Cutting Edge: Insufficient Perforin Expression in CD8+ T Cells in Response to Hemagglutinin from Avian Influenza (H5N1) Virus

Hsieh, Szu‐Min; Chang, Shan-Chwen

doi:10.4049/jimmunol.176.8.4530

Cited by 52 publications

(54 citation statements)

References 14 publications

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“…They occur in the context of severe viral infections, especially Epstein-Barr virus infection, cancer, and autoinflammatory and autoimmune diseases, in all age groups. 3,21,22 The probably diverse mechanisms that lead to secondary HLH are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice

Maschalidi

Sepulveda

Garrigue

et al. 2016

Blood

171

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Key Points• Treatment with clinical dose of JAK1/2 inhibitor (ruxolitinib) countered manifestations of HLH in 2 cytotoxicityimpaired murine models. • JAK1/2 inhibitor therapy in mice is effective on survival, cytopenia, inflammatory syndrome, central nervous system involvement, and liver tissue repair.Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome, characterized by severe hyperinflammation and immunopathological manifestations in several tissues. These features result from organ infiltration by overactivated CD8 T-cells and macrophages, which produce high levels of pro-inflammatory cytokines, such as IFN-g, TNF-a, IL-6, and IL-18. Recently, several Janus kinase 1/2 (JAK1/2) inhibitors, such as ruxolitinib, have been developed as immunosuppressive agents. They have proven beneficial effects in the treatment of myeloproliferative disorders and inflammatory conditions. To determine whether pharmacological inhibition of the JAK1/2 not only prevents the onset of HLH immunopathology but also is effective against existing HLH, cytotoxicity-impaired Prf1 2/2 and Rab27a 2/2 mice with full-blown HLH syndrome were treated with a clinically relevant dose of ruxolitinib. In vivo, ruxolitinib treatment suppressed signal transducer and activator of transcription 1 activation and led to recovery from HLH manifestations in both murine models. In the Prf1 2/2 mice, these beneficial effects were evidenced by a greater survival rate, and in both murine models, they were evidenced by the correction of blood cytopenia and a rapid decrease in serum IL-6 and TNF-a levels. During ruxolitinib treatment, liver tissue damage receded concomitantly with a decrease in the number of infiltrating inflammatory macrophages and an increase in the number of alternatively activated macrophages. In Rab27a 2/2 mice, central nervous system involvement was significantly reduced by ruxolitinib therapy. Our findings demonstrate that clinically relevant doses of the JAK1/2 inhibitor ruxolitinib suppresses the harmful consequences of macrophage overactivation characterizing HLH in 2 murine models. The results could be readily translated into the clinic for the treatment of primary, and perhaps even secondary, forms of HLH. (Blood. 2016; 128(1):60-71)

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Section: Introductionmentioning

confidence: 99%

Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice

Maschalidi

Sepulveda

Garrigue

et al. 2016

Blood

171

View full text Add to dashboard Cite

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“…The mechanism of lymphopenia induced after H5N1 influenza virus infection is largely unknown. Remarkably, H5N1 influenza virus seems to reduce the effector function of CD8 + T cells by an insufficient perforin expression (10). Moreover, it was reported that H5N1 viruses are able to infect cells of the immune system, leading to an impaired adaptive immune response (11).…”

Section: Nfluenza a Virus Infection Causes Severe Disease In Humansmentioning

confidence: 99%

Highly Pathogenic Influenza Virus Infection of the Thymus Interferes with T Lymphocyte Development

Vogel

Haasbach

Reiling

et al. 2010

The Journal of Immunology

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Highly pathogenic avian influenza viruses (HPAIVs) cause severe disease in humans. Still, the basis for their increased pathogenesis remains unclear. Additionally, the high morbidity in the younger population stays inexplicable, and the recent pandemic H1N1v outbreak in 2009 demonstrated the urgent need for a better understanding about influenza virus infection. In the present study, we demonstrated that HPAIV infection of mice not only led to lung destruction but also to functional damage of the thymus. Moreover, respiratory dendritic cells in the lung functioned as targets for HPAIV infection being able to transport infectious virus from the lung into the thymus. The pandemic H1N1 influenza virus was able to infect respiratory dendritic cells without a proper transport to the thymus. The strong interference of HPAIV with the immune system is especially devastating for the host and can lead to lymphopenia. In summary, from our data, we conclude that highly pathogenic influenza viruses are able to reach the thymus via dendritic cells and to interfere with T lymphocyte development. Moreover, this exceptional mechanism might not only be found in influenza virus infection, but also might be the reason for the increased immune evasion of some new emerging pathogens.

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“…This so-called cytokine storm could pathogenically contribute to tissue damage and progressive systemic organ failure. Improper intracellular trafficking and impaired apoptosis have also been implicated [1,20,21]. The strikingly inflammatory state promoted by hypercytokinemia could explain the beneficial role of high dose steroids that we observed.…”

Section: Comorbidities/ Co-morbid Infectionsmentioning

confidence: 52%

“…Unfortunately, treatment was never started in many cases because of delayed diagnosis. In the study by Beutel et al [14], the median time from the onset of symptoms to the diagnosis of VAHS was 23 days (interquartile range [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. This could explain, at least in part, the poor prognosis of HPS secondary to influenza A infection.…”

Section: Comorbidities/ Co-morbid Infectionsmentioning

confidence: 99%

“…In the case of avian influenza and influenza H1N1 associated hemophagocytic syndrome, the mortality is around 50%-89% [1,14,21]. Because of the high mortality observed in HPS secondary to influenza A infection, we believe it is crucial to make an early diagnosis and start antiviral and immunomodulatory treatment as soon as possible.…”

Section: Comorbidities/ Co-morbid Infectionsmentioning

confidence: 99%

See 1 more Smart Citation

Influenza-Associated Hemophagocytic Syndrome in Adults: Case Report and Review

Trujillo¹,

Lalueza²,

Blanco³

et al. 2018

J Antivir Antiretrovir

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Cutting Edge: Insufficient Perforin Expression in CD8+ T Cells in Response to Hemagglutinin from Avian Influenza (H5N1) Virus

Cited by 52 publications

References 14 publications

Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice

Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice

Highly Pathogenic Influenza Virus Infection of the Thymus Interferes with T Lymphocyte Development

Influenza-Associated Hemophagocytic Syndrome in Adults: Case Report and Review

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