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The Immune Response to Influenza Infection

When the influenza virus infects the cells of the respiratory tract, both innate and adaptive immune responses are stimulated. The innate immune response develops very quickly and controls virus replication during the early stages of infection. While the innate immune system recognizes virus-infected cells through mechanisms that are not antigen-specific, the cytokines produced during this early phase of the host's defence do facilitate activation of subsequent antigen-specific adaptive immune mechanisms. 1 x JE Durbin, A Fernandez-Sesma, CK Lee, et al.. Type I IFN modulates innate and specific antiviral immunity. J Immunol 164 (2000) (4220 - 4228) An important element of the transition from the innate to the adaptive immune response is the stimulation of Toll-like receptors (TLRs) in endosomes of antigen-presenting cells (primarily dendritic cells). 2 x SS Diebold, T Kaisho, H Hemmi, et al.. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303 (2004) (1529 - 1531) Crossref. TLRs recognize and bind to structural components such as single-stranded viral RNA, which are shared by different pathogens, and are important triggers of the “danger signal”. Stimulation of immunological memory from prior exposure to viral antigens (by natural infection with the virus or through vaccination) also stimulates specific pathways in the adaptive immune response. Stimulation of immunological memory accelerates the adaptive response, which is delayed during a primary exposure to the antigen. A major aspect of the adaptive immune response involves virus binding to immunoglobulin receptors on B lymphocytes, which subsequently differentiate to plasma cells that produce virus-specific antibodies. 3 x BO Lee, J Rangel-Moreno, JE Moyron-Quiroz, et al.. CD4 T cell-independent antibody response promotes resolution of primary influenza infection and helps to prevent reinfection. J Immunol 175 (2005) (5827 - 5838) Activation of the adaptive immune response occurs through peptides derived from viral proteins, which are presented on antigen-presenting cells to the T lymphocytes. Helper T cells, through the production of cytokines, contribute to B cell proliferation and differentiation to plasma cells, and to the activation and proliferation of virus-specific cytotoxic T lymphocytes (CTLs). 4 x PC Doherty, DJ Topham, RA Tripp, et al.. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol Rev 159 (1997) (105 - 117) Crossref. Figure 16 details many of the interactions of the different cell populations involved.

Figure 16 Immune responses to viral infections. Innate immune mechanisms include the production of cytokines and the activation of antigen-presenting cells (macrophages and dendritic cells) and natural killer (NK) cells. The adaptive, antigen-specific, immune response involves both the generation of antibodies by B cells and the activation of both T helper cells (mainly CD4-positive T cells) and CTLs (mainly CD8-positive T cells). Antibodies restrict the spread of virus primarily by neutralizing the virus so that it cannot enter the cell and replicate. CTLs recognize and destroy virus-infected cells, shortening the duration of viral shedding, and are responsible for clearing virus-infected cells from the lungs. source: Reproduced from Abbas AK, Lichtman AH. Cellular and Molecular Immunology, 5th edn. WB Saunders, 2003 with permission from Elsevier.

f04-16-9780723434337

References in context

  • Helper T cells, through the production of cytokines, contribute to B cell proliferation and differentiation to plasma cells, and to the activation and proliferation of virus-specific cytotoxic T lymphocytes (CTLs).4 Figure 16 details many of the interactions of the different cell populations involved.
    Go to context

Key Messages

  • Innate immune responses control influenza virus replication during the early stages of infection.
  • Adaptive immune responses are antigen-specific and develop immunological memory that provides a more rapid response upon re-exposure to the virus.
  • Adaptive immune response is activated by antigen presentation through professional antigen-presenting cells, dendritic cells (DCs) in particular, which stimulate T cells.
  • T helper type 1 (Th1) responses stimulate antibody production (IgG2a) and cytotoxic T lymphocytes (CTLs). T helper type 2 (Th2) responses stimulate antibody production (IgG1), but not CTLs.
  • In the effector phase of the adaptive immune response, secretory antibodies prevent infection at mucosal surfaces of the respiratory tract, while circulating antibodies diffuse to and protect the lungs.
  • Cytotoxic T lymphocytes (CTLs) contribute to elimination of the infection by lysing virus-infected cells.
  • Immunological memory for B cell responses is lifelong, and subtype- and strain-specific. In contrast, T cell memory is more cross-reactive among different subtypes of influenza, while the duration of T cell memory is variable, even among younger adults (months to years).
  • Since antibodies are strain-specific, influenza vaccine composition must be updated regularly for protection against newly circulating strains of the virus.
  • A significant decline in CTL-mediated immunity is directly linked to the increased risk of influenza illness in older people.

Virus-specific antibodies and CTLs represent the principal effector mechanisms of the adaptive immune response. Influenza virus strain-specific antibodies bind to and neutralize the virus on mucosal surfaces to prevent entry and replication inside the cell. Both IgA (secretory antibodies) and IgG (plasma antibodies) contribute to strain-specific protection along the respiratory tract. T helper (Th1 and Th2) cytokines reciprocally down-regulate each other and only Th1 cytokines facilitate CTL activation. 5 x PC Doherty, W Allan, M Eichelberger, SR Carding. Roles of alpha beta and gamma delta T cell subsets in viral immunity. Ann Rev Immunol 10 (1992) (123 - 151) Crossref. Activation of CTLs and the associated increase in granzyme B (Grz B) that leads to programmed cell death (apoptosis) of virus-infected cells is another critical component of the adaptive antiviral immune response. 6, x BJ Johnson, EO Costelloe, DR Fitzpatrick, et al.. Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+ T cells in influenza virus-infected mice. Proc Natl Acad Sci USA 100 (2003) (2657 - 2662) Crossref. 7 x CW Lawrence, RM Ream, TJ Braciale. Frequency, specificity, and sites of expansion of CD8+ T cells during primary pulmonary influenza virus infection. J Immunol 174 (2005) (5332 - 5340) With ageing, the loss of CTL-mediated immunity has been directly linked to the increased risk of influenza illness in older people, while antibody responses appear to be relatively preserved in otherwise healthy older adults.

This chapter will first briefly discuss innate immunity to viral infections and then focus on the adaptive immune response to influenza with special reference to how this response is affected during ageing.

 
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Figure 16 Immune responses to viral infections. Innate immune mechanisms include the production of cytokines and the activation of antigen-presenting cells (macrophages and dendritic cells) and natural killer (NK) cells. The adaptive, antigen-specific, immune response involves both the generation of antibodies by B cells and the activation of both T helper cells (mainly CD4-positive T cells) and CTLs (mainly CD8-positive T cells). Antibodies restrict the spread of virus primarily by neutralizing the virus so that it cannot enter the cell and replicate. CTLs recognize and destroy virus-infected cells, shortening the duration of viral shedding, and are responsible for clearing virus-infected cells from the lungs. source: Reproduced from Abbas AK, Lichtman AH. Cellular and Molecular Immunology, 5th edn. WB Saunders, 2003 with permission from Elsevier.

f04-16-9780723434337

References in context

  • Helper T cells, through the production of cytokines, contribute to B cell proliferation and differentiation to plasma cells, and to the activation and proliferation of virus-specific cytotoxic T lymphocytes (CTLs).4 Figure 16 details many of the interactions of the different cell populations involved.
    Go to context

References

Label Authors Title Source Year
1

References in context

  • While the innate immune system recognizes virus-infected cells through mechanisms that are not antigen-specific, the cytokines produced during this early phase of the host's defence do facilitate activation of subsequent antigen-specific adaptive immune mechanisms.1 An important element of the transition from the innate to the adaptive immune response is the stimulation of Toll-like receptors (TLRs) in endosomes of antigen-presenting cells (primarily dendritic cells).2 TLRs recognize and bind to structural components such as single-stranded viral RNA, which are shared by different pathogens, and are important triggers of the “danger signal”.
    Go to context

JE Durbin, A Fernandez-Sesma, CK Lee, et al.. Type I IFN modulates innate and specific antiviral immunity. J Immunol 164 (2000) (4220 - 4228) 2000
2

References in context

  • While the innate immune system recognizes virus-infected cells through mechanisms that are not antigen-specific, the cytokines produced during this early phase of the host's defence do facilitate activation of subsequent antigen-specific adaptive immune mechanisms.1 An important element of the transition from the innate to the adaptive immune response is the stimulation of Toll-like receptors (TLRs) in endosomes of antigen-presenting cells (primarily dendritic cells).2 TLRs recognize and bind to structural components such as single-stranded viral RNA, which are shared by different pathogens, and are important triggers of the “danger signal”.
    Go to context

SS Diebold, T Kaisho, H Hemmi, et al.. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Crossref. Science 303 (2004) (1529 - 1531) 2004
3

References in context

  • A major aspect of the adaptive immune response involves virus binding to immunoglobulin receptors on B lymphocytes, which subsequently differentiate to plasma cells that produce virus-specific antibodies.3 Activation of the adaptive immune response occurs through peptides derived from viral proteins, which are presented on antigen-presenting cells to the T lymphocytes.
    Go to context

BO Lee, J Rangel-Moreno, JE Moyron-Quiroz, et al.. CD4 T cell-independent antibody response promotes resolution of primary influenza infection and helps to prevent reinfection. J Immunol 175 (2005) (5827 - 5838) 2005
4

References in context

  • Helper T cells, through the production of cytokines, contribute to B cell proliferation and differentiation to plasma cells, and to the activation and proliferation of virus-specific cytotoxic T lymphocytes (CTLs).4 Figure 16 details many of the interactions of the different cell populations involved.
    Go to context

  • The mechanisms by which CTLs induce lysis of virus-infected cells include perforin- or granule-mediated killing.4 Granule-mediated killing appears to be the critical effector function of CTLs against influenza-infected cells.
    Go to context

PC Doherty, DJ Topham, RA Tripp, et al.. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Crossref. Immunol Rev 159 (1997) (105 - 117) 1997
5

References in context

  • T helper (Th1 and Th2) cytokines reciprocally down-regulate each other and only Th1 cytokines facilitate CTL activation.5 Activation of CTLs and the associated increase in granzyme B (Grz B) that leads to programmed cell death (apoptosis) of virus-infected cells is another critical component of the adaptive antiviral immune response.6,7 With ageing, the loss of CTL-mediated immunity has been directly linked to the increased risk of influenza illness in older people, while antibody responses appear to be relatively preserved in otherwise healthy older adults.
    Go to context

PC Doherty, W Allan, M Eichelberger, SR Carding. Roles of alpha beta and gamma delta T cell subsets in viral immunity. Crossref. Ann Rev Immunol 10 (1992) (123 - 151) 1992
6

References in context

  • T helper (Th1 and Th2) cytokines reciprocally down-regulate each other and only Th1 cytokines facilitate CTL activation.5 Activation of CTLs and the associated increase in granzyme B (Grz B) that leads to programmed cell death (apoptosis) of virus-infected cells is another critical component of the adaptive antiviral immune response.6,7 With ageing, the loss of CTL-mediated immunity has been directly linked to the increased risk of influenza illness in older people, while antibody responses appear to be relatively preserved in otherwise healthy older adults.
    Go to context

BJ Johnson, EO Costelloe, DR Fitzpatrick, et al.. Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+ T cells in influenza virus-infected mice. Crossref. Proc Natl Acad Sci USA 100 (2003) (2657 - 2662) 2003
7

References in context

  • T helper (Th1 and Th2) cytokines reciprocally down-regulate each other and only Th1 cytokines facilitate CTL activation.5 Activation of CTLs and the associated increase in granzyme B (Grz B) that leads to programmed cell death (apoptosis) of virus-infected cells is another critical component of the adaptive antiviral immune response.6,7 With ageing, the loss of CTL-mediated immunity has been directly linked to the increased risk of influenza illness in older people, while antibody responses appear to be relatively preserved in otherwise healthy older adults.
    Go to context

CW Lawrence, RM Ream, TJ Braciale. Frequency, specificity, and sites of expansion of CD8+ T cells during primary pulmonary influenza virus infection. J Immunol 174 (2005) (5332 - 5340) 2005

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