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Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFNγ Autoantibodies
Abstract
Interferon-gamma (IFNγ) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFNγ-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFNγ contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions. 2015 Published by Oxford University Press for the Infectious Diseases Society of America 2015.
... However, the specific mechanism of immune deficiency of anti-IFN-γ autoantibodies is still unclear. In addition, anti-IFN-γ autoantibodies have not widely been cognizant in tuberculosis [4]. Thus, we report a case of a 56-year-old HIV-negative Chinese man, with a high levels of anti-IFN-γ autoantibodies, simultaneously diagnosed disseminated Mycobacterium tuberculosis and Talaromyces marneffei co-infection by using metagenomics nextgeneration sequencing (mNGS), aims to attract clinical attention and attempts to study the possible immune deficiency mechanism of anti-IFN-γ autoantibodies. ...
... Meanwhile, remarkable high titer of anti-IFN-γ autoantibodies found in tuberculosis is rare reported. Before our case, there was only one Thai woman with a disseminated tuberculosis single infection and a dramatic paradoxical inflammatory response after treatment initiation, was found to have a high-titer of neutralizing anti-IFN-γ autoantibodies [4]. However, our patient had disseminated tuberculosis and a TM co-infection combined with a high level of anti-IFN-γ autoantibodies, phenomena that triggered an inflammatory storm, resulting in rapid death. ...
Background
High-titer anti-interferon (IFN)-γ autoantibodies are strongly associated with intracellular pathogens such as nontuberculous mycobacteria and Talaromyces marneffei, but they are not as commonly associated with Talaromyces marneffei co-infected with Mycobacterium tuberculosis.
Case presentation
Herein, we report a case of an HIV-negative Chinese man with a severe, disseminated co-infection of Talaromyces marneffei and Mycobacterium tuberculosis, who had a high-titer of anti IFN-γ autoantibodies and a CFI heterozygous nonsense gene mutation. The patient rapidly developed sepsis and died. Through by flow cytometry for CD4⁺ T cells’ intracellular phosphorylated STAT-1 and Th1 cells (CD4⁺ IFN-γ⁺ cells), we found that the patient’s serum can inhibited IFN γ-induced CD4⁺ T cells’ STAT-1 phosphorylation and Th1 cell differentiation in normal peripheral blood mononuclear cells, but this phenomenon was not observed in normal control’s serum. In addition, the higher serum concentration in the culture medium, the more obvious inhibition of Th1 cell differentiation.
Conclusions
For HIV-negative individuals with relapsing, refractory, fatal double or multiple intracellular pathogen infections, especially Talaromyces marneffei, clinicians should be aware that if they might be dealing with adult-onset immunodeficiency syndrome due to high-titer anti-IFN-γ autoantibodies. Systematic genetic and immunological investigations should also be performed.
... Immune deficiency, which is caused by anti-interferon-γ autoantibodies (anti-IFN-γ autoAbs), is an adult immune deficiency syndrome that was first described among patients with mycobacterial infection [1]. Patients have high titers of serum anti-IFN-γ autoAbs, which can inhibit signal transducer and activator of transcription 1 (STAT1) phosphorylation and interleukin-12 production, resulting in severe dysfunction of the Th1 response [2][3][4] and increased risk of infection by multiple intracellular pathogens, including nontuberculous Mycobacterium (NTM), Talaromyces marneffei (T. marneffei), Cryptococcus neoformans, and other intracellular pathogens [1][2][3][4][5][6][7][8][9][10][11][12]. ...
... Patients have high titers of serum anti-IFN-γ autoAbs, which can inhibit signal transducer and activator of transcription 1 (STAT1) phosphorylation and interleukin-12 production, resulting in severe dysfunction of the Th1 response [2][3][4] and increased risk of infection by multiple intracellular pathogens, including nontuberculous Mycobacterium (NTM), Talaromyces marneffei (T. marneffei), Cryptococcus neoformans, and other intracellular pathogens [1][2][3][4][5][6][7][8][9][10][11][12]. Talaromycosis is a severe deep mycosis that mainly involves organs rich in monocyte-macrophages (i.e., the lungs, liver, and lymph nodes) and can be categorized into localized and disseminated disease. ...
Background
Talaromyces marneffei ( T. marneffei) infection has been associated with adult-onset immunodeficiency due to anti-IFN-γ autoantibodies. We aimed to investigate the clinical features of non-HIV-infected patients with T. marneffei infection in southern China.
Methods
Between January 2018 and September 2020, we enrolled patients with T. marneffei infection who were HIV-negative (group TM, n = 42), including anti-IFN-γ autoantibody-positive (group TMP, n = 22) and anti-IFN-γ autoantibody-negative (group TMN, n = 20) patients and healthy controls (group HC, n = 40). Anti-IFN-γ autoantibodies were detected by ELISA. Clinical characteristics and clinical laboratory parameters were recorded.
Results
Compared with anti-IFN-γ autoantibody-negative patients with T. marneffei infection, anti-IFN-γ autoantibody-positive patients did not have underlying respiratory disease; more frequently exhibited dissemination of systemic infections with severe pleural effusion; had higher WBC counts, C-reactive protein levels, erythrocyte sedimentation rates, and neutrophil and CD8 ⁺ T cell counts; had lower hemoglobin levels; and were more likely to have other intracellular pathogen infections. Most of these patients had poor outcomes despite standardized antimicrobial therapy.
Conclusion
T. marneffei -infected patients with higher anti-IFN-γ autoantibody titers have more severe disease and complex clinical conditions.
... Since adults comprise the major population that suffers from this autoimmune disease, it is called adult-onset immunodeficiency (AOID). The prevalence of AOID is increasing over the years, especially in Asian countries [4][5][6]. Some reports have proposed that genetic factors and cell-mediated immunity may trigger the disease [7][8][9]. ...
... 6HIS MBP-mSA-CGC/biotinylated-IFN-γ was sprayed on the conjugate pad. The assembled strips were dipped into anti-IFN-γ mAb (clone B27) spiked in PBS (A) and human serum (B) at concentrations of 100,000, 10,000, 1000, 100, and 10 ng/mL(1- 5), along with irrelevant anti-MA mAb (clone G53) at concentrations of 100,000 and 10,000 ng/mL(6)(7). ...
Adult-onset immunodeficiency syndrome (AOID) patients with autoantibodies (autoAbs) against interferon-gamma (IFN-γ) generally suffer from recurrent and recalcitrant disseminated non-tuberculous mycobacterial diseases. Since the early stages of AOID do not present specific symptoms, diagnosis and treatment of the condition are not practical. A simplified diagnostic method for differentiating AOID from other immunodeficiencies, such as HIV infection, was created. Anti-IFN-γ is generally identified using enzyme-linked immunosorbent assay (ELISA), which involves an instrument and a cumbersome process. Recombinant IFN-γ indirectly conjugated to colloidal gold was used in the modified immunochromatographic (IC) strips. The biotinylated-IFN-γ was incorporated with colloidal-gold-labeled 6HIS-maltose binding protein-monomeric streptavidin (6HISMBP-mSA) and absorbed at the conjugate pad. The efficacy of the IC strip upon applying an anti-IFN-γ autoAb cut-off ELISA titer of 2500, the sensitivity and specificity were 84% and 90.24%, respectively. When a cut-off ELISA titer of 500 was applied, the sensitivity and specificity were 73.52% and 100%, respectively.
... This is because relapse is common in nIFNγ-autoAbs-related disseminated NTM infection after treatment discontinuation, and has been reported to occur in 64% of patients [15], 1 month to 2.5 years after the treatment discontinuation [5]. The immune reconstitution inflammatory syndrome-like phenomenon, observed in our patient, is not fully understood, but has previously reported in a patient with disseminated tuberculosis with nIFNγ-autoAbs [18]. Therefore, to ensure a favorable outcome, precise long-term management is crucial, both during anti-NTM therapy, and after treatment discontinuation. ...
Adult-onset immunodeficiency due to interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) can remain underdiagnosed. We present a case of severe Mycobacterium colombiense infection with nIFNγ-autoAbs. To ensure early diagnosis, clinicians should have a high index of suspicion in patients of Asian descent with opportunistic infections and perform QuantiFERON-TB assay for disease screening.
... Previous studies have confirmed that the expression of ρ-STAT1 was significantly inhibited when PBMCs of infected patients were cultured in vitro with serum containing anti-IFN-γ autoAbs. 9,15,40,41 These results suggest that the production of anti-IFN-γ autoAbs is key to the pathogenesis of T. marneffei infection, which contrasts with the pathogenesis of defects in the IFN-γ signaling pathway caused by congenital STAT mutations. 42,43 Although we have successfully demonstrated the effect of anti-IFN-γ autoAbs on CD4 + and CD8 + T cell immune function, several limitations need to be acknowledged. ...
Background:
Although anti-IFN-γ autoantibodies predispose patients to Talaromyces marneffei infection, whether this is mediated by T cell attenuation remains elusive.
Methods:
Total peripheral blood mononuclear cells (PBMCs) from healthy donors or patients with T. marneffei infection were stimulated with M158-66, and immunodominant influenza H1N1 peptide, or heat-inactivated T. marneffei in the presence of serum from anti-IFN-γ autoantibody-positive patients or healthy controls. The percentages of IFN-γ+TNF+CD8+ T cells and IFN-γ+CD4+ T cells were determined by flow cytometry and cytokines released in the supernatant were detected by Cytometric Bead Array. Furthermore, PBMCs from patients with T. marneffei infection and healthy individuals were stimulated with IFN-γ and anti-CD3/CD28 beads, and the levels of STAT1 and STAT3 phosphorylation were detected by Western blot.
Results:
The M1-reactive CD8+ T cells that expressed IFN-γ+ TNF-α+ of healthy controls were clearly reduced in serum with high-titer anti-IFN-γ autoantibodies. In addition, the CD4+ T cell response, designated by the expression of IFN-γ, against T. marneffei in PBMCs of patients were significantly decreased when cultured in high-titer anti-IFN-γ autoantibody serum culture, compared to the healthy compartments. Moreover, the release of the cytokines IFN-γ, TNF-α and IL-2 was significantly decreased, while IL-10 was significantly increased. There was no significant difference in the phosphorylation levels of STAT1 and STAT3 protein between patients and healthy controls after IFN-γ or anti-CD3/CD28 beads stimulation.
Conclusion:
Anti-IFN-γ autoantibodies presence in the serum inhibited CD4+ Th1 and CD8+ T cell immune responses. There was no congenital dysfunction of STAT1 and STAT3 in anti-IFN-γ autoantibody-positive patients with T. marneffei infection. These results suggest that the production of anti-IFN-γ autoAbs impair T-lymphocyte responses.
... As many patients have exacerbated symptoms, a combination therapy of corticosteroid and anti-tuberculosis is recommended. 27 The use of corticosteroid is systemic and short term. There are no severe steroid-related complications reported. ...
Introduction:
Paradoxical reaction refers to deterioration of the original tuberculosis lesions or emergence of new infiltrative lesions during anti-tuberculosis treatment. The common manifestations of paradoxical reaction include new pleural effusion, cerebral tuberculosis and lymphadenitis. Paradoxical reaction manifested by new pulmonary mass is rare.
Patients and methods:
This article summarizes and analyzes the clinical manifestations, chest CT, laboratory findings, treatments, pathological biopsy results of five patients diagnosed as paradoxical reaction in the form of new pulmonary mass. A literature review related to paradoxical reaction was conducted.
Results:
Five patients diagnosed as pulmonary tuberculosis or tuberculous pleuritis received systematic anti-tuberculosis treatmensssts. New pulmonary masses were found by CT scans during the follow-ups. The patients were negative for tumor markers, examination of rheumatoid connective tissue disease and G/GM test. The original anti-tuberculosis treatments were continued. All of the masses were diminished gradually.
Conclusion:
Paradoxical reaction needs to be taken into consideration when a new pulmonary mass occurs during anti-tuberculosis treatments. The diagnosis should be based on the patients' clinical manifestations, laboratory results, imaging examinsssations and lung biopsy examinations. The original anti-tuberculosis therapy can be continued in patients without severe clinical symptoms. A close follow-up is needed.
... Currently, there are many methods that have been described for detecting anti-IFN-γ autoAbs. Total anti-IFN-γ autoAbs were detected by indirect ELISA, western blot analysis, or a particle-based technique (4,16,17). However, these methods cannot evaluate the neutralizing activity. ...
Adult-onset immunodeficiency (AOID) with anti-interferon-γ (IFN-γ) autoantibodies (autoAbs) is an emerging immunodeficiency syndrome in Asian countries. The presence
of neutralizing anti-IFN-γ autoAbs are significantly associated with severe disseminated opportunistic infections. However, the characteristics of the neutralizing antibodies in patients are poorly defined. To better understand the properties of the anti-IFN-γ autoAbs
in patients with opportunistic infections, a simplified competitive-binding ELISA was developed. The domains recognized by anti-IFN-γ autoAbs were assessed based on
their competition with commercial neutralizing mouse anti-IFN-γ monoclonal antibodies (mAbs). First, the binding affinity and neutralizing capacity of these mAbs (clones B27,
B133.5, and MD-1) were characterized. Kinetic analysis and epitope binning using bio-layer interferometry showed the comparable binding affinity of these mAbs to full-length IFN-γ and to the adjacent binding region. These mAbs did not recognize the synthetic 20-mer peptides and inhibited IFN-γ-mediated functions differently. In a
competitive-binding ELISA, the anti-IFN-γ autoAbs in AOID serum blocked B27, B133.5, and MD-1 mAb binding. This evidence suggested that the autoAbs that competed with neutralizing mouse anti-IFN-γ mAbs recognized a discontinuous epitope of homodimeric
IFN-γ as these mAbs. The patient autoAbs that recognized the B27 epitope exhibited strong neutralizing activity that was determined by the functional analysis. Our results
demonstrated the heterogeneity of the autoAbs against IFN-γ in AOID patients and the different patterns among individuals. These data expand upon the fundamental knowledge of neutralizing anti-IFN-γ autoAbs in AOID patients.
... Currently, there are many methods that have been described for detecting anti-IFN-γ autoAbs. Total anti-IFN-γ autoAbs were detected by indirect ELISA, western blot analysis, or a particle-based technique (4,16,17). However, these methods cannot evaluate the neutralizing activity. ...
Adult-onset immunodeficiency (AOID) with anti-interferon-γ (IFN-γ) autoantibodies (autoAbs) is an emerging immunodeficiency syndrome in Asian countries. The presence of neutralizing anti-IFN-γ autoAbs are significantly associated with severe disseminated opportunistic infections. However, the characteristics of the neutralizing antibodies in patients are poorly defined. To better understand the properties of the anti-IFN-γ autoAbs in patients with opportunistic infections, a simplified competitive-binding ELISA was developed. The domains recognized by anti-IFN-γ autoAbs were assessed based on their competition with commercial neutralizing mouse anti-IFN-γ monoclonal antibodies (mAbs). First, the binding affinity and neutralizing capacity of these mAbs (clones B27, B133.5, and MD-1) were characterized. Kinetic analysis and epitope binning using bio-layer interferometry showed the comparable binding affinity of these mAbs to full-length IFN-γ and to the adjacent binding region. These mAbs did not recognize the synthetic 20-mer peptides and inhibited IFN-γ-mediated functions differently. In a competitive-binding ELISA, the anti-IFN-γ autoAbs in AOID serum blocked B27, B133.5, and MD-1 mAb binding. This evidence suggested that the autoAbs that competed with neutralizing mouse anti-IFN-γ mAbs recognized a discontinuous epitope of homodimeric IFN-γ as these mAbs. The patient autoAbs that recognized the B27 epitope exhibited strong neutralizing activity that was determined by the functional analysis. Our results demonstrated the heterogeneity of the autoAbs against IFN-γ in AOID patients and the different patterns among individuals. These data expand upon the fundamental knowledge of neutralizing anti-IFN-γ autoAbs in AOID patients.
... 14 The importance of IFN-c is demonstrated by the susceptibility to mycobacterial infections of those with innate or acquired impaired IFN-c-mediated immunity. 15,16 Because IFN-c production from Tcells increases in response to increased TB antigenic burden, a decline in IFN-c concentrations may signal a successful treatment response. As IFN-c expression in response to tuberculous infection is easily measured using the QuantiFERON-TB Gold or T-SPOT.TB IGRA kits, many studies have used these kits to assess whether changes in IFN-c levels correlate with treatment response. ...
Background:
Interferon-gamma (IFN-γ) release assays (IGRAs) are used to diagnose tuberculosis (TB) but not to measure treatment response.
Objective:
To measure IFN-γ response to active anti-tuberculosis treatment.
Design:
Patients from the Henan Provincial Chest Hospital, Henan, China, with TB symptoms and/or signs were enrolled into this prospective, observational cohort study and followed for 6 months of treatment, with blood and sputum samples collected at 0, 2, 4, 6, 8, 16 and 24 weeks. The QuantiFERON® TB-Gold assay was run on collected blood samples. Participants received a follow-up telephone call at 24 months to determine relapse status.
Results:
Of the 152 TB patients enrolled, 135 were eligible for this analysis: 118 pulmonary (PTB) and 17 extra-pulmonary TB (EPTB) patients. IFN-γ levels declined significantly over time among all patients (P = 0.002), with this decline driven by PTB patients (P = 0.001), largely during the initial 8 weeks of treatment (P = 0.019). IFN-γ levels did not change among EPTB patients over time or against baseline culture or drug resistance status.
Conclusion:
After 6 months of effective anti-tuberculosis treatment, IFN-γ levels decreased significantly in PTB patients, largely over the initial 8 weeks of treatment. IFN-γ concentrations may offer some value for monitoring anti-tuberculosis treatment response among PTB patients.
... This was further corroborated by the report of a patient with disseminated TB with IFN-c neutralizing autoantibodies who developed a severe paradoxical inflammatory response after TB therapy. This indicates that IFN-c could potentially be essential for controlling TB infection, although not required in the initiation of IRIS (Xie et al, 2016). Lastly, even though lymphopenia is known to increase the risk of developing IRIS after CD4 + T-cell repopulation, it is not a requirement for the reconstitution disease Barber et al, 2010). ...
In this review, we will describe the immunopathogies of immune reconstitution inflammatory syndrome, IRIS. IRIS occurs in a small subset of HIV patient, initiating combination antiretroviral therapy (ART), where immune reconstitution becomes dysregulated, resulting in an overly robust antigen-specific inflammatory reaction. We will discuss IRIS in terms of the associated coinfections: mycobacteria, cryptococci, and viruses. Published 2016. This article is a U.S. Government work and is in the public domain in the USA
... Certain opportunistic infections and complications such as penicillum marneffei may be found predominantly in Asian countries, but not in patients of this ethnicity living elsewhere [5 && ,8,9]. Xie et al. [10] reported a patient with disseminated tuberculosis and nAIGAs in the absence of other opportunistic infections. Nearly all published patients so far where of Southeast Asian origin. ...
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 IFN-1 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 fragment crystallizable-mediated clearance. Single mAbs in contrast may lead to higher GM-CSF bioavailability. Antitype interferon-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 in the context of autoimmune polyglandular syndrome type I and may be thus considered to be protective. Hypomorphic severe combined immune deficiency is a syndrome with complex anticytokine pattern. The emergence of anti-IFN-1 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.
... Our patient had disseminated, drugsensitive tuberculosis, associated with anti-IFNγ autoantibodies, yet still developed a severe paradoxical immune reaction [4]. This suggests that intact IFNγ signaling is dispensable for the tuberculosis paradoxical reaction. ...
... TO THE EDITOR-We read with interest the report by Xie et al describing hightiter neutralizing anti-interferon-gamma (IFN-γ) autoantibodies in an Asian patient with disseminated Mycobacterium tuberculosis and severe paradoxical reaction [1]. Although we concur and demonstrate here that these autoantibodies are biologically active in inhibiting the pivotal IFN-γ/interleukin (IL)-12 axis, however, the antibody level and neutralizing capacity may not be linked to the clinical course or severity of disease. ...
Background
The clinical presentation of adult-onset immunodeficiency with anti-interferon (IFN)-γ autoantibodies with intracellular pathogens can be highly variable, which can lead to misdiagnosis during the early stage of disease.
Case presentation
We report a complex case of a 54-year-old Chinese male who was human immunodeficiency virus-negative. He had a presence of anti-IFN-γ autoantibodies and suffered from various intracellular pathogenic infections. The patient was admitted to our hospital for the first time in July 2016 with severe pneumonia, and he experienced multiple pneumonia infections between 2017 and 2019. In March 2019, the patient was hospitalized due to pulmonary lesions and multiple-bone destruction. During hospitalization, the patient was confirmed to have disseminated Talaromyces marneffei infection and was successfully treated with antifungal therapy for 1 year. In June 2021, Mycobacterium kansasii infection was detected by positive culture and progressive bone destruction. A high concentration of anti-IFN-γ antibodies was observed in the patient’s serum. In addition, Listeria monocytogenes was isolated by blood culture, and the presence of L. monocytogenes in cerebrospinal fluid was confirmed by next-generation sequencing. Following anti-non-tuberculous mycobacteria (NTM) therapy and anti-bacterial therapy, the patient’s symptoms, pulmonary lesions, and bone destruction gradually improved.
Conclusions
Although the clinical presentation of adult-onset immunodeficiency with anti-IFN-γ autoantibodies can be highly variable, the diagnosis should be considered if patients suffer from unexplained repeated bacterial or opportunistic infections.
Conventional and advanced molecular testing should be used, as needed, for microbiological diagnoses among this special immunodeficient population.
Tuberculosis remains a major public health concern. Millions of tuberculosis cases and associated deaths have been reported worldwide. The Indo-Oceanic lineage Mycobacterium tuberculosis is common in Southeast Asia and causes extrapulmonary lesions. Only a few case studies on this lineage with genetic analysis using whole-genome sequencing have been reported in the literature. We present a case of disseminated tuberculosis, characterized by a variety of extrapulmonary lesions and paradoxical reactions, caused by the Indo-Oceanic lineage M. tuberculosis in a woman in Myanmar. A 22-year-old Burmese woman had arthritis in the right knee, with unknown aetiology, and was referred to our hospital. Computed tomography of the trunk revealed multiple nodular shadows in both lungs; swollen mediastinal lymph nodes; and small, low-density areas in the spleen. M. tuberculosis was detected in the sputum sample, joint aspirate, subcutaneous tumor, and exudate. She experienced a variety of paradoxical reactions together with aggressive tuberculosis dissemination in all areas of the body. Whole-genome sequencing of the DNA of MTB obtained from sputum and the right cervical subcutaneous abscess confirmed the Indo-Oceanic lineage of M. tuberculosis, the predominant strain in Myanmar. The Indo-Oceanic lineage M. tuberculosis causes disseminated tuberculosis all over the body including the periungual region. When patients show unusual symptoms, physicians should consider the introduction of new strains from foreign countries. Genetic analyses of the strains are recommended to define and confirm the lineages.
Background: Talaromyces marneffei (T. marneffei) infection has been associated with adult-onset immunodeficiency due to anti-IFN-γ autoantibodies. We aimed to investigate the clinical features of non-HIV-infected patients with T. marneffei infection in southern China.
Methods: Between January 2018 and September 2020, we enrolled patients aged 18 years or older who were HIV-negative. Patients were further stratified into four main groups: patients with T. marneffei infection (group 1, n=42), including anti-IFN-γ autoantibody-positive (group 1P) and anti-IFN-γ autoantibody-negative (group 1N) patients; patients with NTM infection (group 2, n=20); patients with pulmonary cryptococcosis (group 3, n=20); and healthy controls (group 4, n=40). Anti-IFN-γ autoantibodies were detected by ELISA. Clinical characteristics and clinical laboratory parameters were recorded.
Results: High anti-IFN-γ autoantibody titers were found in both groups 1 and 2. Compared with anti-IFN-γ autoantibody-negative patients with T. marneffei infection, anti-IFN-γ autoantibody-positive patients did not have underlying respiratory disease; more frequently exhibited dissemination of systemic infections with severe pleural effusion; had higher WBC counts, C-reactive protein levels, erythrocyte sedimentation rates, and neutrophil and CD8⁺ T cell counts; had lower hemoglobin levels; and were more likely to have other intracellular pathogen infections. However, the anti-IFN-γ autoantibody level did not correlate with the clinical disease course. Most of these patients had poor outcomes despite standardized antimicrobial therapy.
Conclusion: T. marneffei-infected patients with higher anti-IFN-γ autoantibody titers have more severe disease and complex clinical conditions.
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.
A paradoxical reaction (PR) is an excessive immune response occurring during antitubercular therapy (ATT), but is rare in patients with miliary tuberculosis. A 78-year-old woman complained of general malaise, loss of appetite, and fever for 10 days. Chest computed tomography (CT) showed diffuse, bilateral, discrete miliary nodules. The patient was treated with ATT for miliary tuberculosis. Nine days after starting the treatment, she developed a spiking fever and worsening malaise. Repeat CT showed new localized ground-glass opacity (GGO) in the right upper lobe. After excluding possible etiologies, she was diagnosed with PR due to ATT. She was successfully managed with oral prednisolone while continuing ATT. The GGO diminished and did not recur after discontinuation of the steroids. We reviewed 28 reported cases of miliary tuberculosis with a PR in patients not infected with human immunodeficiency virus. Those not on immunosuppressive therapy were likely to develop a PR early. This case illustrates that a PR may present as localized GGO in miliary tuberculosis in the lung of patients treated with ATT. In cases of a PR with marked symptoms, steroid therapy may be valuable.
Disseminated nontuberculous mycobacterial (NTM) infections usually occur in severely immunosuppressed patients. These infections may also occur in previously immunocompetent patients with acquired anti-IFN-gamma antibodies (anti-IFN-γ Abs). A previously healthy 33-year-old man presented with a 3-week history of cough and fever. Chest computed tomography showed air-space consolidation in the middle lobe of the right lung and enlargement of the supraclavicular, mediastinal, and hilar lymph nodes. Tissue samples obtained via mediastinoscopy showed granuloma formation with acid-fast bacteria; cultures from the tissue revealed Mycobacterium kansasii. Accordingly, a diagnosis of disseminated M. kansasii disease was made. The positive control tested negative in the QuantiFERON-TB Gold In-tube test, suggesting the presence of anti-IFN-γ Abs. The ELISA test for anti-IFN-γ Abs demonstrated an increased titer. Antimycobacterial drug treatments were initiated after diagnosis. His symptoms improved over 2 months, and he remains well on outpatient management. Disseminated M. kansasii disease is a very rare condition suggestive of immunosuppression. Testing for anti-IFN-γ antibodies might be important in all cases of disseminated M. kansasii disease.
This study was to investigate the differences of lymphocyte in the cerebrospinal fluid (CSF) of patients with syphilis meningitis (SM) and tuberculous meningitis (TBM) for new diagnostic insights. Totally, 79 cases of SM and 45 cases of TBM were enrolled. In the CSF, the CD4, CD45RO or CD20 positive lymphocytes were detected by immunohistochemistry. The proportion of CD4 T cells in the CSF lymphocytes in patients with SM was significantly higher than that in patients with TBM (p < 0.05). After medical therapy, there was a significantly decline trend of the CD4 T-cell proportion in both groups (p < 0.05). The proportion of CD45RO T cells in CSF lymphocytes of patients with SM was less than that of patients with TBM (p < 0.05). After medical therapy, the positive ratio of CD45RO T cells was increased in the CSF of both group patients (p < 0.05). The proportion of CD20B cells in the CSF lymphocytes was not obviously different between the two groups during every stage. In conclusion, there are strong differences of CD4 and CD45RO T-cell ratio, but not the CD20 B cells in the meningitis. CD4 and CD45RO T cells in CSF are a useful complement in differentially diagnosing SM and TBM; it contributes to further understand the pathogenesis and prognosis of SM and TBM.
Interleukin-8 (IL-8) has been implicated in the pathogenesis of several human respiratory diseases, including tuberculosis (TB). Importantly and in direct relevance to the objectives of this report quite a few findings suggest that the presence of IL-8 may be beneficial for the host. IL-8 may aid with mounting an adequate response during infection with
Mycobacterium tuberculosis (M. tb)
; however, the underlying mechanism remains largely unknown. The major goal of our study was to investigate the contribution of IL-8 to the inflammatory processes that are typically elicited in patients with TB. We have shown for the first time that IL-8 can directly bind to tubercle bacilli. We have also demonstrated that association of IL-8 with
M. tb
molecules leads to the augmentation of the ability of leukocytes (neutrophils and macrophages) to phagocyte and kill these bacilli. In addition, we have shown that significant amount of IL-8 present in the blood of TB patients associates with erythrocytes. Finally, we have noted that IL-8 is the major chemokine responsible for recruiting T lymphocytes (CD3
+
, CD4
+
, and CD8
+
T cells). In summary, our data suggest that the association of IL-8 with
M. tb
molecules may modify and possibly enhance the innate immune response in patients with TB.
Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.
Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation.
We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ(2) tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls.
Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18-0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0-80·0]) and tumour necrosis factor (TNF)α (7·8 [1·1-55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2-2·5]) and TNFα (1·5 [1·0-2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3-6·1]), IL-12p40 (1·8 [1·0-3·4]), and IL-15 (2·0 [1·1-3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006).
Distinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis.
National Institutes of Health and the Penn Center for AIDS Research.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Immune reconstitution inflammatory syndrome (IRIS) is a major adverse event of antiretroviral therapy in HIV infection, and paradoxically occurs as HIV viremia is suppressed and CD4 T cell numbers recover. IRIS reflects pathogenic immune responses against opportunistic infections acquired during the period of immunodeficiency, but little is understood about the mechanisms of inflammatory pathology. In this study, we show that IL-6 and C-reactive protein levels transiently rise at the time of the IRIS event in HIV-infected patients, umasking Mycobacterium avium complex infection after starting antiretroviral therapy. To directly test the role of IL-6 in IRIS pathology, we used a model of experimentally inducible IRIS in which M. avium-infected T cell-deficient mice undergo a fatal inflammatory disease after reconstitution with CD4 T cells. We find that IL-6 neutralization reduces C-reactive protein levels, alleviates wasting disease, and extends host survival during experimental IRIS. Moreover, we show that combined blockade of IL-6 and IFN-γ further reduces IRIS pathology, even after the onset of wasting disease. The combination of these clinical and experimental-model data show that the IL-6 pathway is not only a biomarker of mycobacterial IRIS but also a major mediator of pathology distinct from IFN-γ and may be a useful target for therapeutic intervention.
Mycobacterial infections are critically controlled by interferon-γ (IFN-γ) and the cellular responses it elaborates, as shown
by patients with mutations in the IFN-γ receptor ligand-binding chain (IFN-γR1) who have disseminated nontuberculous mycobacterial
infections. The immunologic sequelae of IFN-γR1 deficiency were characterized in 2 unrelated patients from the Indian subcontinent
with novel homozygous recessive IFN-γR1 mutations. In vitro, these patients' peripheral blood mononuclear cells produced 10%
of normal IFN-γ and interleukin-12 (IL-12) in response to phytohemagglutinin (PHA) but normal amounts of IFN-γ in response
to PHA plus IL-12. Tumor necrosis factor-α (TNF-α) production was normal in response to endotoxin and to PHA but was not augmented
by the addition of IFN-γ. An abnormal phenotype was not found in heterozygous patient relatives. These patients demonstrate
the critical role that the IFN-γ receptor plays in the regulation of IFN-γ, IL-12, and TNF-α.
Cryptococcal meningitis has been described in immunocompromised patients, as well as in those for whom no immune defect has been identified. GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryptococcal control. We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in four current patients with cryptococcal meningitis and identified and tested 103 archived plasma/cerebrospinal fluid samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody-containing plasmas to inhibit GM-CSF signaling. We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis (PAP). Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified seven HIV-negative patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the seven later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT5 phosphorylation and MIP-1α production in normal PBMCs. This effect was limited to their IgG fraction. Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated PAP.
Autoantibodies against interferon-γ are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown.
We enrolled 203 persons from sites in Thailand and Taiwan in five groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained.
Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-γ in normal cells. High-titer anti-interferon-γ autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering.
Neutralizing anti-interferon-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research; ClinicalTrials.gov number, NCT00814827.).
Depletion of T cells following infection by Mycobacterium tuberculosis (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised.
We found that lymphopenia (<1.5 × 10(9) cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from Mycobacterium bovis Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system.
Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.
Since the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as immune reconstitution inflammatory syndrome (IRIS). Studying the etiology and immunopathology of IRIS has been hampered by the fact that the symptoms and associated opportunistic infections are highly varied. We hypothesized that there is a common mechanism underlying IRIS pathogenesis and investigated a patient group with IRIS related to different pathogens. Functional and phenotypic characterization of PBMC samples was performed by polychromatic flow cytometry after in vitro stimulation with relevant antigenic preparations. In most patients, IRIS events were characterized by the robust increase of preexisting polyfunctional, highly differentiated effector CD4(+) T-cell responses that specifically targeted the antigens of the underlying co-infection. T-cell responses to HIV-1 or other underlying infections were not affected and did not differ between IRIS and non-IRIS patients. These data suggest that patients with IRIS do not have a generalized T-cell dysfunction; instead, IRIS represents a dysregulated CD4(+) T-cell response against residual opportunistic infection antigen. These studies were registered at www.clinical-trials.gov as NCT00557570 and NCT00286767.
Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity.
The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations.
The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10(-3).
The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders.
Following antiretroviral therapy, a significant proportion of HIV(+) patients with mycobacterial coinfections develop a paradoxical, poorly understood inflammatory disease termed immune reconstitution inflammatory syndrome (IRIS). Here, we show that Mycobacterium avium-infected T cell-deficient mice injected with CD4 T cells also develop an immune reconstitution disease (IRD) manifesting as weight loss, impaired lung function, and rapid mortality. This form of IRD requires Ag recognition and interferonγ production by the donor CD4 T cells and correlates with marked alterations in blood and tissue CD11b(+) myeloid cells. Interestingly, disease is associated with impaired, rather than augmented, T-cell expansion and function and is not strictly dependent on lymphopenia-induced T-cell proliferation. Instead, our findings suggest that mycobacterial-associated IRIS results from a heightened sensitivity of infected lymphopenic hosts to the detrimental effects of Ag-driven CD4 T-cell responses.
Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD-specific IFN-gamma-secreting CD4(+) T cells. Objectives: To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV-TB IRIS.
Longitudinal and cross-sectional studies of Mycobacterium tuberculosis-specific IFN-gamma enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1-associated tuberculosis, 98 of whom were prescribed cART.
In cross-sectional analysis the frequency of IFN-gamma-secreting T cells recognizing early secretory antigenic target (ESAT)-6, alpha-crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB-IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P <or= 0.03). The biggest difference was in the recognition of alpha-crystallin molecules: peptide mapping indicated a polyclonal response. Flow cytometric analysis indicated equal proportions of CD4(+) and CD8(+) cells positive for activation markers HLA-DR and CD71 in both patients with TB-IRIS and non-IRIS patients. The percentage of CD4(+) cells positive for FoxP3 (Forkhead box P3) was low in both groups (TB-IRIS, 5.3 +/- 4.5; non-IRIS, 2.46 +/- 2.46; P = 0.13). Eight weeks of longitudinal analysis of patients with tuberculosis who were starting cART showed dynamic changes in antigen-specific IFN-gamma-secreting T cells in both the TB-IRIS and non-IRIS groups: the only significant trend was an increased response to PPD in the TB-IRIS group (P = 0.041).
There is an association between helper T-cell type 1 expansions and TB-IRIS, but the occurrence of similar expansions in non-IRIS brings into question whether these are causal. The defect in immune regulation responsible for TB-IRIS remains to be fully elucidated.
Among the cytokines involved in defensive mechanisms against Mycobacterium tuberculosis infection, special attention has been given to interferon-gamma (IFN-gamma); a local synthesis of this cytokine as well as IL-2 (type 1 cytokines) at the site of disease in patients with tuberculous pleuritis has been demonstrated. Moreover, high levels of IgG autoantibodies against IFN-gamma have been shown in several clinical situations. It has been suggested that these antibodies could serve to limit the intensity or duration of the immune response or be able to interfere with the pathophysiological effects of IFN-gamma.
To investigate the potential role of anti-IFN-gamma antibodies in the course of M. tuberculosis infection.
Investigation of the presence of these antibodies in sera from healthy and ill subjects infected with M. tuberculosis in relation to the extent of the disease and the presence of IFN-gamma in sera by enzyme-linked-immunosorbent assay (ELISA). In order to investigate the presence of these antibodies at the site of infection we included 12 pleural fluids from tuberculosis patients and 9 pleural fluids from other origins.
In the course of M. tuberculosis infection the production of anti-IFN-gamma IgG antibodies is induced, being particularly higher in healthy skin test converters. Among tuberculosis patients, the presence of anti-IFN-gamma autoantibodies is significantly associated with detectable levels of the cytokine in sera. Levels of anti-IFN-gamma antibodies in moderately advanced and far advanced tuberculosis patients are significantly greater than in healthy individuals. These antibodies increase at the site of infection.
Anti-IFN-gamma antibodies must be considered as a new element in the immune response to M. tuberculosis. It would be of great interest to investigate this point especially at the site of infection.
Mycobacterial infections are critically controlled by interferon-gamma (IFN-gamma) and the cellular responses it elaborates, as shown by patients with mutations in the IFN-gamma receptor ligand-binding chain (IFN-gamma R1) who have disseminated nontuberculous mycobacterial infections. The immunologic sequelae of IFN-gamma R1 deficiency were characterized in 2 unrelated patients from the Indian subcontinent with novel homozygous recessive IFN-gamma R1 mutations. In vitro, these patients' peripheral blood mononuclear cells produced 10% of normal IFN-gamma and interleukin-12 (IL-12) in response to phytohemagglutinin (PHA) but normal amounts of IFN-gamma in response to PHA plus IL-12. Tumor necrosis factor-alpha (TNF-alpha) production was normal in response to endotoxin and to PHA but was not augmented by the addition of IFN-gamma. An abnormal phenotype was not found in heterozygous patient relatives. These patients demonstrate the critical role that the IFN-gamma receptor plays in the regulation of IFN-gamma, IL-12, and TNF-alpha.
Immunological and clinical profiles were evaluated in 2 groups: human immunodeficiency virus (HIV)—uninfected and HIV-infected
patients, with newly diagnosed pulmonary tuberculosis (TB), and tuberculin-skin-test—reactive healthy control subjects. HIV-uninfected
patients with TB were also followed up longitudinally during and after chemotherapy. At the time of diagnosis, purified protein
derivative (PPD)—stimulated production of interferon (IFN)—γ by peripheral blood mononuclear cells from TB patients was depressed,
compared with that of healthy control subjects, whereas levels of transforming growth factor (TGF)—β and interleukin (IL)—10
were increased. In longitudinal studies, PPD stimulated production of IL-10 and TGF-β returned to baseline by 3 months, whereas
IFN-γ production remained depressed for at least 12 months. These data indicate that the immunosuppression of TB is not only
immediate and apparently dependent (at least in part) on immunosuppressive cytokines early during the course of Mycobacterium TB infection but is also long lasting, presumably relating to a primary abnormality in T-cell function.
We evaluated a patient with disseminated Mycobacterium tuberculosis and Mycobacterium chelonae infection, of which he died. He also developed autoimmune (type I) diabetes and primary hypothyroidism. His serum contained
a high titer of immunoglobulin G autoantibody to interferon-γ (IFN-γ) capable of blocking in vitro responses to this cytokine
by peripheral blood mononuclear cells from normal donors. These results suggest that autoantibodies to IFN-γ can induce susceptibility
to disseminated mycobacterial infection, which may be refractory to chemotherapy.
In a retrospective analysis, paradoxical deterioration of lymph node tuberculosis in human immunodeficiency virus-uninfected
patients was common, occurring in 25 (23%) of 109 patients after treatment had been given for a median of 46 days (interquartile
range, 21–139 days) and persisting for a median of 67.5 days (interquartile range, 34–111 days). We found no association between
the use of steroids and the duration of reaction.
HIV treatment has been greatly impacted by transmitted resistance to antiretrovirals (ARV). Several studies have documented resistance in naïve individuals and estimates of transmitted drug resistance mutations range from <5% to as high as 25%. Washington, D.C. has one of the highest human immunodeficiency virus (HIV) prevalence rates in the United States (3.2% in 2009), but local data regarding the frequency of major mutations and antiretroviral (ARV) resistance has been limited. Medical records of HIV positive, ARV-naïve adults at two facilities in Washington, D.C., The George Washington University Medical Center and the Veterans Affairs Medical Center, were retrospectively analyzed in subjects who had genotypic resistance testing from 2007 to 2010. Of 407 ARV-naïve patients, at least one transmitted drug resistance mutation was detected in 17% of our patients, with non-nucleoside reverse transcriptase (NNRTI) mutations observed in 15%. Among patients with at least one reverse transcriptase (RT) or major protease region (Pr) resistance mutation, 85% had resistance against a single ARV class. Dual and triple class resistance mutations were seen in 8 patients (2%) and 3 patients (0.7%), respectively. Most of the multiple class resistance was seen in 2010. A gradual increase in NNRTI resistance was noted during 2008 to 2010. Our prevalence of transmitted RT, major Pr mutations (17.4%) and ARV resistance (8.6%) were high but similar to rates reported by others within the United States. Given the high HIV prevalence in the District of Columbia, this has important implications for treatment of these ARV-naïve patients.
The role of Treg in patients with late-stage HIV disease, who commence
combination antiretroviral therapy (cART) and develop pathogen-specific
immunopathology manifesting as immune restoration disease (IRD) remains unclear.
We hypothesised that Treg could be defective in either numbers and/or function
and therefore unable to ensure the physiological equilibrium of the immune system
in patients with IRD. Phenotypic and functional CD4(+) T-cell subsets of eight
late-stage HIV patients with nadir CD4 count <50 cells/microL, who developed
mycobacterial IRD upon commencing cART were compared with six therapy naive
HIV(+) patients (nadir CD4 count <50 cells/microL), who did not develop an IRD
after cART. Mycobacterium-avium-specific CD4(+) T cells from IRD patients
produced high levels of IFN-gamma and IL-2 compared with controls (p<0.001).
Surprisingly, we found a significant expansion of CD127(lo)Foxp3(+)CD25(+) Treg
in IRD patients and a higher ratio of Treg to effector/memory subsets (p<0.001).
In vitro suppression assays demonstrated reduced functional capacity of
suppressor cells and diminished IL-10 secretion in IRD patients. Plasma levels of
IL-7 were increased in patients and, interestingly, exogenous IL-7 and other
cytokines strongly inhibited Treg suppression. These data suggest that despite
substantial Treg expansion in IRD, their ability to induce suppression, and
thereby downregulate aberrant immune responses, is compromised.
Patients with anti-IFN-γ autoantibodies have impaired IFN-γ signaling, leading to severe disseminated infections with intracellular pathogens, especially nontuberculous mycobacteria. Disease may be severe and progressive, despite aggressive treatment. To address the underlying pathogenic IFN-γ autoantibodies we used the therapeutic monoclonal rituximab (anti-CD20) to target patient B cells. All subjects received between 8 and 12 doses of rituximab within the first year to maintain disease remission. Subsequent doses were given for relapsed infection. We report 4 patients with refractory disease treated with rituximab who had clinical and laboratory evidence of therapeutic response as determined by clearance of infection, resolution of inflammation, reduction of anti-IFN-γ autoantibody levels, and improved IFN-γ signaling.
Anticytokine autoantibodies cause numerous human diseases, ranging from pure red cell aplasia to acquired immunodeficiencies. Rapid, simple, and affordable detection and monitoring of these antibodies is essential. We sought to develop a standardizable assay that is rapid, sensitive, and specific and able to simultaneously detect multiple anticytokine autoantibodies in small volumes (<10 μl).
We conjugated purified human cytokines to commercially available fluorescently labeled microspheres and tested them against sera from well-characterized subjects with at least one high-titer, disease-associated anticytokine autoantibody.
Cytokine-conjugated microspheres efficiently and rapidly determined plasma concentration and IgG subclass of anticytokine autoantibodies in single or multiplex formats.
This particle-based multiplex assay can reproducibly characterize anticytokine autoantibodies. This efficient and inexpensive approach to diagnosing and monitoring anticytokine autoantibodies has clinical applications.
Immune defects in interleukin-12-dependent interferon-gamma (IFN-γ) pathways are associated with disseminated infections caused by non-tuberculous mycobacteria (NTM) and Salmonella. Recently, there have been an increasing number of reports of acquired autoantibodies to IFN-γ in adults, especially in Asian patients. We describe here three human immunodeficiency virus-negative Thai adults who had persistent or recurrent disseminated infections caused by NTM, Salmonella, and other opportunistic pathogens, possibly due to anti-IFN-γ autoantibodies. The antibodies were shown to exhibit very high inhibitory activity to IFN-γ. Two patients also developed Sweet's syndrome during the course of infections. In addition, we also review all previous reports of patients with anti-IFN-γ antibodies who were susceptible to NTM and Salmonella infections.
The role of Treg in patients with late-stage HIV disease, who commence combination antiretroviral therapy (cART) and develop pathogen-specific immunopathology manifesting as immune restoration disease (IRD) remains unclear. We hypothesised that Treg could be defective in either numbers and/or function and therefore unable to ensure the physiological equilibrium of the immune system in patients with IRD. Phenotypic and functional CD4(+) T-cell subsets of eight late-stage HIV patients with nadir CD4 count <50 cells/microL, who developed mycobacterial IRD upon commencing cART were compared with six therapy naive HIV(+) patients (nadir CD4 count <50 cells/microL), who did not develop an IRD after cART. Mycobacterium-avium-specific CD4(+) T cells from IRD patients produced high levels of IFN-gamma and IL-2 compared with controls (p<0.001). Surprisingly, we found a significant expansion of CD127(lo)Foxp3(+)CD25(+) Treg in IRD patients and a higher ratio of Treg to effector/memory subsets (p<0.001). In vitro suppression assays demonstrated reduced functional capacity of suppressor cells and diminished IL-10 secretion in IRD patients. Plasma levels of IL-7 were increased in patients and, interestingly, exogenous IL-7 and other cytokines strongly inhibited Treg suppression. These data suggest that despite substantial Treg expansion in IRD, their ability to induce suppression, and thereby downregulate aberrant immune responses, is compromised.
Primary immunodeficiencies (PIDs) were long thought to be exclusively recessive traits -- autosomal recessive (AR) in most cases, with a few X-linked recessive (XR) diseases. In recent years, autosomal dominant (AD), mitochondrial, polygenic, and even somatic PIDs have been described. However, AR remains the most frequent inheritance pattern among recently described PIDs. Some PIDs have been shown to be genetically heterogeneous. Mendelian susceptibility to mycobacterial diseases (MSMD) displays a high level of genetic heterogeneity. There are 6 MSMD-causing genes, including 1 X-linked gene (nuclear factor-kappaB-essential modulator [NEMO]) and 5 autosomal genes (IFN-gamma receptor 1 [IFNGR1], IFN-gamma receptor 2 [IFNGR2], signal transducer and activator of transcription 1 [STAT1], IL-12 p40 subunit [IL12P40], and IL-12 receptor beta-subunit [IL12RB1]). The X-linked trait is XR; STAT1 deficiency is AD; the IFNGR2, IL12P40 subunit, and IL12RB1 deficiencies are AR; and IFNGR1 deficiency may be AD or AR. Two of the AR traits (IFNGR1, IFNGR2) may be subdivided into complete and partial deficiencies, and 3 AR complete deficiencies (IFNGR1, IFNGR2, IL12RB1) may be subdivided into disorders with and without cell surface expression. Finally, there are 2 types of AD STAT1 deficiency, depending on whether the mutation impairs phosphorylation or DNA binding. Thirteen genetic disorders conferring MSMD have been described, involving 1 XR, 3 AD (2 genes), and 9 AR traits (4 genes). However, no genetic etiology has yet been identified for about half of all patients with MSMD. We expect to identify new XR and AD causes of MSMD, but new AR etiologies of MSMD are also likely to be discovered. The investigation of children from areas in which consanguineous marriages are common will probably facilitate the description of many more AR traits.
Genetic defects in the IFN-gamma response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. We postulated that acquired defects in macrophage activation by IFN-gamma may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency. Macrophage activation in response to IFN-gamma and IFN-gamma production were studied in whole blood and PBMCs of 3 patients with severe, unexplained nontuberculous mycobacterial infection. In all 3 patients, IFN-gamma was undetectable following mitogen stimulation of whole blood, but significant quantities were detectable in the supernatants of PBMCs when stimulated in the absence of the patients' own plasma. The patients' plasma inhibited the ability of IFN-gamma to increase production of TNF-alpha by both autologous and normal donor PBMCs, and recovery of exogenous IFN-gamma from the patients' plasma was greatly reduced. Using affinity chromatography, surface-enhanced laser desorption/ionization mass spectrometry, and sequencing, we isolated an IFN-gamma-neutralizing factor from the patients' plasma and showed it to be an autoantibody against IFN-gamma. The purified anti-IFN-gamma antibody was shown to be functional first in blocking the upregulation of TNF-alpha production in response to endotoxin; second in blocking induction of IFN-gamma-inducible genes (according to results of high-density cDNA microarrays); and third in inhibiting upregulation of HLA class II expression on PBMCs. Acquired defects in the IFN-gamma pathway may explain unusual susceptibility to intracellular pathogens in other patients without underlying, genetically determined immunological defects.
Immune reconstitution inflammatory syndrome in HIV-infected patients
- NF Walker
- J Scriven
- G Meintjes
- RJ Wilkinson
Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy
- CS Hirsch
- Z Toossi
- C Othieno
The genetic heterogeneity of Mendelian susceptibility to mycobacterial diseases
- S Al-Muhsen
- JL Casanova