2014 L4 - Immune response to pathogens

Pathogen

An organism that causes disease, such as bacteria, viruses, fungi, or parasites.

Interferon

A type of protein produced by cells in response to viral infections that helps to inhibit viral replication and activate immune cells (this then produces IFNα and IFNβ

IFNα and IFNβ (type I interferons)

• Produced by all virally infected cells

• Induce antiviral state in cells (act on adjacent cells)

  • via inhibition of viral protein synthesis

  • degradation of viral RNA

• Activate NK cells and dendritic cells

Impared/ delayed antiviral response causes severe illness (can be due to older age or certain treatment).

Pattern recognition receptors (PRRs)

• Proteins

• Expressed on immune cells (dendritic cells and macrophages)

• Recognises Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to initiate an immune response

NK cells

Natural Killer cells, a type of immune cell that can destroy virus-infected cells and tumor cells. Are recruited to infection site by chemokines and interferons produced by infected cells.

NK cell activation

Some viral infected cells downregulate MHC class I on cell surface. NK cells are activated by lack of MHC class I and induce apoptosis of such cells.

MHC class I

A set of molecules displayed on cell surfaces that present endogenous antigens to CD8+ T cells, playing a crucial role in the immune response.

CD4+ T cells

A type of T lymphocyte that is critical for the adaptive immune response and assists other immune cells.

CD4+ T cells become activated when antigen presenting cells (APC) (e.g. dendritic cells) present viral antigens on MHC class II molecules to CD4+ T cells.

Activated CD4+ T cells then undergo clonal expansion and differentiation into effector CD4+ T cells.

Effector CD4+ T cells

Secrete antiviral cytokines such as interferon gamma. Helps activate B cells and CD8+ T cells.

CD8+ T cells

Become activated when viral Ag present on MHC class I is detected.

Then undergo clonal expansion and differentiation into effector CD8+ T cells.

Effector CD8+ T cells

Secrete antiviral cytokines (e.g. interferon gamma) - acts on other immune system cells & virally infected cells.

Kill virus infected cells via 2 mechanisms:

• Releasing granular contents such as perforin and granzyme

• By delivering death signals to infected cells

Factors effecting viral infection outcomes

Type of cells the virus infects (virus trophism):

• If specialised (e.g. neurones), destruction of even a few is dangerous

• If less specialised (e.g. epithelial cells), destruction of many cells will have no impact

Genetic capability of the individual

Co-morbid illnesses: diabetes, obesity can reduce antiviral response and results in pro-inflammatory response to the virus

Immunosuppressive diseases or drugs

How viruses evade recognition

• Produce proteins that mimic host proteins (can lead to autoimmune disease occurring)

• Evading T cell recognition by down regulating MHC class I & II expression

• Evading NK cell recognition by producing proteins mimicing MHC molecules, so NK not activated

• Continuously changing cell surface proteins (prevents binding)

• Antigenic drift and antigenic shift

Antigenic Drift

A subtle change in the surface glycoprotein caused by a point mutation or deletion in the viral gene (Eg:  influenza virus), leading to variants of the virus that can evade immune recognition.

Antigenic Shift

A more significant change in the virus (new hemagglutinin or neuraminidase type produced), often resulting from reassortment of genetic material, leading to new viral strains.

Much less frequent than antigenic drift.

Phagocytosis

The process by which phagocytes engulf and digest pathogens.

Immune responses to bacterial infection

• Barrier defences - epithelium, mucosal immunity

• Phagocytosis

• Completement activation

• Acute phase proteins

B cells in intracellular bacterial infection

Intact macrophage and T cell function is vital. CMI plays a crucial role in determining the outcome of infection.

T cells that are involved in formation of the TB granuloma determines if the bacteria can be kept dormant or if the patient has a active infection.

Superantigens

Produced by bacteria. A class of antigens that result in excessive activation of the immune system, leading to cytokine storms.

Are very powerful T cell stimulators (directly bind to MHC class II molecules and T cell receptors outside peptide binding groove.

Activate many macrophages, monocytes, neutrophils and mast cells.

Cytokine Storm

An overreaction of the immune system characterized by high levels of inflammatory cytokines.

Complement Activation

A part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells.

B cell

A type of lymphocyte that produces virus-specific antibodies to neutralize pathogens via binding.

Dendritic Cells

Antigen-presenting cells that process antigen material and present it to T cells.

Humoral Immune Response

The component of the immune response that involves the production of antibodies by B cells.

Cell Mediated Immunity (CMI)

The immune response that relies on the activation of T cells to fight infections.

Phagocyte

A type of immune cell that engulfs and digests foreign particles and pathogens.

MHC Class II

A class of molecules on antigen-presenting cells that present antigens to CD4+ T cells.

Innate immune responses to fungi

• Macrophages are the primary cells involved in fungal killing during infection by Cryptococcus and Pneumocystis

• Neutrophilsare the primary effector cells in preventing infection by Candida albicans and Aspergillus fumigatus

PRRs in macrophages get activated by fungal molecules much as glycans (produce many inflammatory mediators).

Adaptive immune responses to fungi

CMI major role in fungi infection elimination. CD4+ T cells are most important in fungi immunity, main cytokine produced is IL-17, which is important for recruitent and activation of neutrophils and macrophages.

Antibodies help defnd against fungi

• Prevention of adherence

• Neutralization of fungal toxins by coating the fungi

• Helping natural killer cells in killing cells infected with fungi (ADCC)

How fungi evade immune system

• Inducing secretion of immune suppressive cytokines (e.g. Candida)

• Down regulate pathogen recognition receptors (PRR) so they cant recognise them

• Modulate the production of anti-inflammatory cytokines by immune cells

• Prevention of phagosome fusion with the lysosome