Public Health 162A Midterm 2

Immunity

ability of an individual during a lifetime to make proteins that target a pathogen

there's Adaptive and innate immunity

Synonyms: resistance, defense, protection, etc

living organisms and immune systems

all living organisms have an immune system

pathogens and nonpathogens can be similar with slight differences

sterile

things that are free of living germs and microorganisms

ex: blood, organs

nonsterile

things that have living germs and microorganisms

facing outside environment

ex: digestive system

microbes compete with pathogens for space inside the body, more nonharmful microbes --> higher dose of pathogen needed to get an infection since they compete for resources within the body to establish a niche

challenges facing the immune system

microbes replicate and evolve quickly

immune system has to react to virtually any pathogen but not react to itself

immune responses have to clear infected tissues without causing to the host

innate immunity general features

recognizes infection, alerts rest of the immune system, holds infections in check

timing: rapid (minutes- hours)

specificity: germline encoded

cell involved: most if not all cells

functions: hold pathogens in check, stimulate adaptive immune responses

adaptive immunity general features

more powerful and tailored response that eliminates infection

timing: slower (days)

specificity: somatically generated, highly specific

cells involved: primarily B and T cells (selectively absent in SCID)

functions: b cells make antibodies, cytotoxic t cells kill infected cells, helper t cells make cytokines, memory

allows vertebrates to counter newly evolving pathogens

hematopoietic stem cell

located in bone marrow

becomes either common myeloid progenitor or common lymphoid progenitor

common myloid progenitor becomes...

red blood cell, platelets, masts, neutrophils, monocytes

common lymphoid progenitor becomes...

natural killer (NK) cells (innate cells), t cells and b cells (adaptive immunity cells)

bone marrow and immunity

stire of hematopoiesis and b cell development

thymus

site of T cell development

spleen

where T cells and B cells are activated when infection is in the blood, filters blood and removes damaged RBCs

lymph nodes

sites where B and T cells are activated when infection occurs in tissues

mechanical barriers to infection

mucus, tight junctions, skin, flow of fluid

mucus

hard for bacteria to push through and get through thick polysaccharides

lysosimes in tears

breaks down peptidoglycans

chemical

acitidy, eznymes, lysosimes

microbiological

normal biological flora

response from bacterial pathogen entering through a cut in the skin

redness, swelling, pain, heat, inflammation (innate immune system)

influenza virus enters through respiratory tract

fever, muscle aches, cytokines/ prostaglandins (innate immune system)

intestinal parasite enters through the mouth and takes up residence in gut mucosa

abdominal cramping, smooth muscle contractions for parasite expulsion (innate immune system)

phagocytes

Initiate inflammatory response

Initiate and influence adaptive immune response

kill pathogens

3 types: dendritic cells, macrophages, neutrophils

macrophage

phagocytosis and killing of microorganisms, activation of T cells and initiation of immune responses

neutrophil

phagocytosis and killing of microorganisms

lyososome

protective mechhanism

protons acidify the environment and activate hydrolases

antimicrobial peptides are found in the lysosome and are active at acid pH

metabolite transporter pump essential metals and other nutrients out of the lysosome

proteases in lyososome

digest cell wall proteins

glycosidases in lysosome

cleave cell wall sugars

lipases in lysosome

cleave cell wall lipids

antimicrobial peptides

make holes in pathogen membranes

electrostatic attraction and transmembrane electric field bring the defensin into the lipid bilayer

defensin peptides form a pore

oxidative burst of macrophages and neutrophils

neutrophils kill microbes by producing reactive oxygen species

neutrophils

kill pathogens with extruded nets composed of DNA and protein

Differentiated cells that can decondense part of the DNA, extrude it and pump it out of the cells and make a net

And can catch DNA

Good at concentrating antibacterial enzymes, more likely to kill bacteria to prevent them from hurting human cells

complement

set of protein made by hepatocytes in the liver and pumped into the blood that combats pathogens

chemotaxis: Get activated and deposited on membrane

Membrane attack complex which pokes holes

Signal for phagocytes and immune cells to arrive

Activated a little all the time to protect ourselves

regulation

prevents host cells from activating complement system

transformation

bacteria capsule (thick layer of polysaccharide, we have mucus they have a capsule) where its slippery hard to bind sugars to protect the bacteria

slipper capsule of S. pneumoniae helps these bacteria avoid being eaten by neutrophils

if you can't grab bacteria you can't engulf it

inflammation

promotes entry of immune cells into infected tissues

increase blood flow: redness, heat

increased vascular permeability: swelling

easier for plasma proteins and cells to pass out of the blood and into site of the infection

damage model sensing pathogens

sense damage or alterations to host physiology induced by pathogens

self-nonself discrimination

sense specific features found on pathogen that are not present on normal self

receptors to these things to notice the bacteria

Flagellum receptors

Viral detection can be done by finding nucleic acids or double stranded RNA in the cytosol

Don't really detect viral membranes because the virus is in the host

Surface proteins are hard to catch on to

pathogen associated molecular patterns (PAMPs)

invariant components of pathogens recognized by the innate immune system

conserved among many pathogens

not found on human cells

difficult for pathogen to alter

alert the immune system that a microbe is present

toll like receptors (TLRs)

survey extracellular space and endosomes/ lysosomes

sense PAMPs

cytokines

soluble proteins that diffuse through blood and activate other cells

can be produced after sensing PAMPs

canonical inflammatory cytokine: tumor necrosis factor alpha (TNF-alpha)

inflammatory cytokines and immune response

proteins (chemokines) are produced that attract immune cells: macrophages, neutrophils

blood vessels become sticky for specific immune cells

vasodialation increases blood flow to the inflamed site (heat, redness)

blood vessels become leaky and plasma enters tissues (swelling)

recognition of viral PAMPs activate the Type I Interferon

virus infected cell --> activate IFN alpha and beta --> interferon response

3 outcomes: induce resistance to viral replication in all cells, increase expression of ligands for receptors on NK cells, activate NK cells to kill virus infected cells

Type I Interferon

group of signaling proteins (cytokines) that your body makes to fight viruses and control the immune system

transcriptional targets of type I IFN

include intrinsic antiviral factors

worm recognition

recognition of worm components (ex: chitin) that initiate effector functions that act to kill and expel worms

weep and sweep: increased mucus production, smooth muscle contraction

macorphages secrete chitinases and proteases

esoinophils degranulate toxic granules onto surface of the worm

make environment less hospitable

2 main branches of adaptive immunity

humoral and cellular

many pathogens require both arms for elimination

humoral immunity

where B cells produce antibodies to target and neutralize extracellular pathogens like bacteria and toxins in body fluids

Pathogen Target: Extracellular pathogens (like free-floating bacteria or parasites) and extracellular toxins floating in body fluids.

Responding Lymphocyte: B cells (B lymphocytes).

Effector Mechanism: Activated B cells differentiate into plasma cells that secrete antibodies. These antibodies bind to the pathogens or toxins, neutralizing them and marking them for destruction/elimination

cellular immunity (microbes in macrophages)

targets pathogens inside host cells and is split into two primary mechanisms mediated by T cells (T lymphocytes)

Pathogen Target: Microbes that have been engulfed (phagocytosed) by macrophages but survive inside the cell's vesicles.

Responding Lymphocyte: Helper T cells ($CD4^+$ T cells).

Effector Mechanism: The T cell activates the macrophage (via cytokines like IFN-$\gamma$), inducing the macrophage to destroy the ingested microbes.

cellular immunity (virus infected cell)

Pathogen Target: Intracellular pathogens replicating inside host cells (such as viruses).

Responding Lymphocyte: Cytotoxic T lymphocytes (CTLs / $CD8^+$ T cells).

Effector Mechanism: The T cell directly induces lysis (destruction) of the infected host cell, destroying the viral reservoir and stopping viral replication.

active immunity

a type of immune protection that occurs when your own immune system produces antibodies and memory cells in response to direct contact with a disease-causing pathogen or antigen

naive t and b cells require a series of signals to become active

adaptive immunity steps

activation: dendritic cell captures pathogens and presents foreign antigen, activates naive cytotoxic T cell who has a receptor that binds to the antigen signaling danger

proliferation and differentiation: naive t cell proliferates and matures into functional effector cytotoxic T cells (Tc cells)

effector action and consequence: Tc cells recognize infected cells that display the foreign antigen and then delivers death packages into the infected cell and apoptosis ensues

what's inside death packages?

cytotixc molecules like perforin and granzymes

dendritic cells

pick up microbes/ pathogen fragments at site of infection and carry them to lymph nodes

bring it to the circulating b and t cells that meet antigen presenting cells

activation of t cells during immune response

activate naive T cells

some activated T cells help B cells become activated

activated T cells leave lypmph node and travel to the site of infection

activation of b cells during immune response

b cells receive signal from antigen via antigen receptors

b cells process antigen and present it on MHC-II molecules

activated T helper cells help B cells activate

activated B cells produce antibody at the lymph nodes and at the site of infection

lymphocytes

constantly recirculate in blood and lymphatic system

enter tissues and lymph

plasma cells

differentiation of B cells that secrete large quantities of antibodies

lymph exchange in capillaries

blood travels from the heart through arteries to systemic and pulmonary blood capillaries

plasma leaves capillaries into tissues as interstitial fluid

lymph drainage

excess interstitial fluid with antigen-presenting cells and extracellular antigens enter lymphatic capillaries to become lymph

lymph node transit

lymph flows through one way lymphatic vessels (valves) into lymmph nodes

lymph to blood

cleaned lymph exits through the lymphatic duct and drains into the subclavian vein returning fluid and lymphocytes back into bloodstream

effect of toll like receptor (TLR) on dendritic cells

increased presentation of antigen on cell surface: peptides complexed with MHC molecules

expression and secretion of cytokines that influence the differentiation and activation of T cells

migration from tissues to draining lymph nodes through a lymphatic vessel

antibody structure

shaped like a Y

top part has specificity for antigens and antigen binding sites

bottom part (heavy chains) interact with diseases

top binds bottom tells other cells they have the target

how is diversity generated to account for all antigens?

theres a lot of specificity in b cell receptors

in normal DNA the gene that codes for the one light chain and one heavy chain of the antibody contains multiple redundant parts

VDJC are spliced together in B and T cells randomly to produce a unique sequence characteristic of that cell

key innovation in adaptive immunity

generate diversity through randomly splicing DNA in B and T cells

antigen

any molecule that specifically binds either a B cell receptor or T cell receptor leading to activation of the cell

T cell antigens are peptides

T cell receptor (TCR) diversity

allows for recognition of virtually any pathogen

diversity is generated at the antigen binding site by genetic recombination events targeted to the TCR gene

T cells recognize protein antigens presented by MHC (HLA) molecules

each t cell has a unique receptor with specificity for a particular antigen presented by MHC

T cells specific for an antigen find dendritic cells presenting that antigen

more than 1bil T cells

MHC I

expressed in almost every cell type in the body

binds and presents antigens derived from the cytosol

MHC II

expression of MHC II is restricted to immune cells: macrophages, dendritic cells, B cells

MHC II binds and presents antigens derived from the endosomal/ lysosomal network

t cell function

makes contact with other cells and induces change

CD8 (kiler) T cell

specific additional molecules on it

CD8 is a protein on killer cells

important because kills infected cells displaying antigens on MHC I

viruses replicate in cytosol and MHC I pressents antigens from cytosol

CD4 (helper) T cells

CD4 t cells once activated if they recognize an B cell with their matching antigen is if the antibody is specific for the antigen

master regulators of immune response

once activated secretes cytokines

important for activating B cells and macrophages (extracellular pathogens)

MHC II presents antigens from endocytosis and only presents on Dendritic cells, B cells, and macrophages

CD4 Helper T cell cytokine function

required for B cell production of antibodies

aid in activation of immune effector cells

help activate CD8 T cells

MHC activation of specific T cell subsets

CD8 cells --> MHC I

CD4 cell --> MHC II

B cell receptor (BCR)

membrane bound antibody molecule

diversity generated at the antigen binding site by genetic recombination events targeted to the BCR

antibodies are released upon B cell activation as extracellular molecules

dendritic cells

specialized immune cells that act as the crucial bridge between the innate immune system and the adaptive immune system

antigens and B cell receptors directly bind antigen

b cells can recognize virtually any type of antigen (protein, nucleic acid, carbohydrates) on the surface of a pathogen or soluble antigens such as protein toxin

lock and key

way of binding of antibody to antigenic epitopes

b cell receptor/ antibody recognizes only one antigen

unique shape that goes into other shape that matches it

B cell activatoin

activated when binding to antigen to receptor but requires CD4 T cell to help

requires 2 signals

signal 1: b cell binds a specific antigen using its b cell receptor

signal 2: t cell recognizes antigen presented by the b cell and sends a signal

purpose of a b cell

make an antibody

upon activation B cells differntiate into plasma cells or memory cells

plasma cells secrete large amounts of antibody

memory cells are long lived and respond if the infection is encountered again

antibody neutralization

antibodies bind directly to the toxin which block them from interacting with host receptors

neutralized toxin-antibody complex is recognized and ingested by a macrophage for degradation via phagocytosis

antibody opsonization

antibodies coat surface of the bacterial cell, stem regions project outward where they're easily recognized by Fc receptors on phagocytes like macrophages

binding to Fc receptors triggers phagocytosis, leading to internal degradation of the bacterium by the macrophage

antibody complement activation

antibodies coat the surface of a bacterium in plasma and recruit complement proteins

triggers 2 mechanisms: forms membrane attack complex, deomposition of complement fragments onto the bacterium enhancing ingestion and digestion by macrophages

membrane attack complex

creates pores in bacteria cell membrane and induses lysis

types of B cell antibody

IgM,IgG, IgD, IgA, IgE

makes IgM first

isotype switching occurs later and changes the isotype

class switching pathway A

changes isotype of antibody produced by a B cell without altering its specificity

steps:

naive b cell programmed to express IgM and IgD on its surface, rearrange heavy-chain gene loci in its DNA

if no class switching signals occur, the B cell DNA remains intact b cell continues to produce IgM antibodies using the intact gene sequence

class switching pathway B

activated helper T cells and cytokines instruct the B cell to switch to a different isotype IgG

enzyme activation induced cytodiine deaminase (AID) introduced double-stranded breaks at specific conserved DNA called Switch (S) regions located upstream of the constant gene segments

the intervening DNA segment containing the unwanted constant regions is looped out, excised, and permanently deleted from the B cell's genome

outcome: the B cell now expresses and excretes IgG, variable region DNA remains unaltered

distribution of Ig in adult tissue

IgG and IgA: in the vascular system and fluid compartments of body tissues

IgM: localized in bloodstream/ heart and major vessels

Dimeric IgA: concentrated at mucosal surfaces (GI tract, respiratory tract, urogenital lining)

IgE: found primarily beneath epithelial surfaces associated with mast cells in skin, gut, and respiratory linings (orange)

transfer of antibodies from mother to child

maternal IgG is transported across placenta via neonatal Fc receptors into fetus

gives passive immunity to developing fetus

mothers milk delivers dimeric IgA to infants gastointestinal tract

adult serum immunoglobulins

as you grow the amount of antibodies increase

neutralizing IgA

prevents infection of mucosal surfaces in the pharynx by preventing bacteria from adhering

lymphoid tissue

germinal centers form within lymphoid tissue in lymph node

lymph nodes are like a meeting place for antigen presenting cells, dendritic cells, circulating B and T cells

marbug 2024 virus outbreak rwanda

filovirus, negative strand RNA virus

primary reservoir is fruit bats

causes hemorrhagic fever and multiorgan failure

transmission via contact with body fluid

front line workers are at the most risk

really deadly

history of marbug houtbreaks

number of cases is usually not very big

large outbreak in early 2010s in africa

lower fatality rate because rwanda signed up for a vaccine rollout

marbug vaccine trial in rwanda

enrolled frontline worker into trial for vaccine quickly

successful because earlier you catc the outbreak then the higher chances of good contact tracing and combating it

how to know if vaccine works

precilinical trials (animals) to see if its safe and effective in animals

measure antibodies, rate of disease, and mortality

shows if it works in monkeys

human phase I

look at safety of vaccine

looking at possible side effects

higher dose of vaccine --> greater symptoms

determine optimal dosage

human phase II

efficacy

may need to wait for outbreak to test it

memory cells (T cell)

differentiate during the primary immune respones to infection

naive T cell is activated by pathogen

clone of pathogen specific effector and memory t cells is produced (many)

effector t cells outnumber memory t cells during primary infection

get new transcriptional program that maintaines them longterm without new antigen stimulation and become memory cells to protect your body