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Harnessing Mechanistic Knowledge on Beneficial Versus Deleterious IFN-I Effects to Design Innovative Immunotherapies Targeting Cytokine Activity to Specific Cell Types.

Tomasello E, Pollet E, Vu Manh TP, Uzé G, Dalod M - Front Immunol (2014)

Bottom Line: First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic anti-viral immunity.We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including (i) the subtypes and dose of IFN-I produced, (ii) the cell types affected by IFN-I, and (iii) the source and timing of IFN-I production.Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.

View Article: PubMed Central - PubMed

Affiliation: UM2, Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University , Marseille , France ; U1104, Institut National de la Santé et de la Recherche Médicale (INSERM) , Marseille , France ; UMR7280, Centre National de la Recherche Scientifique (CNRS) , Marseille , France.

ABSTRACT
Type I interferons (IFN-I) were identified over 50 years ago as cytokines critical for host defense against viral infections. IFN-I promote anti-viral defense through two main mechanisms. First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic anti-viral immunity. Second, IFN-I orchestrate innate and adaptive anti-viral immunity. However, IFN-I responses can be deleterious for the host in a number of circumstances, including secondary bacterial or fungal infections, several autoimmune diseases, and, paradoxically, certain chronic viral infections. We will review the proposed nature of protective versus deleterious IFN-I responses in selected diseases. Emphasis will be put on the potentially deleterious functions of IFN-I in human immunodeficiency virus type 1 (HIV-1) infection, and on the respective roles of IFN-I and IFN-III in promoting resolution of hepatitis C virus (HCV) infection. We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including (i) the subtypes and dose of IFN-I produced, (ii) the cell types affected by IFN-I, and (iii) the source and timing of IFN-I production. Finally, we will speculate how integration of this knowledge combined with advanced biochemical manipulation of the activity of the cytokines should allow designing innovative immunotherapeutic treatments in patients. Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.

No MeSH data available.


Related in: MedlinePlus

A simplified model of the deleterious role of IFN-I in several autoimmune diseases. When exposed to different kinds of injuries (microbial infection, commensal microbiota dysbiosis, chemical or physical insults), healthy tissues can undergo cell damage and death. These events induce the release of apoptotic bodies encompassing self RNA or DNA. Neutrophil recruitment and activation in inflamed tissues can also constitute a potent source of self nucleic acids, through the release of neutrophil extracellular traps (NET). Self RNA or DNA can associate with cationic peptides (e.g., LL37) as shown in psoriatic patients or with inflammatory molecules (e.g., high mobility group box 1, HMGB1) to generate nanoparticles that are extremely efficient for IFN-I production by pDC and eventually other cell types. pDC can also be efficiently activated for IFN-I production by immune complexes (ICs) generated by the association between self nucleic acids and auto-antibodies as frequently found in the serum of systemic lupus erythematosus patients. IFN-I promote the differentiation and/or the maturation of antigen-presenting cells, in particular different subsets of DC. Activated DC can then present self-antigens for activation of auto-reactive T CD4+ cells, including follicular helper lymphocytes, which in turn activate auto-reactive B cells for auto-antibody secretion, leading to a vicious circle of reciprocal activation between innate and auto-reactive adaptive immune cells. iDC, immature DC; mDC, mature DC; Mo-DC, monocyte-derived DC. See main text for further details.
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Figure 4: A simplified model of the deleterious role of IFN-I in several autoimmune diseases. When exposed to different kinds of injuries (microbial infection, commensal microbiota dysbiosis, chemical or physical insults), healthy tissues can undergo cell damage and death. These events induce the release of apoptotic bodies encompassing self RNA or DNA. Neutrophil recruitment and activation in inflamed tissues can also constitute a potent source of self nucleic acids, through the release of neutrophil extracellular traps (NET). Self RNA or DNA can associate with cationic peptides (e.g., LL37) as shown in psoriatic patients or with inflammatory molecules (e.g., high mobility group box 1, HMGB1) to generate nanoparticles that are extremely efficient for IFN-I production by pDC and eventually other cell types. pDC can also be efficiently activated for IFN-I production by immune complexes (ICs) generated by the association between self nucleic acids and auto-antibodies as frequently found in the serum of systemic lupus erythematosus patients. IFN-I promote the differentiation and/or the maturation of antigen-presenting cells, in particular different subsets of DC. Activated DC can then present self-antigens for activation of auto-reactive T CD4+ cells, including follicular helper lymphocytes, which in turn activate auto-reactive B cells for auto-antibody secretion, leading to a vicious circle of reciprocal activation between innate and auto-reactive adaptive immune cells. iDC, immature DC; mDC, mature DC; Mo-DC, monocyte-derived DC. See main text for further details.

Mentions: A frequent side effect of IFN-I treatment against cancer or chronic viral infections is the induction of autoimmune reactions. Consistently, ISG expression is a hallmark of many spontaneous systemic or tissue-specific autoimmune diseases, including systemic lupus erythematosous (SLE), Sjogren’s syndrome, psoriasis, and other skin disorders (11). The dysregulation of IFN-I responses observed in patients with these autoimmune diseases likely results from both genetic and environmental factors. Genome-wide association studies show that polymorphisms in genes involved in IFN-I responses strongly correlate with increased susceptibility to many autoimmune diseases (11). Diverse environmental factors can also contribute to the onset of autoimmune diseases. Microbial infections often precede first clinical manifestations of autoimmune diseases. Whether infections (116) and/or alterations in the commensal microbiota of the affected barrier tissues (117, 118) are the cause or rather the consequence of autoimmunity is still matter of debate. Infection- or dysbiosis-induced tissue damages and unbridled IFN-I responses can contribute to initiate autoimmune reactions. Gender is another prominent factor affecting susceptibility to autoimmune diseases. Women are more prone to autoimmunity, which may result from endocrine regulation of IFN-I responses. pDC IFN-I production is enhanced in human and mouse females, due at least in part to cell-intrinsic enhancement of TLR7/9 responses by the female hormone estradiol (119). In autoimmune diseases, different mechanisms could operate to initiate the dysregulation of immune responses leading to a vicious circle of reciprocal activation between innate IFN-I responses and adaptive self-reactive lymphocyte responses (Figure 4). Adaptive immune cells are educated to spare “self.” This occurs through negative selection of potentially autoimmune B and T cells during their development in the bone marrow or thymus, respectively, a process called central tolerance. Self-reactive B or T cells that have escaped this pruning can be either deleted or functionally inactivated once they have egressed in secondary lymphoid organs or non-lymphoid tissues, a process called peripheral tolerance. In some individuals, polymorphisms in genes involved in the promotion of central or peripheral tolerance lead to a higher number, diversity, and/or responsiveness of self-reactive lymphocytes in the periphery, in particular of B cells secreting anti-DNA or anti-RNP antibodies (120, 121). Mammalian DNA or RNA are poor inducers of pDC IFN-I induction under normal conditions. However, pre-existing anti-DNA or anti-RNP autoantibodies can break this innate tolerance of pDC. Indeed, antibodies binding to self nucleic acids can protect them from degradation and compact them into nanoparticles that are very effective for the induction of IFN-I in pDC (Figure 4). DNA-containing immune complexes (ICs) are frequently found in the serum of SLE patients (SLE-ICs) and can activate pDC IFN-I production (122). In turn, pDC IFN-I activate cDCs, monocytes (123), and B cells, leading to a vicious circle of reciprocal activation between DCs and self-reactive lymphocytes and to the exacerbation of autoimmune responses (Figure 4). Certain infections or dysbiosis of the commensal microbiota of the affected barrier tissues could promote chronic production of host amphiphatic peptides able to combine with eukaryotic DNA or RNA, likely released from dying cells, thus forming pDC-activating nanoparticles. Indeed, in psoriatic skin, both a high expression of LL37 and a massive infiltration of pDCs is observed (124) (Figure 4). Hence, to treat many autoimmune diseases, novel therapeutic strategies could be designed to target dysregulated pDC IFN-I production or B cell activation by IFN-I.


Harnessing Mechanistic Knowledge on Beneficial Versus Deleterious IFN-I Effects to Design Innovative Immunotherapies Targeting Cytokine Activity to Specific Cell Types.

Tomasello E, Pollet E, Vu Manh TP, Uzé G, Dalod M - Front Immunol (2014)

A simplified model of the deleterious role of IFN-I in several autoimmune diseases. When exposed to different kinds of injuries (microbial infection, commensal microbiota dysbiosis, chemical or physical insults), healthy tissues can undergo cell damage and death. These events induce the release of apoptotic bodies encompassing self RNA or DNA. Neutrophil recruitment and activation in inflamed tissues can also constitute a potent source of self nucleic acids, through the release of neutrophil extracellular traps (NET). Self RNA or DNA can associate with cationic peptides (e.g., LL37) as shown in psoriatic patients or with inflammatory molecules (e.g., high mobility group box 1, HMGB1) to generate nanoparticles that are extremely efficient for IFN-I production by pDC and eventually other cell types. pDC can also be efficiently activated for IFN-I production by immune complexes (ICs) generated by the association between self nucleic acids and auto-antibodies as frequently found in the serum of systemic lupus erythematosus patients. IFN-I promote the differentiation and/or the maturation of antigen-presenting cells, in particular different subsets of DC. Activated DC can then present self-antigens for activation of auto-reactive T CD4+ cells, including follicular helper lymphocytes, which in turn activate auto-reactive B cells for auto-antibody secretion, leading to a vicious circle of reciprocal activation between innate and auto-reactive adaptive immune cells. iDC, immature DC; mDC, mature DC; Mo-DC, monocyte-derived DC. See main text for further details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214202&req=5

Figure 4: A simplified model of the deleterious role of IFN-I in several autoimmune diseases. When exposed to different kinds of injuries (microbial infection, commensal microbiota dysbiosis, chemical or physical insults), healthy tissues can undergo cell damage and death. These events induce the release of apoptotic bodies encompassing self RNA or DNA. Neutrophil recruitment and activation in inflamed tissues can also constitute a potent source of self nucleic acids, through the release of neutrophil extracellular traps (NET). Self RNA or DNA can associate with cationic peptides (e.g., LL37) as shown in psoriatic patients or with inflammatory molecules (e.g., high mobility group box 1, HMGB1) to generate nanoparticles that are extremely efficient for IFN-I production by pDC and eventually other cell types. pDC can also be efficiently activated for IFN-I production by immune complexes (ICs) generated by the association between self nucleic acids and auto-antibodies as frequently found in the serum of systemic lupus erythematosus patients. IFN-I promote the differentiation and/or the maturation of antigen-presenting cells, in particular different subsets of DC. Activated DC can then present self-antigens for activation of auto-reactive T CD4+ cells, including follicular helper lymphocytes, which in turn activate auto-reactive B cells for auto-antibody secretion, leading to a vicious circle of reciprocal activation between innate and auto-reactive adaptive immune cells. iDC, immature DC; mDC, mature DC; Mo-DC, monocyte-derived DC. See main text for further details.
Mentions: A frequent side effect of IFN-I treatment against cancer or chronic viral infections is the induction of autoimmune reactions. Consistently, ISG expression is a hallmark of many spontaneous systemic or tissue-specific autoimmune diseases, including systemic lupus erythematosous (SLE), Sjogren’s syndrome, psoriasis, and other skin disorders (11). The dysregulation of IFN-I responses observed in patients with these autoimmune diseases likely results from both genetic and environmental factors. Genome-wide association studies show that polymorphisms in genes involved in IFN-I responses strongly correlate with increased susceptibility to many autoimmune diseases (11). Diverse environmental factors can also contribute to the onset of autoimmune diseases. Microbial infections often precede first clinical manifestations of autoimmune diseases. Whether infections (116) and/or alterations in the commensal microbiota of the affected barrier tissues (117, 118) are the cause or rather the consequence of autoimmunity is still matter of debate. Infection- or dysbiosis-induced tissue damages and unbridled IFN-I responses can contribute to initiate autoimmune reactions. Gender is another prominent factor affecting susceptibility to autoimmune diseases. Women are more prone to autoimmunity, which may result from endocrine regulation of IFN-I responses. pDC IFN-I production is enhanced in human and mouse females, due at least in part to cell-intrinsic enhancement of TLR7/9 responses by the female hormone estradiol (119). In autoimmune diseases, different mechanisms could operate to initiate the dysregulation of immune responses leading to a vicious circle of reciprocal activation between innate IFN-I responses and adaptive self-reactive lymphocyte responses (Figure 4). Adaptive immune cells are educated to spare “self.” This occurs through negative selection of potentially autoimmune B and T cells during their development in the bone marrow or thymus, respectively, a process called central tolerance. Self-reactive B or T cells that have escaped this pruning can be either deleted or functionally inactivated once they have egressed in secondary lymphoid organs or non-lymphoid tissues, a process called peripheral tolerance. In some individuals, polymorphisms in genes involved in the promotion of central or peripheral tolerance lead to a higher number, diversity, and/or responsiveness of self-reactive lymphocytes in the periphery, in particular of B cells secreting anti-DNA or anti-RNP antibodies (120, 121). Mammalian DNA or RNA are poor inducers of pDC IFN-I induction under normal conditions. However, pre-existing anti-DNA or anti-RNP autoantibodies can break this innate tolerance of pDC. Indeed, antibodies binding to self nucleic acids can protect them from degradation and compact them into nanoparticles that are very effective for the induction of IFN-I in pDC (Figure 4). DNA-containing immune complexes (ICs) are frequently found in the serum of SLE patients (SLE-ICs) and can activate pDC IFN-I production (122). In turn, pDC IFN-I activate cDCs, monocytes (123), and B cells, leading to a vicious circle of reciprocal activation between DCs and self-reactive lymphocytes and to the exacerbation of autoimmune responses (Figure 4). Certain infections or dysbiosis of the commensal microbiota of the affected barrier tissues could promote chronic production of host amphiphatic peptides able to combine with eukaryotic DNA or RNA, likely released from dying cells, thus forming pDC-activating nanoparticles. Indeed, in psoriatic skin, both a high expression of LL37 and a massive infiltration of pDCs is observed (124) (Figure 4). Hence, to treat many autoimmune diseases, novel therapeutic strategies could be designed to target dysregulated pDC IFN-I production or B cell activation by IFN-I.

Bottom Line: First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic anti-viral immunity.We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including (i) the subtypes and dose of IFN-I produced, (ii) the cell types affected by IFN-I, and (iii) the source and timing of IFN-I production.Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.

View Article: PubMed Central - PubMed

Affiliation: UM2, Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University , Marseille , France ; U1104, Institut National de la Santé et de la Recherche Médicale (INSERM) , Marseille , France ; UMR7280, Centre National de la Recherche Scientifique (CNRS) , Marseille , France.

ABSTRACT
Type I interferons (IFN-I) were identified over 50 years ago as cytokines critical for host defense against viral infections. IFN-I promote anti-viral defense through two main mechanisms. First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic anti-viral immunity. Second, IFN-I orchestrate innate and adaptive anti-viral immunity. However, IFN-I responses can be deleterious for the host in a number of circumstances, including secondary bacterial or fungal infections, several autoimmune diseases, and, paradoxically, certain chronic viral infections. We will review the proposed nature of protective versus deleterious IFN-I responses in selected diseases. Emphasis will be put on the potentially deleterious functions of IFN-I in human immunodeficiency virus type 1 (HIV-1) infection, and on the respective roles of IFN-I and IFN-III in promoting resolution of hepatitis C virus (HCV) infection. We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including (i) the subtypes and dose of IFN-I produced, (ii) the cell types affected by IFN-I, and (iii) the source and timing of IFN-I production. Finally, we will speculate how integration of this knowledge combined with advanced biochemical manipulation of the activity of the cytokines should allow designing innovative immunotherapeutic treatments in patients. Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.

No MeSH data available.


Related in: MedlinePlus