Bicd 140 Immunology

what are the three principles of immunity

-self vs non-self

-healthy vs sick

-primary vs secondary

self vs nonself

-the collective response upon introduction of a foreign substance is called the immune response

-generally gettin rid of non self however this can be harmful like rejecting a donor organ or overreacting to a foreign body(allergy)

healthy vs sick

immunopathology- mechanisms that eliminate pathogens can also cause tissue damage

-reason you become sick is because of the immune response(want optimal immune response not necessarily always a strong immune response)

primary vs secondary

immunity may decide individual is capable of resolving infection after one encounter or will protect from reinfection of the same pathogen(secondary/memory response)

types of infectious agents

fungus, parasites, bacteria, viruses

where do fungi replicate/propagate

extracellular

where do parasites replicate/propagate

intra and extracellular

where do bacteria replicate/propagate

both intracellular and extracellular bacteria

where do viruses replicate/propagate

intracellular

does where an infectious agent propagates mean it is always found there?

no

major disease killers

malaria, tuberculosis, and HIV

new diseases and battles

SARS, Ebola, MERS

virulence theory

-the ability of a pathogen to do damage to a host

-a pathogen is selected to carry out replication and transmission

-if it kills the host before it replicates it will die too so it doesn’t do this

-more hosts means the parasite is better transmitted

what does the most dangerous pathogen isn’t the deadliest pathogen mean?

the most dangerous pathogen makes the high die so fast(ebola) but the deadliest pathogen may have a low chance of death but causes extreme population spread and damage(COVID)

How are pathogens selected for?

-they are selected to maximize replication and transmission

-THEY ARE NOT SELECTED TO BE DESTRUCTIVE

How is the immune system selected

-it is selected to be slightly different and more effective over time

-it reacts to infection doesn’t necessarily prevent it

innate immunity

-all animals have it

-innate immunity is manifest in all cells of the body

-immediate response (fast)

-no memory response

adaptive immunity

-only in vertebrate animals

-special immune cells only(B and T cells)

-slower response

-highly specific response

what immunity is lacking if the number of microorganisms continues to increase

lacking the innate immune response

what immunity is lacking if the microorganisms increase, stall for a little bit, then increase again

lacking adaptive immunity only

ways to prevent pathogens from crossing the epithelia

mechanical, chemical, and microbiological barriers

mechanical barriers

-physical barriers(epithelial cells joined by tight junctions)

-fluid around(flow of fluid, music, food, and saliva)

chemical barriers

-primarily enzymes and PH levels

-antimicrobial peptides

microbiological barriers

non-pathogenic commensals

-ex) prebiotics in gut

-flora of the gastrointestinal tract

gut lumen commensal bacteria and antibiotics

-the commensal bacteria create a buffer of space that prevents the pathogen from reaching the body(good)

-antibiotics would kill this barrier

-therefore it is better for the body to take care of pathogen if it can before using antibiotics

where do the immune system cells originate

bone marrow

immune cell types

-neutrophils

-macrophages

-dendritic cells

-natural killer cells

neutrophils (walking bomb)

-antimicrobial proteins

-most abundant because when they kill they explode and release their DNA which traps the pathogen

macrophages(garbage collector)

-phagocytosis

-eats pathogens directly and cleans the body

dendritic cells(detectives)

-antigen presentation: presents antigen from the pathogen to the T cells

-con stimulatory signals

natural killer cells(border patrol)

-lysis of viral-infected cells

*it doesn’t kill virus it kills the cells with the virus to remove them and to prevent further damage to the body*

Main innate immune mechanisms

direct killing and accessory roles

direct killing mechanisms of the innate immune system

-phagocytosis

-secreting microbial peptides

-lysis of microbes(perforation of pathogen cell membrane through secreting complement)

accessory role mechanisms of the innate immune system

-increases pathogen uptake(opsonization)

-recruiting more immune cells(complement and chemokines)

-activating more immune cells(cytokines)

-induce systemic inflammatory responses(cytokines)

cytokines

small signaling protein molecules that are secreted by numerous cells to affect the behavior of others-allows immune cells to communicate

interleukins(IL)

group of cytokines that were first expressed in white blood cells- communication

chemokines

family of small cytokines with the ability to induce directed chemotaxis in nearby responsive cells-they are chemotactic cytokines

-direct cells to migrate to a location

process of phagocytosis

-bacteria is phagocytosed

-phagosome fuses with azurophillic and specific granules which have enzymes and change pH for degradation

-

lysis of microbes-C5b

C5b is a major component of complement that forms pores on the membrane of the pathogen that leads to lysis

what is the complement system?

A system of plasma proteins made by the liver that play multiple roles in innate immunity

-liver is making c3 and c5 all the time regardless of infection

-at the time of infection c3 binds the pathogen and is cleaved into c3a and c3b

• c3a is released

• c3b stays on the pathogen and codes it

  • essential for c5 to be cleaved into c5a and c5b

  • c5a is released

  • c5b inserts pores into pathogen to destroy it

opsonin

any molecule that enhances phagocytosis by marking an antigen for an immune response

increases pathogen uptake(opsonization)

-c3b is on the bacteria

-pathogen coded by c3b causes macrophages to produce CR1(complement receptor 1) that binds c3b and facilitates phagocytosis

recruiting more immune cells-complement

c3a and c5a that were released from complement system increase vascular permeability and recruit more immune cells-causes heat, redness, and pain

what are the 3 pathways of complement activation

-recruitment of inflammatory cells by c3a and c5a

-opsonization of pathogens, facilitating uptake and killing by phagocytosis by c3b

-perforation of pathogen cell membranes by c5b

cytokines and mannose-binding lectin and c-reactive protein

-bacteria induces macrophages to produce IL-6

-IL-6 targets the liver and causes liver to make mannose-binding lectin and c-reactive protein

-c3 recognizes certain patterns but its limited but now these two can serve as opsonin and as a complement activator to cleave c3

Three pathways complement activation

-alternative pathway

-lectin pathway

-classical pathway

*all lead to complement activation and eventually death of pathogen*

alternative pathway

pathogen surface creates local environment conducive to complement activation

-first to act

lectin pathway

mannose-binding lectin binds to the pathogen surface

-second to act

classical pathway

c-reactive protein or antibody binds to specific antigen on pathogen surface

-third to act

cytokines and activating more immune cells

-interferon responds to viral infection by inducing resistance to viral replication in cells, increases expression of ligands for receptors on NK cells, and activating NK cells to kill virus-infected cells more efficiently

TNF alpha

gets neutrophils out of the bone marrow and into the blood stream

chemokines recruiting more immune cells

-provides directional signals for migrating cells

concentration of chemokine stronger by the site of infection telling immune cells where to go

cytokines and inducing systemic inflammatory responses

-IL-1 secreted by phagocytes travels in the blood to the hypothalamus

-increases body temperature to the point set by the hypothalamic thermostat to create a fever to kill pathogen

septic shock

TNF alpha causes cells to make platelet activating factor which prevents pathogens from entering the blood

-in the extreme case this results in systemic edema followed by excessive coagulation and organs are starved and shut down

PAMPs

-pathogen associated molecular patterns

-molecules associated with groups of pathogens that are recognized by cells of the innate immune system

PRRs

-pattern recognition receptors

-innate immune system receptors that recognize different PAMPs

How can pathogens be recognized

-binding of bacteria to phagocytic receptors on macrophages induces their engulfment and degradation

-binding of bacterial components to signaling receptors on macrophages induces the synthesis of inflammatory cytokines

innate defense mechanisms of pathogens in the interstitial spaces, blood, and lymph(extracellular)

-complement system

-macrophages

-neutrophils

innate defense mechanisms for pathogens on epithelial surfaces(extracellular)

-antimicrobial peptides can be produced by skin cells

innate defense mechanisms against pathogens in the cytoplasm(intracellular)

-NK cells

innate defense mechanisms against pathogens in vesicles(intracellular)

-activated macrophages

different types of PRRs

-Toll-like receptors

-mannose receptors

-scavenger receptors

-nod-like sensors

-CARD-family sensors

what are nod-like sensors

for intracellular bacteria detection in cytoplasm

what are CARD-family sensors

detect viruses in the cytoplasm

Toll-like receptors

type of PRR that recognizes molecules that are broadly shared by pathogens and their name is because it is similar to the protein coding Toll gene in drosophila

Types of Toll-like receptors(TLRs)

surface: TLR4(LPS) and TLR5(flagellin)

endosomal: TLR3(dsRNA) TLR7(ssRNA) TLR9(CpGDNA)

what are lipopolysaccharides(LPS)?

a component of the cell wall of gram neg bacteria

-it is a type of PAMP recognized by a PRR

what is an endotoxin

a toxin kept within bacterial cells. presence of endotoxins in the blood can cause unwanted inflammatory responses

what does multiple TLRs may recognize different structures in the same pathogen

for example, TLR4 recognizes LPS but the flagella of the same pathogen is recognized by TLR5

what is CD14

it is the binding receptor that binds LPS and is required for recognition by TLR4

what is CD(cluster of designation)

a protocol used for identifying the cell surface molecules that provide targets for the immunophenotyping of cells. They act as receptors or ligands

TLR engagement and cascade

This is the MyD88 dependent pathway

-complex of TLR4, MD2, CD14, and LPS assembles at the microphage surface

-MyD88 binds TLR4 and activates IRAK4 which leads to activation of IKK

-IKK leads to the degradation of IkB and the release of NFkB which goes into the nucleus

-NFkB activates transcription of genes for inflammatory cytokines which are synthesized in the cytoplasm and secreted

MyD88 independent pathway

-uses TRIF as an adaptor protein

-kinase cascade leads to IRF3 activation and into the nucleus

-synthesis and secretion of IFNs for fighting viral infection

interferon regulatory factors(IRFs)

proteins which regulate the transcription of interferons

Nod-like receptor recognition

-bacteria recognized in cytosol by NOD2

-leads to activation of transcription factor NFkB and cytokine release

CARD-family sensor recognition

-recognize dsRNA and ssRNA by RIG-I in cytosol

-leads to expression of interferons(IFNs) for viral infection

antigen

-substance that the antibody binds to. something the adaptive immune system is able to see and recognize

antigen presenting cells(APGs)

cells that produce antigens and present them to T cells

what do dendritic cells link

the innate immune system to the adaptive immune system

How do NK cells recognize and kill virally infected cells?

-a healthy cell expresses MHC class I which signals the NK cells to not kill it

-an unhealthy cell MHC call I expression is inhibited and signals the NK cells to kill it

where is the innate immune system present in the body

tissue, lymphoid organs, blood

(mostly tissue)

where in the body is the adaptive immune system present

lymphoid organs, blood, tissue

(mostly lymphoid organs)

lymph

plasma that has leaked through blood into tissues and is collected through lymphatic vessels

lymphoid organs

contain lymphocytes and other types of cell structures to support the production, maintenance, and circulation of lymphocytes

primary lymphoid organs

where lymphocytes are generated from immature cells to mature lymphocytes

ex) bone marrow, thymus

secondary lymphoid organs

where mature naive lymphocytes reside and an adaptive immune response can be initiated

how do lymphocytes interact with secondary lymphoid organs

they continuously survey them for infection by traveling through lymph and blood

how do secondary lymphoid organs deal with infection

they compartementalize the infection and provide a meeting place for the cells of the adaptive immune response pa

parts of the lymph node

-afferent lymphatic vessel

-T-cell area

-lymphoid follicle

-artery vein

-efferent lymphatic vessel

T cell area of lymph node

where naive mature T lymphocytes live

lymphoid follicle of lymph node

where mature naive b cells reside

the spleen

deals with pathogens that make it into the blood

-white pulp contains mini lymphocytes

-pathogens and lymphocytes enter spleen through the blood NO CONNECTIONS TO LYMPHATICS

gut associated lymphoid tissue

gut lumen

-commensals close the to gut in case pathogen enters from eating

-along the intestine

GALT

gut associated lymphoid tissue specialized immune system in digestive tract Mc

M cell in gut lumen

allows dendritic cells to access pathogen before the body does

rules of clonal selection

1. each lymphocyte bears a single type of receptor with a unique specificity

2. foreign molecule and lymphocyte receptor capable of binding with high affinity leads to lymphocyte activation

3. effector cells derived from activated lymphocyte bear receptors of identical specificity to those of the parental cell from which the lymphocyte was derived

4. lymphocytes bearing receptors for self molecules are deleted in early lymphoid development and absent from mature lymphocytes

B cells

secrete antigen receptor

-make antibodies

-once antibody produced you dont need B cell anymore

T cells

do not secrete antigen receptor but they kill infected cells directly and can activate other cells to do so too hu

humoral immunity

eliminations pathogens outside cells

-B cells

-not needed once antibodies are made

cell-mediated immunity

-eliminates pathogens inside the cell

-lymphocytes

-macrophage by microbial killing by helper T cells

-lysis of infected cell by cytotoxic T cells