Discrepancy between Mtb-specific IFN-γ and IgG responses in HIV-positive people with low CD4 counts

Mthembu, Maphe; Bowman, Kathryn; Davies, Leela; Khuzwayo, Sharon; Mazibuko, Lusanda; Bassett, Thierry; Ramjit, Dirhona; Mhlane, Zoey; Karim, Farina; Alter, Galit; Ndung’u, Thumbi; Wong, Emily

doi:10.1016/j.ebiom.2023.104504

Cited by 7 publications

(7 citation statements)

References 40 publications

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“…Consequently, assays based on T cell immune responses do not work well and underestimate TB diagnosis in advanced PLHIV. In agreement with previous reports, 8 31 32 stratifying participants in the study by CD4 + T cell revealed a decrease in the diagnostic accuracy of IGRA, the current gold standard immunodiagnostic for Mtb infection, in those with lower CD4 + T-cell counts. However, the performance of the TB prediction model incorporating the four-cytokine biosignature was not affected by low CD4 + T-cell counts.…”

Section: Discussionsupporting

confidence: 92%

“… 21 22 Although host responses-based detection methods, such as tuberculin skin test (TST) and IGRA, provide alternative solutions for diagnosing Mtb infection, they share the limitation of being unable to distinguish active TB from LTBI and exhibit reduced efficacy in advanced PLHIV with low CD4 + T-cell counts. 8 23 24 Other host biomarkers, apart from TST and IGRA, are in earlier stages of development for TB diagnostics.…”

Section: Discussionmentioning

confidence: 99%

“…However, IGRA cannot distinguish TB from latent TB infection (LTBI) and has diminished diagnostic accuracy in advanced HIV-positive patients with decreased T-cell functions. 8 9 …”

Section: Introductionmentioning

confidence: 99%

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Serum cytokine biosignatures for identification of tuberculosis among HIV-positive inpatients

Zhang,

Li,

Liu

et al. 2024

Thorax

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BackgroundSerum cytokines correlate with tuberculosis (TB) progression and are predictors of TB recurrence in people living with HIV. We investigated whether serum cytokine biosignatures could diagnose TB among HIV-positive inpatients.MethodsWe recruited HIV-positive inpatients with symptoms of TB and measured serum levels of inflammation biomarkers including IL-2, IL-4, IL-6, IL-10, tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). We then built and tested our TB prediction model.Results236 HIV-positive inpatients were enrolled in the first cohort and all the inflammation biomarkers were significantly higher in participants with microbiologically confirmed TB than those without TB. A binary support vector machine (SVM) model was built, incorporating the data of four biomarkers (IL-6, IL-10, TNF-α and IFN-γ). Efficacy of the SVM model was assessed in training (n=189) and validation (n=47) sets with area under the curve (AUC) of 0.92 (95% CI 0.88 to 0.96) and 0.85 (95% CI 0.72 to 0.97), respectively. In an independent test set (n=110), the SVM model yielded an AUC of 0.85 (95% CI 0.76 to 0.94) with 78% (95% CI 68% to 87%) specificity and 85% (95% CI 66% to 96%) sensitivity. Moreover, the SVM model outperformed interferon-gamma release assay (IGRA) among advanced HIV-positive inpatients irrespective of CD4+T-cell counts, which may be an alternative approach for identifyingMycobacterium tuberculosisinfection among HIV-positive inpatients with negative IGRA.ConclusionsThe four-cytokine biosignature model successfully identified TB among HIV-positive inpatients. This diagnostic model may be an alternative approach to diagnose TB in advanced HIV-positive inpatients with low CD4+T-cell counts.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Serum cytokine biosignatures for identification of tuberculosis among HIV-positive inpatients

Zhang,

Li,

Liu

et al. 2024

Thorax

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“…Study subjects were not tested for Mtb infection by interferon gamma release assay (IGRA) or other means. However, the force of infection in Durban is extremely high and approximately 60% of HIV uninfected participants in a recent study from a similar Durban Cohort were found to be IGRA positive ( 29 ). Thus, this group is highly likely to contain both IGRA+ve and IGRA-ve participants.…”

Section: Methodsmentioning

confidence: 99%

Myeloid cell expression of CD200R is modulated in active TB disease and regulates Mycobacterium tuberculosis infection in a biomimetic model

Ahmed,

Tezera,

Herbert

et al. 2024

Front. Immunol.

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A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.

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“…However, the roles of other cytokines produced by CD8 T cells are still not exactly known [9] . In the study of CD4 T cells, Mthembu M et al found that CD4 count was independently associated with the production of IFN-γ no matter the HIV status [11] , and in HIV patients were more likely presented with disseminated diseases and miliary in ltrates [12] .While in the study of CD8 T cells, the study in rhesus macaques showed that the depletion of CD8 T cells led to a decreased vaccine-induced immunity against tuberculosis [13] . Li, Q. et al revealed that in HIV-negative TB patients, the proportion of CD8 T cells, rather than CD4 T cells, was positively associated with the prevalence of disseminated infection [14] .…”

Section: Introductionmentioning

confidence: 99%

CD8 T cell count was not associated with the severity of pulmonary tuberculosis

Xiang

Liu

et al. 2023

Preprint

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Purposes: Tuberculosis is still a global health threat, among those, severe pulmonary tuberculosis causes significant mortality. CD8 T cell plays an important role in the pathogenesis of tuberculosis. However, the association between CD8 T cell count and the severity of pulmonary TB (PTB) has not been evaluated. Methods: Patients admitted to a tertiary hospital from January 2013 to December 2017 and diagnosed as PTB with T cell subtypes tested were screened for recruitment. We compared the demographics and clinical manifestations between severe PTB patients and non-severe PTB patients, then analyzed the independent risk factors related to severe PTB after adjusting covariates. Results: There were 279 patients enrolled for analysis, 180 were severe PTB (64.5%) and 99 were non-severe PTB (35.5%). Through univariate and multivariate analysis, lung cavity (aOR 4.631, 95% CI [1.798-12.853], P= 0.002) and albumin (aOR 0.952,95% CI [0.905-1.000], P=0.05) were associated severe PTB. While CD4 T cell count (aOR 1.00,95% CI [0.999-1.001], P=0.794), CD8 T cell count (aOR 1.00,95% CI [0.999-1.001], P=0.973), and lymphocyte (aOR 0.82,95% CI [0.389-1.774], P=0.603) were not associated with severe PTB. Conclusions: Lung cavity and lower albumin level were related with an increased risk of severe PTB, while CD4, CD8 T cells count and lymphocytes were not with the severity of PTB. May be not the count, but the function of T cells plays a crucial role in the pathogenesis of tuberculosis.

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Discrepancy between Mtb-specific IFN-γ and IgG responses in HIV-positive people with low CD4 counts

Cited by 7 publications

References 40 publications

Serum cytokine biosignatures for identification of tuberculosis among HIV-positive inpatients

Serum cytokine biosignatures for identification of tuberculosis among HIV-positive inpatients

Myeloid cell expression of CD200R is modulated in active TB disease and regulates Mycobacterium tuberculosis infection in a biomimetic model

CD8 T cell count was not associated with the severity of pulmonary tuberculosis

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