Microbio 4000.01 - Innate and Adaptive Immune System

immune cells

Erythrocytes

• red blood cells

• platelets

lymphoid cells

• B cells

• T cells

• Natural killer cells

myeloid cells

• mast cells

• eosinophils

• neutrophils

• basophils

• monocytes

  • macrophages

  • dendritic cells

Neutrophils

innate WBC that can phagocytose and kill microbes

• ~70% of WBC

programmed to undergo apoptosis - then phagocytosed by macrophages and degraded

Eosinophils and basophils

innate WBC that secrete antimicrobial compounds

mast cells

innate WBC only found in tissues and secrete antimicrobial compounds

monocytes

circulate in the blood and engulf foreign material (phagocytosis)

• In the tissue: innate WBC that differentiate into macrophages or dendritic cells

macrophages

from monocyte - phagocytic, present antigens to the adaptive immune system (B & T cells)

• first to make contact with invading pathogens

• stays in the local tissue the monocyte was in

phagocytes:

neutrophils, monocytes, macrophages, dendritic cells

APCS:

monocytes, dendritic cells, macrophages

dendritic cell

from monocyte - phagocytose, process, and present small antigens on their surface

• can take up small soluble antigens from the surroundings

• bridge between innate and adaptive immunity

• can travel in the lymphatic system

phagocytes

cells that can engulf bacteria through phagocytosis

• neutrophils

• monocytes

• macrophages

• dendritic cells

Antigen-presenting cells

activate the adaptive immune system

• killing the pathogen is important step for antigen presentation

oxidative burst

microbes are killed by reactive oxygen species and degradative enzymes when the lysosome and phagosome fuse

Inflammation

Caused by extravasation - the movement of WBC from the bloodstream into the tissues (mostly neutrophils)

marked by HERPA:

• heat

• edema

• redness

• pain

• altered function/movement

cytokines

signaling peptides that communicate with immune cells

chemokines

signaling peptides that guide immune cells to the site of the infection (chemotaxis along conc. gradient)

vasoactive factors

increases vascular permeability - vasodilation

• cytokines, bradykinin, and histamine are vasodilators

prostaglandin

tells nerve cells to send a pain input to the brain

acute inflammation

causes cell damage as a cost to clear out the pathogen

• damage is quickly repairable

chronic inflammation

occurs when the foreign body persists in the tissues

• cycle of inflammation can cause permanent tissue damage

natural killer cells

kill defective host cells

• do NOT directly kill microbes

• not specific - attacks any cells that express less MHC-I than regular host cells

1. insert perforin (pore-forming protein)

2. release granzyme into the cell and initiate apoptosis

PAMPs

conserved components that only occur in microbes

• helps immune cells recognize microbial invaders

DAMPs

patterns that host cells can leak out when damaged

• detection of these patterns results in sterile inflammation

Pattern recognition receptors

(PRRs) immune cells use these to sense PAMPs and DAMPs and initiate the appropriate response

• activation of PRR → produce cytokines

Toll-Like Receptors

(TLR) - a type of PRR that detect PAMPs and DAMPs

• located on cell membrane → extracellular environment

• located on endosomal membranes → intracellular bacteria/viruses (PAMPS taken up by endocytosis)

interferons

tell neighboring cells to express interferon-stimulated genes and establish an antiviral state in the immediate area

• cytokines produced by eukaryotic cells in response to intracellular infection

Sepsis

A systemic (rather than local tissue) inflammatory response to infection

• monocytes and platelets have TLRs that sense bacterial infiltration into the bloodstream

• overreaction of the host immune response can lead to septic shock or death

fever

body temp exceeding 38 C

• caused by pyrogens (any molecule that causes fever) ex. interferon

• pyrogens influence hypothalamus to increase body temperature

• high temp creates an environment inhospitable to bacterial growth

opsonization

coats bacterial cells and enhances phagocytosis - complement proteins promote this

complement

series of 20 blood proteins that broadly attack bacterial cell membranes

• needs to be activated to bind to bacteria membranes

• forms membrane attack complex - makes large pores in bacterial cells

• promotes opsonization

Immunogen

an antigen that leads to the production of antibodies

epitope

antigens can have one or more of these

antigenicity

measures how well an antigen initiates an immune response

• proteins are more antigenic

• the more distant the antigen structure is from “self,” the greater the antigenic it is

protein antigens

most antigenic

• can form a variety of shapes

• maintain 3d shape

• made of many diff. amino acid combinations

best targeted by antibodies and T-cell receptors

Class I MHC

expressed on ALL cells

• displays intracellular antigens

• interacts with NK and CTLs

A cell uses MHC I to tell the cell that it is infected.

Class II MHC

expressed on APCs

• displays extracellular antigens

• interacts with helper T cells

Antigen-presenting cells

Monocytes, macrophages, dendritic cells

• place antigen on MHC I proteins

• show antigen to T-cells

B cells

can read free-floating antigens in the lymph

• an APC - but does not trigger apoptosis

• regulated by helper T cell

• activate into plasma cells or memory B cells

• undergo clonal expansion

Humoral immunity

mediated by antibodies secreted by plasma cells (activated B cells)

Cell-mediated immunity

mediated by cytotoxic T cells (CTLs)

helper T cells

activates both humoral immunity and cell-mediated immunity

B cell receptor

binds to free floating antigens

• each BCR is specific to a different antigen

naive B cells

B cells that have not encountered an antigen before

• will not secrete antibodies the B cell binds to an antigen and is activated

first B cell activation comes from the…

BCR

second B cell activation comes from the…

helper T cell

Clonal expansion

activated B cells undergo this to make thousands of cells that recognize the same antigen

• these clones differentiate into memory B cells or plasma cells

plasma cells

from activated B cells

• PACKED with endoplasmic reticulum - focus on producing antibodies

antibody structure

Fab and Fc

Fc

• the same between each isotype

• the Fc between each isotype has different effector functions

• enhances phagocytosis

• activates complement

The part of the antibody that reacts with complement/binds to surface of cells - undergo isotope switching to find best match

Complement

a pathway that can be activated spontaneously, but is not the most effective

• can be quickly and effectively activated via the Fc region of the antibody

Fac

variable between each B cell clone

isotype

IgG, IgA, IgM, IgE

• B cells undergo isotype switching to chose the Fc region most appropriate for that infection

IgG

abundant in blood and tissue fluids

• majority of immunity

• protective immunity

• shaped like a Y

• higher affinity

IgA

secreted in mucosal surfaces

• blocks pathogens in mucosa

• shaped like a dimer

IgM

found in naive B cells and secreted early after activation → quickly replaced by IgG through isotype switching

• weaker affinity

• made of 5 monomers of BCR

• shaped like a ferris wheel

IgE

important against parasites

causes allergy

• Fc region immediately binds to IgE receptors on mast cells, basophils, and eosinophils as soon as they are secreted by B cells = low population

• when IgE Fab region binds to antigen → cell degranulates → release lots of histamine and inflammatory cytokines

affinity

tightness of antibody/antigen binding

• usually increases from primary response → secondary response

primary response of memory B cells

IgM is secreted in the initial antibody response → quickly replaced by IgG via isotope switching

• weaker affinity

• plasma cells die within 3 months

Secondary response of memory b cells

memory B cells divide and make up to 40% of the B cell population

• plasma cells isotype switch to IgG

• reinfection → memory B cells expand and differentiate into more memory and plasma cells

activation of cell-mediated immunity

T helper cells and CTLs are activated by antigens presented by APCs

• CTLs need 2 signals:

  • binding to APC presenting antigen

  • cytokines secreted by helper T cells

• CTLs will then enter bloodstream and tissues to directly kill infected cells

Proteasome

degrades foreign proteins (made in the cytoplasm) into peptides (antigens)

How MHC I is made

Made in the ER

• antigens made by proteasome are loaded in the ER

• they are then loaded onto MHC I

• secretory vesicles fuse with the membrane and carry the MHC I-antigen complex out

How MHC II is made

Made in the ER

• MHC II blocks antigen loading in the ER with a phagolysosome

• transported into endosomal compartments + the blocking protein is degraded

• a phagocytosed microbe is degraded by proteases and transported in an endosome.

• the two endosomes fuse and the peptide antigens attach to the MHC II molecule and they are then exported

T cell receptor

binds to MHC-antigen complexes → activates and differentiates T cell

• each naive T cell expresses a unique TCR that recognizes a specific MHC-antigen complex

Helper T cell TCR

expresses CD4 = helps TCR bind to MHC-II/antigen complexes (extracellular microbes)

• increase proliferation and differentiation of T and B cells (clonal expansion)

Cytotoxic T cell TCR

expresses CD8 = helps TCR bind to MHC-II/antigen complexes (intracellular microbes)

T cells

binds to MHC-antigen complexes

helper T cell and cytotoxic T cell

• both need 2nd signal (from APC) to fully activate

mucus

sticky and contains antimicrobial compounds

lactoperoxidase

produces toxic superoxide radicals

defensins

positively-charged small molecules, target membranes