scholarly journals Neither Classical nor Alternative Macrophage Activation Is Required for Pneumocystis Clearance during Immune Reconstitution Inflammatory Syndrome

2015 ◽  
Vol 83 (12) ◽  
pp. 4594-4603 ◽  
Author(s):  
Zhuo-Qian Zhang ◽  
Jing Wang ◽  
Zachary Hoy ◽  
Achsah Keegan ◽  
Samir Bhagwat ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Macrophage Activation ◽  
Macrophage Polarization ◽  
Severe Disease ◽  
Interleukin 4 ◽  
Content Type ◽  
Ifn Γ ◽  
Inflammatory Syndrome

Pneumocystisis a respiratory fungal pathogen that causes pneumonia (Pneumocystispneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4+T cell-dependent clearance ofPneumocystis, and previous studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement for either classically or alternatively activated macrophages forPneumocystisclearance has not been determined. Therefore, RAG2−/−mice lacking either the interferon gamma (IFN-γ) receptor (IFN-γR) or interleukin 4 receptor alpha (IL-4Rα) were infected withPneumocystis. These mice were then immune reconstituted with wild-type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2−/−mice developed severe disease but effectively clearedPneumocystisand resolved IRIS. Neither RAG/IFN-γR−/−nor RAG/IL-4Rα−/−mice displayed impairedPneumocystisclearance. However, RAG/IFN-γR−/−mice developed a dysregulated immune response, with exacerbated IRIS and greater pulmonary function deficits than those in RAG2 and RAG/IL-4Rα−/−mice. RAG/IFN-γR−/−mice had elevated numbers of lung CD4+T cells, neutrophils, eosinophils, and NK cells but severely depressed numbers of lung CD8+T suppressor cells. Impaired lung CD8+T cell responses in RAG/IFN-γR−/−mice were associated with elevated lung IFN-γ levels, and neutralization of IFN-γ restored the CD8 response. These data demonstrate that restricting the ability of macrophages to polarize in response to Th1 or Th2 cytokines does not impairPneumocystisclearance. However, a cell type-specific IFN-γ/IFN-γR-dependent mechanism regulates CD8+T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcP-related IRIS.

scholarly journals High Levels of TNF-α and TIM-3 as a Biomarker of Immune Reconstitution Inflammatory Syndrome in People with HIV Infection

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 527
Author(s):  
Lucero A. Ramon-Luing ◽  
Ranferi Ocaña-Guzman ◽  
Norma A. Téllez-Navarrete ◽  
Mario Preciado-García ◽  
Dámaris P. Romero-Rodríguez ◽  
...  
Keyword(s):  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Control Group ◽  
Hiv Patients ◽  
Art Initiation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Α Level ◽  
Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) is an exacerbated immune response that can occur to HIV+ patients after initiating antiretroviral therapy (ART). IRIS pathogenesis is unclear, but dysfunctional and exhausted cells have been reported in IRIS patients, and the TIM-3/Gal-9 axis has been associated with chronic phases of viral infection. This study aimed to evaluate the soluble levels of TIM-3 and Gal-9 and their relationship with IRIS development. TIM-3, Gal-9, TNF-α, IFN-γ, IL-6, TNFR1, TNFR2, E-cadherin, ADAM10, and ADAM17 were measured to search for IRIS-associated biomarkers in plasma samples from 0-, 4-, 8-, 12-, and 24-weeks after ART initiation of 61 HIV+ patients (15 patients developed IRIS, and 46 did not). We found that patients who developed IRIS had higher levels of TIM-3 [median 4806, IQR: 3206–6182] at the time of the IRIS events, compared to any other follow-up time evaluated in these patients or compared with a control group of patients who did not develop IRIS. Similarly, IRIS patients had a higher TNF-α level [median 10.89, IQR: 8.36–12.34] at IRIS events than any other follow-up time evaluated. Other molecules related to the TIM-3 and TNF-α pathway (Gal-9, IL-6, IFN-γ, TNFR1, TNFR2, ADAM-10, and ADAM-17) did not change during the IRIS events. In conclusion, our data suggest that a high level of soluble TIM-3 and TNF-α could be used as an IRIS biomarker.

scholarly journals Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3818-3827 ◽  
Author(s):  
Lis R. V. Antonelli ◽  
Yolanda Mahnke ◽  
Jessica N. Hodge ◽  
Brian O. Porter ◽  
Daniel L. Barber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Interferon Γ ◽  
Effector Memory ◽  
Hiv Patients ◽  
Inflammatory Syndrome

Abstract Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1+, HLA-DR+, and Ki67+ CD4+ T cells than patients without IRIS. Moreover, PD-1+ CD4+ T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.

scholarly journals HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome is Associated with Aberrant T Cell Function and Increased Cytokine Responses

2019 ◽  
Author(s):  
David B. Meya ◽  
Samuel Okurut ◽  
Godfrey Zziwa ◽  
Stephen Cose ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Opportunistic Infection ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Cryptococcal Meningitis ◽  
Immune Reconstitution ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cytokine Responses ◽  
Inflammatory Syndrome

Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15%-20% of HIV-related mortality. A complication of initiating Antiretroviral therapy (ART) following opportunistic infection is Immune Reconstitution Inflammatory Syndrome (IRIS). IRIS afflicts 10-30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-γ and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2+/IL-17+ CD4+ T cells in patients with CM-IRIS. Moreover, CD8+ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell cytokine production in response to cryptococcal antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM infection.

scholarly journals COVID-19 and HIV-Associated Immune Reconstitution Inflammatory Syndrome: Emergence of Pathogen-Specific Immune Responses Adding Fuel to the Fire

2021 ◽  
Vol 12 ◽  
Author(s):  
Nabila Seddiki ◽  
Martyn French
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Macrophage Activation ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
B Cell Differentiation ◽  
Adaptive Immune ◽  
Inflammatory Syndrome

Both coronavirus disease 2019 (COVID-19) and mycobacterial immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-1 infection result from immunopathology that is characterized by increased production of multiple pro-inflammatory chemokines and cytokines associated with activation of myeloid cells (monocytes, macrophages and neutrophils). We propose that both conditions arise because innate immune responses generated in the absence of effective adaptive immune responses lead to monocyte/macrophage activation that is amplified by the emergence of a pathogen-specific adaptive immune response skewed towards monocyte/macrophage activating activity by the immunomodulatory effects of cytokines produced during the innate response, particularly interleukin-18. In mycobacterial IRIS, that disease-enhancing immune response is dominated by a Th1 CD4+ T cell response against mycobacterial antigens. By analogy, it is proposed that in severe COVID-19, amplification of monocyte/macrophage activation results from the effects of a SARS-CoV-2 spike protein antibody response with pro-inflammatory characteristics, including high proportions of IgG3 and IgA2 antibodies and afucosylation of IgG1 antibodies, that arises from B cell differentiation in an extra-follicular pathway promoted by activation of mucosa-associated invariant T cells. We suggest that therapy for the hyperinflammation underlying both COVID-19 and mycobacterial IRIS might be improved by targeting the immunomodulatory as well as the pro-inflammatory effects of the ‘cytokine storm’.

Tuberculosis (TB)-associated immune reconstitution inflammatory syndrome in TB-HIV co-infected patients in Malaysia: prevalence, risk factors, and treatment outcomes

Sexual Health ◽  
2014 ◽  
Vol 11 (6) ◽  
pp. 532 ◽  
Author(s):  
Hong Yien Tan ◽  
Yean Kong Yong ◽  
Sin How Lim ◽  
Sasheela Ponnampalavanar ◽  
Sharifah F. S. Omar ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
Treatment Outcomes ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Cd4 T Cell ◽  
Cell Recovery ◽  
Hiv Patients ◽  
Pathogen Load ◽  
Inflammatory Syndrome

Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important early complication of antiretroviral therapy (ART) in countries with high rates of endemic TB, but data from South-East Asia are incomplete. Identification of prevalence, risk factors and treatment outcomes of TB-IRIS in Malaysia was sought. Methods: A 3-year retrospective study was conducted among TB-HIV co-infected patients treated at the University of Malaya Medical Centre. Simple and adjusted logistic regressions were used to identify the predictors for TB-IRIS while Cox regression was used to assess the influence of TB-IRIS on long-term CD4 T-cell recovery. Results: One hundred and fifty-three TB-HIV patients were enrolled, of whom 106 had received both anti-TB treatment (ATT) and ART. The median (IQR) baseline CD4 T-cell count was 52 cells μL–1 (13–130 cells μL–1). Nine of 96 patients (9.4%) developed paradoxical TB-IRIS and eight developed unmasking TB-IRIS, at a median (IQR) time of 27 (12–64) and 19 (14–65) days, respectively. In adjusted logistic regression analysis, only disseminated TB was predictive of TB-IRIS [OR: 10.7 (95% CI: 1.2–94.3), P = 0.032]. Mortality rates were similar for TB-IRIS (n = 1, 5.9%) and non-TB-IRIS (n = 5, 5.7%) patients and CD4 T-cell recovery post-ART was not different between the two groups (P = 0.363). Conclusion: Disseminated TB was a strong independent predictor of TB-IRIS in Malaysian HIV-TB patients after commencing ART. This finding underscores the role of a high pathogen load in the pathogenesis of TB-IRIS; so interventions that reduce pathogen load before ART may benefit HIV patients with disseminated TB.

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