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Ellegård, Rada
Publications (10 of 20) Show all publications
Bhattacharya, P., Ellegård, R., Khalid, M., Svanberg, C., Govender, M., Keita, Å., . . . Larsson, M. (2020). Complement opsonization of HIV affects primary infection of human colorectal mucosa and subsequent activation of T cells. eLIFE, 9, Article ID e57869.
Open this publication in new window or tab >>Complement opsonization of HIV affects primary infection of human colorectal mucosa and subsequent activation of T cells
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2020 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e57869Article in journal (Refereed) Published
Abstract [en]

HIV transmission via genital and colorectal mucosa are the most common routes of dissemination. Here, we explored the effects of free and complement-opsonized HIV on colorectal tissue. Initially, there was higher antiviral responses in the free HIV compared to complementopsonized virus. The mucosal transcriptional response at 24 hr revealed the involvement of activated T cells, which was mirrored in cellular responses observed at 96 hr in isolated mucosal T cells. Further, HIV exposure led to skewing of T cell phenotypes predominantly to inflammatory CD4+ T cells, that is Th17 and Th1Th17 subsets. Of note, HIV exposure created an environment that altered the CD8+ T cell phenotype, for example expression of regulatory factors, especially when the virions were opsonized with complement factors. Our findings suggest that HIV-opsonization alters the activation and signaling pathways in the colorectal mucosa, which promotes viral establishment by creating an environment that stimulates mucosal T cell activation and inflammatory Th cells.

Place, publisher, year, edition, pages
Cambridge, United Kingdom: ELIFE SCIENCES PUBLICATIONS LTD, 2020
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-170648 (URN)10.7554/eLife.57869 (DOI)000572823900001 ()32876566 (PubMedID)2-s2.0-85091126682 (Scopus ID)
Note

Funding Agencies|Vetenskapsradet Project [AI52731]; Stiftelsen Lakare mot AIDS Forskningsfond Project; Forsknings-ALF Project; Styrelsen for Internationellt Utvecklingssamarbete; SIDA SARC; VINNOVAVinnova; Larsson Linkoping University Hospital Research Fund; Svenska Lakaresallskapet

Available from: 2020-10-31 Created: 2020-10-31 Last updated: 2023-04-25Bibliographically approved
Fernlund, E., Kissopoulou, A., Green, H., Karlsson, J.-E., Ellegård, R., Klang Årstrand, H., . . . Gunnarsson, C. (2020). Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults-The Value of Reevaluating and Expanding Gene Panel Analyses. Genes, 11(12), Article ID 1472.
Open this publication in new window or tab >>Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults-The Value of Reevaluating and Expanding Gene Panel Analyses
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2020 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 11, no 12, article id 1472Article in journal (Refereed) Published
Abstract [en]

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
pediatric cardiomyopathy; hypertrophic; exome sequencing; gene panel; sudden cardiac death
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-172626 (URN)10.3390/genes11121472 (DOI)000602162600001 ()33302605 (PubMedID)
Note

Funding Agencies|Region Ostergotland (ALF); Strategic Research Area in Forensic Science (Strategiomradet i Forensiska Vetenskaper); Futurum (the research council of Region Jonkoping); Swedish Society of Medicine Samariten Foundation; FORSS (Medical Research Council of Southeast Sweden)

Available from: 2021-01-24 Created: 2021-01-24 Last updated: 2021-05-04
Kissopoulou, A., Fernlund, E., Holmgren, C., Isaksson, E., Karlsson, J.-E., Green, H., . . . Gunnarsson, C. (2020). Monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin gene variant. ESC Heart Failure, 7(3), 1210-1216
Open this publication in new window or tab >>Monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin gene variant
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2020 (English)In: ESC Heart Failure, E-ISSN 2055-5822, Vol. 7, no 3, p. 1210-1216Article in journal (Refereed) Published
Abstract [en]

Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST-T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene [NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9)] that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.

Place, publisher, year, edition, pages
WILEY PERIODICALS, INC, 2020
Keywords
Myocarditis; Arrhytmogenic cardiomyopathy; Desmoplakin gene
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-166470 (URN)10.1002/ehf2.12658 (DOI)000536512400053 ()32301586 (PubMedID)
Note

Funding Agencies|Region ostergotland (ALF); FORSS (Medical Research Council of Southeast Sweden); Futurum (the research council of Region Jonkoping)

Available from: 2020-06-20 Created: 2020-06-20 Last updated: 2021-05-04
Ellegård, R., Khalid, M., Svanberg, C., Holgersson, H., Thoren, Y., Wittgren, M. K., . . . Larsson, M. (2018). Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells. Frontiers in Immunology, 9, Article ID 899.
Open this publication in new window or tab >>Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells
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2018 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed) Published
Abstract [en]

Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
dendritic cells; natural killer cells; complement; HIV; cross talk; checkpoint inhibitors; CXCR3; CCR4
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-147922 (URN)10.3389/fimmu.2018.00899 (DOI)000431174300002 ()29760706 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; VINNMER for Vinnova; Linkoping University Hospital Research Fund; ALF Grants Region Ostergotland; FORSS; CERiA, University of Malaya [UM.C.625/1/HIR/139]

Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2024-01-17
Ellegård, R. (2018). Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dendritic cells are key players during HIV pathogenesis, and shape both the immediate immune response at the site of infection as well as directing the adaptive immune response against the virus. HIV has developed a plethora of immune evasion mechanisms that hijack dendritic cell functions, suppressing their ability to mount an accurate immune response and exploiting them for efficient viral transfer to target T cells.

To achieve successful replication within dendritic cells without triggering danger signaling, HIV accomplishes a delicate balance where only a low level of transcription can be sustained without triggering antiviral responses that would harm the virus. Here, we describe how the presence of HSV2 coinfection, which is very common in geographic areas with a high HIV prevalence and almost triples the risk of HIV acquisition, alters dendritic cell state to support much higher levels of HIV infection. We found this effect to be mediated by the STING pathway, which is involved in the sensing of DNA in the cell cytosol. STING activation led to an upregulation of factors such as IRF3 and NFkB that can be used for HIV transcription and a degradation of factors that restrict HIV replication.

In addition, we describe how HIV exploits the human complement system, a group of proteins that usually help the human body to identify dangerous pathogens while avoiding reaction towards self. HIV can coat itself, i.e. become opsonized, in complement fragments that are typically only present on the body’s own cells, allowing it to activate signaling pathways that are associated with tolerance. Dendritic cells that come into contact with complement opsonized HIV do not mount danger responses, despite the fact that HIV-derived single stranded RNA triggers the pathogen recognition receptor TLR8. The suppression of danger responses is mediated by activation of complement receptor 3, and leads to an increased infection of the dendritic cell and affects its interactions with other immune cells. There is a lack of recruitment of NK cells to the site of infection, and an inhibition of NK cell killing, which plays an important role in the destruction of HIV-infected cells in vivo. T cells primed by dendritic cells exposed to complement opsonized HIV have a lower ability to develop towards effector phenotype, and have an increased expression of the markers PD1, TIM3 and LAG3 which are associated with T cell dysfunction and exhaustion. In addition, T cells primed by these dendritic cells in the presence of NK cells upregulate markers CD38, CXCR3 and CCR4, which have been linked to an increased susceptibility to HIV infection.

In summary, we add to the current knowledge on HIV immune evasion mechanisms that allow the virus to establish infection, as well as describing mechanisms that govern whether dendritic cells mount danger signaling and an immune response or not.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 65
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1640
Keywords
HIV, dendritic cells, complement, innate immune response, TLR signaling, T cell activation, NK cells, inflammation, antiviral response, immune evasion
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-151665 (URN)10.3384/diss.diva-151665 (DOI)9789176852217 (ISBN)
Public defence
2018-10-26, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2019-09-30Bibliographically approved
Devito, C., Ellegård, R., Falkeborn, T., Svensson, L., Ohlin, M., Larsson, M., . . . Hinkula, J. (2018). Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro. Scientific Reports, 8, Article ID 10180.
Open this publication in new window or tab >>Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro
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2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 10180Article in journal (Refereed) Published
Abstract [en]

The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-150271 (URN)10.1038/s41598-018-28242-y (DOI)000437413200036 ()29977063 (PubMedID)
Note

Funding Agencies|Swedish Medical Research Fund; MIIC support Fund at Linkoping University

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2022-09-15
Yien Tan, H., Kong Yong, Y., Shankar, E. M., Paukovics, G., Ellegård, R., Larsson, M., . . . Crowe, S. M. (2016). Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome. Journal of Immunology, 196(10), 4052-4063
Open this publication in new window or tab >>Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome
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2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 10, p. 4052-4063Article in journal (Refereed) Published
Abstract [en]

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1 beta, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18R alpha on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-128934 (URN)10.4049/jimmunol.1502203 (DOI)000375831200008 ()27076678 (PubMedID)
Note

Funding Agencies|University of Malaya; Ministry of Higher Education High Impact Research Grant [UM.C/625/1/HIR/MOHE/MED/01]; University of Malaya Research Grants of the Health and Translational Medicine Research Cluster [RP021A-13HTM, RG448-12HTM]; Research Officer Grant Scheme [BR003-2014]; Australian National Health and Medical Research Council; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER from VINNOVA; Linkoping University Hospital research fund; Governmental Funding of Clinical Research within National Health Service; Swedish Society of Medicine; Victorian Operational Infrastructure Support Program

Available from: 2016-06-09 Created: 2016-06-07 Last updated: 2017-11-30
Crisci, E., Ellegård, R., Nyström, S., Rondahl, E., Serrander, L., Bergström, T., . . . Larsson, M. (2016). Complement opsonization promotes HSV-2 infection of human dendritic cells. Journal of Virology, 90(10), 4939-4950
Open this publication in new window or tab >>Complement opsonization promotes HSV-2 infection of human dendritic cells
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2016 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 90, no 10, p. 4939-4950Article in journal (Refereed) Published
Abstract [en]

Herpes virus type 2 (HSV2) is one of the most common sexually transmitted infections globally with a very high prevalence in many countries. During HSV2 infection viral particles become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. In genital mucosa, the primary target cells for HSV2 infection are epithelial cells, but resident immune cells such as dendritic cells (DCs) are also infected. The DCs are the activators of the ensuing immune responses directed against HSV2, and the aim of this study was to examine the effects opsonization of HSV2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV1 or HSV2 specific antibodies more or less abolished the HSV2 infection of DCs.Our results clearly demonstrate the importance of studying HSV2 infection under conditions that ensue in vivo, i.e. when the virions are covered in complement fragments and complement fragments and antibodies, as this will shape the infection and the subsequent immune response and needs to be further elucidated.

IMPORTANCE: During HSV2 infection viral particles should become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. The dendritic cells are the activators of the immune responses directed against HSV2, and the aim of this study was to examine the effects of complement alone or complement and antibodies, on the HSV2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses.Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV2 pathogenesis.

Place, publisher, year, edition, pages
American society of microbiology, 2016
Keywords
HSV2 infection, dendritic cells, complement, antibodies
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-126480 (URN)10.1128/JVI.00224-16 (DOI)000375126100009 ()26937039 (PubMedID)
Note

Funding agencies: Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; Swedish Society of Medicine; Swedis

Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2021-12-29
Saeidi, A., Ellegård, R., Yong, Y. K., Tan, H. Y., Velu, V., Ussher, J. E., . . . Shankar, E. M. (2016). Functional role of mucosal-associated invariant T cells in HIV infection. Journal of Leukocyte Biology, 100(2), 305-314
Open this publication in new window or tab >>Functional role of mucosal-associated invariant T cells in HIV infection
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2016 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 100, no 2, p. 305-314Article, review/survey (Refereed) Published
Abstract [en]

MAIT cells represent an evolutionarily conserved, MR1-restricted, innate-like cell subset that express high levels of CD161; have a canonical semi-invariant TCR iV alpha 7.2; and may have an important role in mucosal immunity against various bacterial and fungal pathogens. Mature MAIT cells are CD161(hi)PLZF(hi)IL-18R alpha(+)iV alpha 7.2(+)gamma delta-CD3(+)CD8(+) T cells and occur in the peripheral blood, liver, and mucosa of humans. MAIT cells are activated by a metabolic precursor of riboflavin synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial properties, their functional role in persistent viral infections is poorly understood. Although there is an increasing line of evidence portraying the depletion of MAIT cells in HIV disease, the magnitude and the potential mechanisms underlying such depletion remain unclear. Recent studies suggest that MAIT cells are vulnerable to immune exhaustion as a consequence of HIV and hepatitis C virus infections and HIV/tuberculosis coinfections. HIV infection also appears to cause functional depletion of MAIT cells resulting from abnormal expression of T-bet and EOMES, and effective ART is unable to completely salvage functional MAIT cell loss. Depletion and exhaustion of peripheral MAIT cells may affect mucosal immunity and could increase susceptibility to opportunistic infections during HIV infection. Here, we review some of the important mechanisms associated with depletion and functional loss of MAIT cells and also suggest potential immunotherapeutic strategies to restore MAIT cell functions, including the use of IL-7 to restore effector functions in HIV disease.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2016
Keywords
CD8(+) T cells; cytotoxicity; exhaustion; PD-1; TCR iV alpha 7.2
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-130371 (URN)10.1189/jlb.4RU0216-084R (DOI)000379738600006 ()27256572 (PubMedID)
Note

Funding Agencies|University of Malaya; Ministry of Higher Education [UM.C/625/1/HIR/MOHE/MED/01]; University of Malaya [RP021A-13HTM, RG448-12HTM]; Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER from VINNOVA; Linkoping University Hospital; National Health Service; Swedish Society of Medicine; U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases [1U19AI109633-01]; [BR003-2014]

Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2018-01-10
Barathan, M., Gopal, K., Mohamed, R., Ellegård, R., Saeidi, A., Vadivelu, J., . . . Shankar, E. M. (2015). Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis (London), 20(4), 466-480
Open this publication in new window or tab >>Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes
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2015 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 20, no 4, p. 466-480Article in journal (Refereed) Published
Abstract [en]

Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(A (R)) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
Apoptosis; Caspase; Hepatitis C; Spontaneous immune exhaustion; TRAIL
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116813 (URN)10.1007/s10495-014-1084-y (DOI)000350669500005 ()25577277 (PubMedID)
Note

Funding Agencies|High Impact Research, University of Malaya [UM.C.625/1/HIR/139]; HIRG-MOHE Grant of University of Malaya [A000003-50001]; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine; University of Malaya Research Grant (UMRG) of the Health and Translational Medicine Research Cluster, University of Malaya [RG448-12HTM]

Available from: 2015-04-07 Created: 2015-04-07 Last updated: 2017-12-04
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