The significance of anti‐granulocyte‐macrophage colony‐stimulating factor antibodies in cryptococcal infection: case series and review of antibody testing

Stevenson, Brittany; Bundell, Christine; Mulrennan, Siobhain; McLean‐Tooke, Andrew; Murray, Ronan J.; Brusch, Anna

doi:10.1111/imj.14637

Cited by 16 publications

(11 citation statements)

References 19 publications

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“…These infections may be secondary to PAP, the use of steroids, and/or impaired GM-CSF signaling directly compromising alveolar macrophage immunity to these pathogens ( Punatar et al, 2012 ). Since 2013, high titers of IgG (mostly IgG1) auto-Abs neutralizing 10 ng/ml GM-CSF (plasma diluted 1/10) have been found in patients with adult-onset isolated idiopathic disseminated disease mostly due to Cryptococcus spp., almost exclusively Cryptococcus gattii ( Applen Clancey et al, 2019 ; Browne et al, 2012a ; Crum-Cianflone et al, 2017 ; Demir et al, 2018 ; Huynh et al, 2020 ; Kuo et al, 2017 ; Panackal et al, 2017 ; Perrineau et al, 2020 ; Rosen et al, 2013 ; Saijo et al, 2014 ; Stevenson et al, 2019 ; Viola et al, 2021 ), Nocardia spp. ( Rosen et al, 2015 ), or more rarely, Aspergillus spp.…”

Section: Neutralizing Auto-abs Against Gm-csfmentioning

confidence: 99%

Human autoantibodies underlying infectious diseases

Puel

Bastard

Bustamante

et al. 2022

Journal of Experimental Medicine

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The vast interindividual clinical variability observed in any microbial infection—ranging from silent infection to lethal disease—is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.

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Section: Neutralizing Auto-abs Against Gm-csfmentioning

confidence: 99%

Human autoantibodies underlying infectious diseases

Puel

Bastard

Bustamante

et al. 2022

Journal of Experimental Medicine

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“…Almost every case of anti-GM-CSF-related disseminated infection in our cohort involved the CNS. The search for anti-GM-CSF antibodies is now recognized as part of the workup in "non-immunocompromised" patients with brain infection with Cryptococcus or Nocardia [40,41].…”

Section: Discussionmentioning

confidence: 99%

Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis

Salvator

Cheng

Rosen

et al. 2022

Preprint

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Background Anti GM-CSF autoantibodies (aAb) have been related to acquired pulmonary alveolar proteinosis (PAP) and described in cases of severe infections such as cryptococcosis and nocardiosis in previously healthy subjects. Whether there are different anti-GM-CSF autoantibodies corresponding to these phenotypes is unclear.MethodsPlasma samples gathered in the National Institute of Health from patients with anti GM-CSF aAb and either PAP (n=15), cryptococcal meningitis (n=15), severe nocardiosis (n=5) or overlapping phenotypes (n=6) were compared in terms of titer and neutralizing activity as assessed by inhibition of GM-CSF-induced intracellular phospho-STAT5 (pSTAT5) in monocytes.ResultsAnti GM-CSF aAb titers were higher in PAP patients compared to those with cryptococcosis (mean 495±464 ug/ml vs 197±159 ug/ml, p = 0.02); there was no difference with patients with nocardiosis (430±493 ug/ml) nor between the two type of infections. The concentration of anti-GM-CSF autoantibody resulting in 50% inhibition of GM-CSF-induced pSTAT5 (IC50) was not significantly different between groups of patients (2.46 ± 2.3, 3.7 ± 3.3 and 1.94 ± 1.1 ug/ml in PAP patients, cryptococcosis and nocardiosis patients, respectively). Nor was the concentration of GM-CSF necessary to induce 50% of maximal GM-CSF-induced pSTAT5 in presence of 10 ug/ml of anti-GM-CSF aAb (EC50). When studying longitudinal samples from patients with PAP or disseminated nocardiosis, the neutralizing effect of anti GM-CSF aAb was relatively constant over time despite targeted treatments and variations in aAb levels. ConclusionsDespite different clinical manifestations, anti-GM-CSF antibodies were similar across PAP, cryptococcosis and nocardiosis. Underlying host genetics and functional analyses may help further differentiate the biology of these conditions.

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“…Nowadays, reports of OIs in patients with confirmed anti-GM-CSF autoantibodies with or without PAP have been increasing. 8,15,18,[23][24][25][26][27][28][29][30] Since the first documented case of anti-GM-CSF autoantibodies associated with disseminated cryptococcosis, 15 a total of 27 cases have been reported in the literature (Table 1). The median age at the time of presentation was 41 years (range 20-73 years).…”

Section: A S E Discussion and Re Vie W Of The Liter Aturementioning

confidence: 99%

Disseminated cryptococcosis and anti‐granulocyte‐macrophage colony‐stimulating factor autoantibodies: An underappreciated association

Viola

Malek

Rosen

et al. 2021

Mycoses

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The development of disseminated cryptococcosis has historically occurred in patients living with advanced human immunodeficiency virus or other immunosuppressive conditions affecting T‐cell function. Recently, patients with anti‐cytokine neutralising autoantibodies have been recognised to be at risk for disseminated infections by opportunistic intracellular pathogens, including Cryptococcus species. Herein, we present a previously healthy 26‐year‐old man who was evaluated with disseminated cryptococcosis involving the bone, lung, mediastinum and brain. The patient's serum cryptococcal antigen titres were >1:1,100,000, and evaluation for an underlying immunodeficiency revealed high titres for anti‐granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) autoantibodies. We also review the literature of all published cases of disseminated cryptococcosis associated with the presence of anti‐GM‐CSF autoantibodies. Clinicians should have a heightened awareness of anti‐cytokine autoantibodies in patients without a known immunodeficiency and development disseminated infections by opportunistic intracellular pathogens.

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The significance of anti‐granulocyte‐macrophage colony‐stimulating factor antibodies in cryptococcal infection: case series and review of antibody testing

Cited by 16 publications

References 19 publications

Human autoantibodies underlying infectious diseases

Human autoantibodies underlying infectious diseases

Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis

Disseminated cryptococcosis and anti‐granulocyte‐macrophage colony‐stimulating factor autoantibodies: An underappreciated association

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