2 Innate Immune System

body's first defense against pathogens

physical, chemical, and biological defense (non-specific)

physical barriers against pathogens

-skin

-GI linings

-genitourinary tract

-Resp. tract

-coughing, sneezing, diarrhea, flushing

chemical barriers against pathogens

-saliva

-tears

-ear wax

-sweat

-mucus (lysozyme)

-peptides

-stomach acid

-proteases

which part of the non-specific defense system is biologic?

GI flora compete for nutrients and change the environment (eg/ pH)

describe innate immunity

-non specific recognition of molecular shapes on pathogens

-always present

what are the major differences between innate and adaptive immune responses?

INNATE:

-no memory

-rapid response (hours)

-fixed immunity

-limited specificity

-constant during response

ADAPTIVE:

-immunologic memory

-slow response (days, weeks)

-variable immunity

-numerous, highly selective specificities to certain antigens on pathogens

-improves during response (ie/ memorizes pathogens so subsequent exposures are faster and stronger)

cells included in the innate immune response

-macrophages

-neutrophils

-eosinophils

-basophils

-monocytes

Innate and adaptive immunity (do/do not) work together

do work together

describe adaptive immunity

-highly specific

-acquired once pathogens evade non-specific physical and chemical barriers and innate immunity

-includes cellular (cytotoxic) and humoral (antibody) defenses

At what point does innate immunity generate a memory?

never generates memory

Functions of the innate immune system

Induce inflammatory response:

-pathogen recognition (seems counterintuitive, but know this one)

-effector cell recruitment

-cytokine production

-complement cascade activation

-foreign substance removal

Activate adaptive immune system

How long is innate immunity present for?

always present

major players in the innate immune system

-phagocytes (neutrophils, macrophages, monocytes)

-mast cells

-basophils

-eosinophils

-NK cells

-complement proteins

-cytokines

Describe neutrophils as they relate to the innate immune system (structure; length of action; relative abundance; when they arrive at the site of infection; primary functions)

-short lived PMN granulocytes

-most abundant leukocyte

-1st cells recruited at infection site

-primarily do phagocytosis, then die

-contain granules w/ toxic substances to kill pathogens

What is a respiratory burst?

An oxidation reaction that occurs in order to kill pathogens that have been recently phagocytized. Generally performed by neutrophils

how are dead neutrophils removed?

phagocytosis by macrophages

what is pus?

dead neutrophils

describe basophils and eosinophils as they relate to the innate immune system (structure; what they defend against and how; how they participate in inflammation)

-PMN granulocytes

-defend against parasites and bacteria

-regulate vascular mediators responsible for inflammation

-responsible for tissue damage during allergic rxns

describe mast cells as they relate to the innate immune system (where they reside; what processes they are associated with; what do they release; what happens when they are activated; when they are activated)

-found in connective tissues and mucus membranes

-associated w/ allergy, anaphylaxis, physical injury, immunologic responses

-granules rich in histamine, heparin, chemokines

-activation leads to degranulation and/or synthesis of lipid-derived chemical mediators involved in inflammation

2 types of phagocytes

-monocytes/ macrophages

-neutrophils

describe macrophages (how long they live; what cell type they're derived from; how they work)

-long lived tissue resident derived from monocytes

-most efficient phagocytes that are able to move outside vasculature and can engulf large numbers of cells and pathogens

what will trigger macrophages, and what do the macrophages do upon being triggered??

-binding of pathogen PAMPs to PRRs on macrophage triggers engulfing of pathogen via respiratory burst

-pathogens also stimulate macrophages to secrete chemokines which attract other immune cells to site of infection

when do macrophages arrive at the site of infection?

>24 hours after neutrophils

describe the process of phagocytic killing (AKA respiratory burst)

1) pathogen binds to and is phagocytosed by neutrophil or macrophage

2) phagosome forms

3) phagosome fuses w/ azurophilic granules and specific granules

4) pH rises, antimicrobial activity ↑, and pathogen dies

5) pH ↓, phagosome fuses w/ lysosomes that secrete more toxic substances to completely degrade pathogen

6) Neutrophil dies via apoptosis and is phagocytosed by macrophage

functions of NK cells

DO NOT directly attack microbes, but instead destroy compromised cells (ie/ virus-infected cells)

why do NK cells require activation in order to kill infected cells?

They don't

what activates NK cells?

IFN-alpha

IFN-beta

what stimulates NK cells to release inflammatory mediators and what are the inflammatory mediators they release?

IL-12 causes production if IFN-gamma and other cytokines

are NK cells involved in the innate or adaptive immune response?

BOTH

where are dendritic cells located and what are their function?

Tissue residents that are phagocytic; mainly found in skin and inner mucosal linings, but also in peripheral organs

function of dendritic cells

-pick up and process degraded pathogens

-antigen-presenting cells that interact with T cells

-serve as link b/w innate and adaptive immune systems

describe the complement system (what comprises it, where are they found)

-composed of plasma proteins C1-C9 (about 30 different proteases made by liver and found in blood, lymph, and extracellular fluids)

-present as inactive proenzymes that are sequentially activated upon infection and kill pathogens

the complement system is a:

biochemical cascade that promotes inflammation and pathogen destruction

4 major functions of complement system

1) lyse bacteria

2) opsonization

3) inflammatory response via triggering histamine release from mast cells

4) clearance of antigen-antibody complexes via ADCC (antibody dependent cell-mediated cytotoxicity)

complement system causes COIL

major cytokines

1) interleukins

2) TNF alpha

3) interferon type 1 (IFN alpha and beta)

4) interferon type 2 (IFN gamma)

who produces interleukins and when?

macrophages and lymphocytes in response to a pathogen or stimulation by other inflammatory mediators

who secretes TNF alpha and when?

-produced by macrophages in response to a pathogen

-increases synthesis of inflammatory proteins

function of TNF alpha

causes muscle wasting, fever, and thrombosis

which IFNs are type 1?

alpha and beta

-where do type 1 IFNs come from?

-what do IFNs do?

secreted by virus-infected cells, which causes an "interferon response" that:

-activate NK cells

-induce resistance to viral replication

-increase expression of ligands for receptors on NK cells

how are IFNs classified?

antiviral

which interferons are type 2?

interferon gamma

where does interferon gamma come from?

made by NK and T cells

remember that IFN alpha and beta stimulate NK cells, so it goes like: IFN alpha and beta → NK cells secrete IFN gamma

function of interferon gamma

increases macrophage microbicidal activity

classic signs of inflammatory response

-redness

-pain and tenderness

-swelling

-fever

what are the benefits of a fever as it relates to the immune system?

-helps immune system fight infection

-slows pathogen replication

-adaptive immune response is more active at higher temperatures

-normal cells are more resistant to effects of TNF alpha at higher temperature

purposes of inflammation

-control infection and prevent further damage

-heal damaged tissues

-initiate adaptive immune response

describe how inflammatory mediators and major cytokines contribute to inflammation (ie/ what are the steps of inflammation)

1) inflammatory mediators are produced by tissue resident effectors upon insult

2) vasodilation and increased vascular permeability

3) recruitment of phagocytes and other inflammatory cells

4) killing of injured or infected cells or damaged tissue cells

inflammatory mediators produced by effector cells

-eicosanoids (prostaglandins and leukotrienes)

-cytokines (ILs, IFNs, TNF, chemokines)

-other toxic substances (histamine, bradykinin, serotonin)

tissue resident effector cells

-macrophages

-dendritic cells

-mast cells

MDM = Most Dense Mofos

where are tissue resident effector cells located?

located in ALL tissues

what chemokines are relevant in inflammation?

Who produces them?

What do they do?

-macrophages produce CXCL8 which bind CXCR1 and CXCR2 to recruit other inflammatory cells

-also produce IL-12 that activates NK cells

which cells perform phagocytosis?

neutrophils and macrophages

describe the process of phagocytosis

1) pathogen is phagocytosed

2) phagosome fuses w/ azurophilic and specific granules

3) pH of phagosome rises, and pathogen is killed

4) pH decreases and lysosomes allow acid hydrolases to completely degrade pathogen

5) If this is a neutrophil, the neutrophil dies and is phagocytosed by a macrophage

consider the complement system and describe these terms:

-lysis

-opsonization

lysis = forming holes via membrane attack complex (MAC), causing pathogen to swell and burst

opsonization = tagging pathogens to enhance phagocytosis

what happens when the complement system activates the inflammatory response?

-increases microbicidal activity of granulocytes (eg/ histamine release from mast cells)

-attracts and triggers inflammatory cells (chemotaxis)

-enhances clearance of immune complexes

potential danger of the complement system and subsequent activation of the inflammatory response

anaphylactic shock

describe the cellular events that take place when the innate immune system responds to a cut on your foot

1) cut allows pathogens into body, causing resident effector cells to secrete cytokines

2) vasodilation and increased permeability allow fluid, protein, and inflammatory cells to leave blood and enter tissue

3) infected tissue becomes inflamed, causing redness, swelling, heat, and pain

how is a fever developed

macrophages produce cytokines: IL-6, TNF alpha, and IL-1B

which cytokines play a role in fever development?

IL-6

IL-1B

TNF alpha

besides fever, where do IL-6, IL-1B, and TNF alpha act in the body and what do they do?

liver: acute phase proteins (C reactive protein, mannose-binding lectin) activate complement

bone marrow and endothelium: neutrophil mobilization for phagocytosis of pathogens

hypothalamus: increased body temperature

fat and muscle: protein and energy mobilization to increase body temperature

the innate immune system provides _________, is __________, and is _______

-initial protection

-rapid

-always present

cell types involved in innate immune system

phagocytic cells (neutrophils, macrophages) and NK cells

broad components of the innate immune system include:

-complement system

-cytokines

T/F; inflammation is a normal and healthy response.

TRUE

innate immune system triggers:

adaptive immune response

adaptive immune response develops _______

slowly

is the innate immune response or adaptive immune response more effective?

adaptive

what triggers the adaptive immune response?

pathogens

the adaptive immune response is (highly/not very) specific

highly specific

Which statement is NOT TRUE about the innate immune system?

A) It induces inflammatory response by recruiting inflammatory cells to the site of infection.

B) Each time the body is exposed to an infectious agent, the immune response remains the same.

C) Specificity and immunological memory are involved.

D) The immune response occurs rapidly, usually within several hours.

C) Specificity and immunological memory are involved

memory and specificity are characteristics of the adaptive immune system.

Which two cell types are the most important phagocytic cells in the innate immune system?

-neutrophils

-macrophages

__________ proteins are a group of 30 proteins sequentially activated during infection, which promotes inflammation and pathogen destruction by phagocytosis.

complement

Which of the following is NOT an example of innate immunity?

a) inflammation

b) phagocytosis of pathogens by neutrophils

c) fever

d) antibody production

d) antibody production

T/F; Mast cell is the most important cell type in the release of histamine to promote inflammation.

TRUE

how do cytokines regulate inflammation

-dilation

-increased permeability

-recruit other immune cells

-activate NK cells

-associated w/ s/sx of inflammation and innate immunity

IFN-alpha and beta are mostly _______(bacterial/viral)__________

viral

what is the very first immune response to infection or injury?

inflammatory response

which cells are tissue resident cells (effector cells)

-macrophages

-mast cells

-dendritic cells

what causes macrophages to produce cytokines?

pathogens

what causes a systemic infection and what is the result?

macrophages release TNF-alpha into the bloodstream instead of the tissue where they normally would. This causes edema, decreased blood volume, and other complications which lead to death.

role of the nervous system in infection

enhances immune response

role of RBCs in immunity

can bind to DNA from pathogens to alert immune system to presence of pathogens and circulating cell-free mitochondrial DNA.

However, RBCs that carry snippets of DNA are killed, which can cause anemia