Type I Interferon Impairs Specific Antibody Responses Early during Establishment of LCMV Infection

Daugan, Matthieu; Murira, Armstrong; Mindt, Barbara C.; Germain, Amélie; Tarrab, Esther; Lapierre, Pascal; Fritz, Jörg H.; Lamarre, Alain

doi:10.3389/fimmu.2016.00564

Cited by 24 publications

(21 citation statements)

References 58 publications

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“…Furthermore, we also evaluated antigen specificity of NP-CGG in the context of vesicular stomatitis virus (an acute infection), which remained unchanged. Remarkably, we observed the rescue of antigen specificity upon IFNAR blockade in addition to a recovery of lymphoid architecture similar to previous studies (2, 3, 67, 68). Most importantly, we also assessed the humoral response using a chimeric mouse model comprising reconstitution of irradiated B6 mice with a mix of bone marrow cells from J H T (B-cell deficient) (69) and IFNAR −/− mice.…”

Section: Ifn-i Responses In Lymphocytic Choriomeningitis Virus (Lcmv)supporting

confidence: 91%

“…Along with others, we observed the extensive impact of IFN-mediated responses on humoral immunity both directly and indirectly in the context of viral persistence. In our study, we found that in addition to the indirect T FH -associated humoral response perturbation, there was a direct IFN-I-mediated effect on B cells (67). Comparing LCMV-Clone 13 versus LCMV-WE (acute), we observed sustained ablation of antigen specificity against a secondary immunogen, nitrophenylacetyl-chicken gamma globulin (NP-CGG), in the former whereas the latter only showed transient impact on antigen specificity.…”

Section: Ifn-i Responses In Lymphocytic Choriomeningitis Virus (Lcmv)mentioning

confidence: 71%

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Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection

2016

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Type I interferons (IFN-I) have long been heralded as key contributors to effective antiviral responses. More widely understood in the context of acute viral infection, the role of this pleiotropic cytokine has been characterized as triggering antiviral states in cells and potentiating adaptive immune responses. Upon induction in the innate immune response, IFN-I triggers the expression of interferon-stimulated genes (ISGs), which upregulate the effector function of immune cells (e.g., dendritic cells, B cells, and T cells) toward successful resolution of infections. However, emerging lines of evidence reveal that viral persistence in the course of chronic infections could be driven by deleterious immunomodulatory effects upon sustained IFN-I expression. In this setting, elevation of IFN-I and ISGs is directly correlated to viral persistence and elevated viral loads. It is important to note that the correlation among IFN-I expression, ISGs, and viral persistence may be a cause or effect of chronic infection and this is an important distinction to make toward establishing the dichotomous nature of IFN-I responses. The aim of this mini review is to (i) summarize the interaction between IFN-I and downstream effector responses and therefore (ii) delineate the function of this cytokine on positive and negative immunoregulation in chronic infection. This is a significant consideration given the current therapeutic administration of IFN-I in chronic viral infections whose therapeutic significance is projected to continue despite emergence of increasingly efficacious antiviral regimens. Furthermore, elucidation of the interplay between virus and the antiviral response in the context of IFN-I will elucidate avenues toward more effective therapeutic and prophylactic measures against chronic viral infections.

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Section: Ifn-i Responses In Lymphocytic Choriomeningitis Virus (Lcmv)supporting

confidence: 91%

Section: Ifn-i Responses In Lymphocytic Choriomeningitis Virus (Lcmv)mentioning

confidence: 71%

Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection

2016

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“…We have recently demonstrated a role for IFN‐I in promoting hypergammaglobulinemia during VL by directly acting on B cells . A similar result was obtained in an LCMV model, where IFN‐I was inhibiting the production of neutralizing antibodies and promoting hypergammaglobulinemia . The fact that treatment with IFN‐I can lead to Lupus‐like symptoms highlights the fine line between chronic infections and the development of autoimmune diseases.…”

Section: Discussionsupporting

confidence: 67%

Hypergammaglobulinemia sustains the development of regulatory responses during chronic Leishmania donovani infection in mice

Silva‐Barrios

Stäger

2019

Eur J Immunol

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Visceral leishmaniasis, a chronic, potentially fatal disease, is characterized by high production of low-affinity antibodies. In humans, hypergammaglobulinemia is prediction of disease progression. Nevertheless, the contribution of hypermutated and/or classswitched immunoglobulins to disease pathogenesis has never been studied. Using Aicda −/− mice and the experimental model of Leishmania donovani infection, we demonstrate that the absence of hypermutated and/or class-switched antibodies was associated with increased resistance to disease, stronger protective Th1 responses, and a lower frequency of regulatory IFNγ + IL-10 + CD4 T cells. Interestingly, stronger Th1 responses and the absence of IFNγ + IL-10 + CD4 T cells during chronic infection in infected Aicda −/− mice were not caused by a T-cell intrinsic effect of AID, but by changes in the cytokine environment during chronic disease. Indeed TNF, IL-10 and IFN-ß expressions were only upregulated in the presence of hypermutated, class-switched antibodies and hypergammaglobulinemia at later stages of infection. Taken together, our results suggest that hypergammaglobulinemia sustains inhibitory responses during chronic visceral leishmaniasis.Keywords: AID r hypergammaglobulinemia r Leishmania donovani r regulatory T cells r T helper cells Additional supporting information may be found online in the Supporting Information section at the end of the article.

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“…Recent evidence in LCMV clone 13-infected mice that were co-immunized with the 4-hydroxy-3-nitrophenylacetic (NP) hapten showed that sustained IFN-I expression was responsible for HGG as well as reduced production of NP-specific Abs [ 63 ]. In this study, Daugan et al also observed the delayed appearance of LCMV-specific neutralizing Abs along with disrupted B-cell follicle structure and high expression of chemokine receptor CXCR4 in germinal center (GC) B-cells [ 63 ] ( Figure 2 ). It is important to note that aberrant expression of this receptor affects the homing of B-cells within the follicles, which resultantly impacts the architecture of this microstructure.…”

Section: Detrimental Role Of Sustained Ifn-i Expression On the Hummentioning

confidence: 99%

“…In addition, it has also been shown that IFNR blockade causes downregulation of cell-death signal cascades by the reduction in Bak expression and Fas-mediated apoptosis in CD4 T-cells using an in vitro HIV-1 infection model [ 66 ]. IFNR blockade also increases total splenic T-lymphocyte and antiviral specific CD4 T-cell numbers during LCMV CL13 infection [ 26 , 29 , 63 ]. Finally, data collected by Cha and colleagues indicates that sustained IFN-I expression in HIV-1-infected patients undergoing ART may promote T-cell loss by accelerating cell turnover and activation-induced cell death while decreasing T-cell homeostasis mediated by IL-7 [ 7 , 60 ].…”

Section: Impact Of Sustained Ifn-i On T-cell Maintenance and Antivmentioning

confidence: 99%

Sustained IFN-I Expression during Established Persistent Viral Infection: A “Bad Seed” for Protective Immunity

Dagenais-Lussier

Loucif

Murira

et al. 2017

Viruses

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Type I interferons (IFN-I) are one of the primary immune defenses against viruses. Similar to all other molecular mechanisms that are central to eliciting protective immune responses, IFN-I expression is subject to homeostatic controls that regulate cytokine levels upon clearing the infection. However, in the case of established persistent viral infection, sustained elevation of IFN-I expression bears deleterious effects to the host and is today considered as the major driver of inflammation and immunosuppression. In fact, numerous emerging studies place sustained IFN-I expression as a common nexus in the pathogenesis of multiple chronic diseases including persistent infections with the human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), as well as the rodent-borne lymphocytic choriomeningitis virus clone 13 (LCMV clone 13). In this review, we highlight recent studies illustrating the molecular dysregulation and resultant cellular dysfunction in both innate and adaptive immune responses driven by sustained IFN-I expression. Here, we place particular emphasis on the efficacy of IFN-I receptor (IFNR) blockade towards improving immune responses against viral infections given the emerging therapeutic approach of blocking IFNR using neutralizing antibodies (Abs) in chronically infected patients.

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Type I Interferon Impairs Specific Antibody Responses Early during Establishment of LCMV Infection

Cited by 24 publications

References 58 publications

Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection

Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection

Hypergammaglobulinemia sustains the development of regulatory responses during chronic Leishmania donovani infection in mice

Sustained IFN-I Expression during Established Persistent Viral Infection: A “Bad Seed” for Protective Immunity

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