(s)
- Leif G Hanitsch
- Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Augustenburger Platz 1/ Südstraße 2, 13353, Berlin, Germany,
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Rosenberg JM, Utz PJ. Protein microarrays: a new tool for the study of autoantibodies in immunodeficiency. Front Immunol 2015; 6:138. [PMID: 25904912 PMCID: PMC4387933 DOI: 10.3389/fimmu.2015.00138] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/12/2015] [Indexed: 12/19/2022] Open
Abstract
Autoimmunity is highly coincident with immunodeficiency. In a small but growing number of primary immunodeficiencies, autoantibodies are diagnostic of a given disease and implicated in disease pathogenesis. In order to improve our understanding of the role of autoantibodies in immunodeficiencies and to discover novel autoantibodies, new proteomic tools are needed. Protein microarrays have the ability to screen for reactivity to hundreds to many thousands of unique autoantigens simultaneously on a single chip using minimal serum input. Here, we review different types of protein microarrays and how they can be useful in framing the study of primary and secondary immunodeficiencies.
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Affiliation(s)
- Jacob M Rosenberg
- Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine , Stanford, CA , USA
| | - Paul J Utz
- Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine , Stanford, CA , USA ; Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine , Stanford, CA , USA
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Vincent T, Plawecki M, Goulabchand R, Guilpain P, Eliaou JF. Emerging clinical phenotypes associated with anti-cytokine autoantibodies. Autoimmun Rev 2015; 14:528-35. [PMID: 25633324 DOI: 10.1016/j.autrev.2015.01.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Accepted: 01/21/2015] [Indexed: 01/23/2023]
Abstract
Anti-cytokine autoantibodies (AAbs) are frequent and involve a very large panel of cytokines both in healthy subjects and in patients with various pathological conditions. In healthy individuals, anti-cytokine AAbs are described as a part of the natural AAb repertoire and are thought to contribute to the fine regulation of cytokine homeostasis. In some patients, neutralizing AAbs targeting cytokines required for the immune protection against specific microbes may induce acquired immunodeficiency leading to very specific infectious phenotypes. For instance, anti-IFNγ AAbs may induce disseminated non-tuberculous mycobacterial infections; anti-IL-17 AAbs are associated with the development of chronic mucosal candidiasis, and anti-IL-6 AAbs with severe staphylococcal or streptococcal infections. In patients with autoimmune diseases, AAbs directed against pathogenic cytokines are able to influence the course of the diseases. In lupus patients, neutralizing anti-IFNα and anti-TNFα AAbs are associated with a decreased bioactivity of the corresponding cytokine and a lower disease severity. Similarly, anti-IL-1α AAbs are associated with nondestructive forms of chronic polyarthritis. More surprisingly, neutralizing anti-BAFF AAbs are observed in the serum of lupus patients with elevated IFNα signature and higher disease activity. In this review, we summarize the current literature describing the different phenotypes and the main mechanisms associated with the occurrence of anti-cytokine AAbs.
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Affiliation(s)
- Thierry Vincent
- St Eloi Hospital, Department of Immunology, Montpellier University, CHRU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France; The Neuroscience Institute of Montpellier, INM, INSERM UMR1051, Saint Eloi Hospital, Montpellier, France.
| | - Maëlle Plawecki
- St Eloi Hospital, Department of Immunology, Montpellier University, CHRU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France
| | - Radjiv Goulabchand
- St Eloi Hospital, Department of Internal Medicine, Montpellier University, CHRU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France
| | - Philippe Guilpain
- St Eloi Hospital, Department of Internal Medicine, Montpellier University, CHRU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France
| | - Jean François Eliaou
- St Eloi Hospital, Department of Immunology, Montpellier University, CHRU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France; INSERM U1194, Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier, Montpellier, France
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