BSCI 437 Exam III - Innate Immune System

Immune System Organs

• Bone marrow

• Thymus

• Spleen

• Lymph Nodes

Bone Marrow

All cells from immune system are derived from the ___ via hematopoiesis

Hematopoiesis

• process of blood cell formation

• bone marrow stem cells develop into mature cells or precursors of cells that migrate out of the bone marrow to continue their maturation somewhere

lymphocytes

• product of bone marrow

  • type of WBC that produce antibodies

• B cells

• Immature T cells

• NK cells

Granulocytes

• product of bone marrow

  • type of white blood cells that are characterized by the presence of granules in their cytoplasm, involved in inflammatory and allergic responses.

• Neutrophils

• Monocytes

• Dendritic cells

RBC + Platelets

• product of bone marrow

• components of blood that are crucial for oxygen transport and blood clotting, respectively

Thymus

• an organ that plays a critical role in the development and maturation of T cells, which are essential for adaptive immunity

  • immature T cells (Pre-T cells) move from bone marrow to ___

Immature T cells

• are precursor cells that originate in the bone marrow and migrate to the thymus for maturation into functional T cells

• Pre-T cells

Thymic Education

• maturation process of pre-T cells

  • once completed, they become mature T cells

• T cells that are beneficial to the immune system are separated

• T cells that evoke detrimental autoimmune responses are eliminated

Mature T Cells

• are fully developed T cells that have completed thymic education

• are capable of recognizing and responding to specific antigens in the immune response

Spleen

• filters antigens directly from the blood that passes through it

• migratory macrophages and dendritic cells bring antigens to the ___ via blood stream

• made of

  • B cells

  • T cells

  • Marcophages

  • Dendritic Cells

  • NK cells

  • RBC

immune response

the body's defense mechanism against pathogens and foreign substances, involving various cells and proteins to identify and eliminate threats. It typically includes both innate and adaptive components

• initiates when macrophage/dendritic cell presents antigen to appropriate B or T cell

Lymph Nodes

• drain fluid from most tissues

• antigens are filtered out of the lymph in the lymph node before returning the lymph to circulation

• made of

  • T cells

  • B cells

  • dendritic cells

  • macrophages

Immune System Cells

Cells involved in the immune response, including:

• B cells

• T cells

• NK cells

• macrophages

• dendritic cells

• antigen presenting cells

B cells

cells that develop antibody secreting plasma cells following stimulation by foreign antigens of bacterial, viral, or timor cells

antibodies

proteins that recognize and bind to specific antigens that caused their stimulation

• production and binding to foreign antigen

  • critical as a means of signaling other cells to engulf, kill, or remove that substance form the body

Innate Immunity

The part of the immune system that provides immediate, non-specific defense against pathogens

• mechanical

• intrinsic intracellular response

• cell mediated—don’t use MHC to recognize a pathogen

Innate Immunity cells

group of cells

• NK cells

• macrophage

• dendritic cells

• neutrophils

Macrophage

A type of white blood cell that engulfs and digests cellular debris and pathogens

• innate immunity

• phagocytosis

  • not as effective as dendritic cells

Neutrophils

A type of white blood cell (most abundant WBC) involved in phagocytosis and the elimination of pathogens.

• innate immunity

• migrate to areas of damage or infection in response to cytokines/complement signals

• migration through BC and interstitial tissue to site of attack

• phagocytose material

  • bacteria

  • pathogens

  • do not recognize antigens in the context of MHC

Adaptive Immunity Cells

group of cells that use MHC

• T Cell

• B Cells

mechanical defense

• method of innate immunity

• that prevents pathogen entry through physical barriers such as:

  • skin

  • epitelial surfaces

Skin

Innate immunity mechanical defense

• largest organ in the body

• strong barrier to infection

• inactivate viruses by desiccation, acids, skin cleansing mechanisms, inhibitors made by commensals

epithelial surfaces

Innate immunity mechanical defense

• inactivates viruses via

  • secretions

  • mucus

  • tears

  • acidic pH

intrinsic cellular defenses

• method of innate immunity

  • conserved, arose in early evolution

  • nonspecific responses to stresses

    • starvation

    • irradiation

    • infection

Immediate

Innate immune system has ___ effects

• innate → response (instant)

delayed

adaptive immune system has ___ effects

• innate → crosstalk → adaptive → response (1-2 weeks)

cross talk

interaction between innate and adaptive immune responses, allowing coordination and enhancement of immune activities

• antigen presentaiton by dendritic cells and macrophages activate specific T cells

• cytokines secreted by macrophages and other innate immune cells stimulate T cells to proliferate (IL-12)

• interferons secreted b infected cels affect both macrophages and T cells

innate immunity inhibits most infections

why are people not perpetually sick?

apotosis

• method of innate immunity

• programed cell death

• viruses can activate either pathway

  • extrinsic and intrinsic

• features

  • blebbing

  • cell shrinkage

  • nuclear fragmentation

  • chromatin condesnation

  • chromosomal DNA fragmentation

  • global mRNA decay

autophagy

• method of innate immunity

• bulk degradation of cellular contents

• one way to kill pathogens

• purposes in cell regulation

RNA silencing

• method of innate immunity

• RNA based gene regulation and defense mechanism

• Targets pathogens and silence genes

• RISC system

• Where

  • main form of defense in plant viurus

  • some functions in eukaryotes

RISC system

RNA-induced silencing complex that facilitates RNA silencing by targeting specific mRNA transcripts for degradation or translational repression

• contains fragments of RNA and derived from the dsRNA of a vieus

  • fragment binds to mRNA or genome

  • RISC complex degrades mRNA complementary to dsRNA

  • usually inhibits mRNA translation into protein

plant virus

• plants utilize RNA silencing as their main form of defense

  • plant viruses make proteins that inhibits to processes

  • knockdown the level of genes in cels to study genes

Innate antiviral response

A defense mechanism that provides immediate protection against viral infections through various innate immune pathways, including RNA silencing and activation of other immune responses

• highly coordinated

innate antiviral response depends on what?

• interplay of secreted proteins

• receptor mediated signaling

• cell to cell communication

what are the steps for innate antiviral responses?

• recognition

• amplification

• control

PRR

(Pattern Recognition Receptor) that detects viral components to initiate the innate immune response.

• proteins expressed by cells of the innate immune system to identify PAMPS

• distinguishes self from nonself by recognizing a conserved microbial product

ex. toll like receptor, RLR, Cytokines

PAMPS

(Pathogen-Associated Molecular Patterns) recognized by PRRs to trigger immune responses. They are distinct molecular signatures of pathogens

DAMPS

(Damage-Associated Molecular Patterns) that signal tissue damage and provoke immune responses by being recognized by PRRs.

• associated with cell components released durign cell damage

  • pathogen recognition receptors/primitivbe pattern recognition receptorfs because they evolved before other parts of hte immune system

Toll Like Receptor (TLR)

A type of extracellular PRR

• PAMPS include

  • cell type specific expression on immune cells

    • macrophage

    • dendritic cells

• induce interferons or trigger apoptosis

TLR signaling

1. Detection of PAMP

2. activation of signaling transduction pathways

3. activation of TFs

4. Production of pro inflammatory cytokines, IFN, and T cell costimulatory molecules—draws in molecules

inflammation

A biological response to harmful stimuli such as pathogens, damaged cells, or irritants, characterized by redness, heat, swelling, and pain.

• leads to damage

• if it goes too far, it can lead to tumor formation

RIG-I like Receptors (RLR)

A type of intracellular PRR

• PAMPS include

  • dsRNA

  • 5’ triphosphate

  • poly U/UC motif (HCV and Measles)

  • Stem loop structures

ex. RIG-I & MDA5

RIG-I

example of RIG-I like Receptor (RLR)

MDA5

example of RIG-I like Receptor (RLR)

RLR signaling

1. detection of PAMP

2. activation of signaling transduction pathways

3. activation of TFs

4. production of proinflammatory cytokines, IFN, and T-cell costimulatory molecules

   1. turn on IFb, just like TLR

cytokines

small soluble proteins made by one cell that can affect behavior of that or other cells

• secreted by cells of innate immune system

• important in signaling several immune processes

• interact with specific receptors and signal transduction pathways to elicit major changes in cell behavior

interferons

• type of cytokines

• produced by host cells in response to viral infections, crucial for mediating antiviral defenses

  • rapid, transient

  • nonspecific response

  • sensitivity to INF varies

issac and linderman’s discovery

• cells plug hear inactivated influenza virus

  • incubate over night

    • discard cells and transfer supernatant onto new cells

      • incubate and add live virus

        • no infection

• molecule in the supernatant with IFN → made in response to the initial infection

  • secreted and protected the cells it was applied to

  • different viruses could be used in the experiment and also inhibited by INF

• general antiviral response to both RNA and DNA

general antiviral response

A broad defense mechanism that the immune system employs to recognize and combat various viral infections

• uses INF for RNA and DNA viruses

Type 1 IFN

antiviral interferons

ex. IFN A and IFN B

IFN-B

type of type I interferon

• produced by many cell types

• encoded by multiple genes and pseudogenes

IFN-A

type of type I interferon

• prodcued by fibroblasts and epithelial cells

• encoded by a single gene

Type II interferon

adaptive immunity interferons

• produced mainly by T cells and NK cells.

ex. IFN-y

IFN-y

type of type II interferon

• produced by activated T cells and NK cells

• plays a role in adaptive immunity

  • increase antigen presentation (MHC I and II)

  • bridges innate and adaptive immunity

JAK1

• janus kinase

• receptor for type I interferon signaling pathway

TYK2

• tyrosine kinase 2

• receptor for type I interferon signaling pathway

STAT 1 and STAT 2

phosphorylated by JAK1 and TYK2

what links JAK1 and TYK2 kinase?

INF

gamma activated sequence

INF gamma

interferon stimulated response element

A DNA sequence that specifically binds interferon regulatory factors (IRFs) to facilitate immune responses and gene expression in response to interferons

• INF alpha/beta

interferon stimulated genes (ISG)

A gene induced by interferons that play a critical role in the antiviral and immune response

• INF gamma/INF alpha and beta turn on these genes

virus infected cell

• cell infected by virus

• produces INF to act on neighboring cells

  • uninfected cells respond to interferon and become refractory to viral growth — antiviral state

  • activates immune cells

antiviral state

A condition in uninfected cells triggered by interferons, rendering them resistant to viral infection and replication

biological activities of INF

• inhibition of viral replication

• inhibition of cell growth

• regulation of cell differentiation

• activation of immune cells

antiviral effects of INF

The antiviral effects of interferon alpha/beta include inhibiting viral replication, activating immune responses, and increasing the resistance of neighboring uninfected cells to future infections.

• PKR

• 2,5 oligoadenylate synthetase

• Mx proteins

• transient INF effects

protein kinase R (PKR)

dsRNA activated protein kinase

• present in cells at low levels

• activated in response to dsRNA made during viral infection, phosphorylating eIF-2a

  • shuts off protein synthesis

NF-kB up regulates transcription of PKR gene

upregulation of PKR gene

• induced by NF-KB

  • leads to more PKR in cell that is stimulated by INF signaling

  • allows cells to respond very quickly to virus infection to stop the virus before it can produce more progeny

2,5 oligoadenylate synthetase

dsRNA activated protein made in response to INF

• when activated, it will synthesize 2,5-linked oligoadenylates in response

  • binds to a nuclease present in cells called RNase

  • inhibits virus replciation

RNase L

An endoribonuclease activated by 2,5-oligoadenylates that degrades viral RNA, thereby inhibiting viral replication and promoting the antiviral response

Mx proteins

antiviral proteins that are stimulated by IFN

• interferes with the replication of viruses, particularly RNA viruses

• prevents assembly

transient INF affects

short-lived changes in gene expression and immune responses due to the presence of IFN, leading to enhanced antiviral defenses

• cells that have established antiviral state reverses and goes back to normal

phagocytic cells

macrophage + dendritic cells

• nonspecific cellular response

  • innate immunity

• sentinel cells

• phagocytotic

• presents foreign antigen to T cells

sentinel cells

immune cells that patrol local area for pathogens

NK cells

• nonspecific cellular response

  • innate immunity

• recognize and kills virus infected cells

• detect altered or missing self molecules

altered self molecules

molecules that are

• MHC I & MHC II

• non-self antigens

missing self molecules

molecules that are

• lacking MHC I or II

• lack activating receptors

dendritic cells

antigen-presenting cells with eceptors on surface that allow them to recognize pathogens

• engulfs pathogens and undergo maturation/migration to lymph networks where they encounter Naive T cells

• present processed antigens from pathogen on their surface via MHC II

  • activates Naive T cells

  • T cells proliferate learning to production of killer T cells that will kill any cell that presents the antigen on its surface

• better than macrophages as antigen presenting cells

NK cells kill by

• releasing perforins + granzyms

• perforate membrane and caused caspase mediated cell death

• kills infected cells coated with antibodies

I

all normal cells have MHC ___

if NK binds to a normal cell → ___

not activated

if NK binds to a cell lacking MHC I

• it will secrete enzymes and other molcueles that pun cture the cell

• cause cell death via apoptosis

advantage

• prevents cytotoxic T cells from recognizing and killing infected cells

virus inhibiting MHC I ___

disadvantage

• makes cells more susceptible to NK cells since they are not protected from innate immune responses

virus inhibiting MHC I ___

complement cascade

A series of protein activations in the immune system

• pokes holes in infected cells

  • targets cel for degradation

    • activates inflammation

complemented antibody

An antibody that has bound complement proteins, enhancing its ability to mark pathogens for destruction

• heat labile serum componment that lysed bacteria in the presence of antibodies

classical, alternative, lectin

3 pathways of complement cascade

Lectin

• carb binding proteins

  • macromolecules that are highly specific for sugar moieties

• sticks to cell membrane

ex. mannose binding lectin

mannose binding lectin (MBL or MBP)

• lectin that is instrumental in innate immunity

• interactions between MBL and lectins on membrane surfaces can activated complement pathway