Innate Immunity: First Line Defenses

physical and chemical barriers that block microbial entry
example: skin, mucous membranes

detect invaders using pattern recognition receptors and the complement system

destroy invaders through mechanisms such as interferon response, phagocytosis, complement activation, inflammatory response and fever

skin: acts as tough water repellent barrier
mucous membranes: line internal tracts and trap microbes

tightly woven fibrous connective tissue

multiple layers of epithelial cells; outermost are dead and filled with keratin, repelling water and maintaining a dry environment

composed of mucus-producing cells; some have cilia to remove microbes

salt, lysozyme, peroxidases, lactoferrin and transferrin, defensins

accumulates on skin from perspiration, creating a hostile environment for microbes

degrades peptidoglycan in bacterial cell walls

form antimicrobials by breaking down hydrogen peroxide

bind iron, limiting microbial access

host defense peptides that form pores in microbial membranes

normal microbiota cover binding sites and consume nutrients, preventing pathogen colonization

some species of microbiota produce fatty acids or bacteriocins that inhibit pathogens

normal microbiota are essential for proper immune system maturation

antibiotic use can predispose to infections by Clostridium difficile or Candida albicans

engulf and destroy bacteria; most abundant and first responders during infection

involved in allergic reactions and inflammation; granules contain histamine

similar to basophils; found in tissues

fight parasitic worms and participate in allergic reactions

circulate in blood and differentiate into macrophages upon entering tissues

sentinel cells found in nearly all tissues; phagocytize debris and invaders

sentinel cells that engulf material and present it to adaptive immune cells

include B and T cells (adaptive immunity), innate lymphoid cells and natural killer (NK) cells

proteins that span the cell membrane and transmit signals upon ligand binding

small proteins that act as cell "voices," including changes such as growth, differentiation, movement or cell death

enable cells to adhere to each other, facilitating migration and interaction

direct chemotaxis of immune cells

stimulate multiplication and differentiation of leukocytes

control viral infections and regulate immune responses

produced by leukocytes; important in both innate and adaptive immunity

induces inflammation and apoptosis

located on cell surfaces, in phagosomes/endosomes and in the cytoplasm; detect microbial components and cell damage

a type of PRR anchored in membranes of sentinel cells; surface TLRs monitor extracellular environment, while TLRs in phagosomal/endosomal membranes characterize ingested material

proteins circulating in blood and tissue fluid named C1 through C9, with activation occuring via three pathways all leading to the formation of C3 contervase which splits C3 into C3a and C3b

triggered by C3b binding to foreign cell surfaces

pattern recognition molecules (MBLs) bind to mannose on microbial cells

activated by antibodies bound to antigens

C3b binds to bacterial cells, promoting engulfment by phagocytes

C5a attracts phagocytes; C3a and C5a increase blood vessel permeability and induce cytokine release

membrane attack complexes (MACs) formed by C5b, C6, C7, C8 and C9 assemble in cell membranes of Gram-negative bacteria

phagocytes are recruited by chemoattractants (eg. C5a)

direct: receptors bind mannose
indirect: binding to opsonins like C3b

pseudopods surround the microbe, forming a phagosome

fusion with lysosomes releases digestive enzymes

toxic reactive oxygen species (ROS), nitric oxide, and enzymes degrade the invader

expulsion of digested remains

1. vascular changes
2. cellular changes
3. clotting
4. pus formation

blood vessel diameter increases, causing heat and redness; fluid (exudate) leaks into tissues causing swelling and pain

cytokines cause endothileal cells to "grab" phagocytes, which move into tissues (diapedesis)
neutrophils arrive first, followed by monocytes and lymphocytes

clotting factors wall off site of infection

accumulation of dead neutrophils and tissue debris forms pus; a localized collection is called an abscess

short-term, mainly neutrophils; macrophages clean up debris

if acute fails, macrophages and giant cells accumulate, forming granulomas

traumatic cell death due to damage

programmed cell death; does not trigger inflammation

trigger inflammatory reponses, sacrificing infected cells

highly specialized defense mechanism that develops to eliminate specific microbial invaders
characterized by molecular specificity, immunological memory and immune tolerance
takes around a week or more to develop after first exposure but subsequent exposures elicit much faster and stronger responses

lymphocytes recognize unique antigens

enables stronger response upon re-exposure; basis of vaccination

prevents immune responses against "self" tissues

involves B lymphocytes that produce antibodies to neutralize pathogens in blood and tissue fluids

involves T lymphocytes that eliminate infected or abnormal "self" cells

induce apoptosis in infected or corrupted cells

direct and assist immune responses

bone marrow (B cell maturation)
thymus (T cell maturation)

sites where mature lymphocytes encounter antigens and become activated

require antigen presentation by MHC molecules; guided by CD markers (CD8 for cytotoxic T cells and CD4 for helper T cells)

membrane-anchored antibodies with two identical antigen-binding sites; bind free antigens

serve as sites where lymphocytes gather to encounter antigens

lymph nodes, spleen, tonsils

specialized for sampling intestinal contents

prevents microbial invasion via mucous membranes

ensures only lymphocytes with receptors specific to an encountered antigen are activated and proliferate, generating a population of clones capable of mounting an effective immune response

each B and T cell recognizes a single epitope, while activation requires antigen binding and additional signals. during expansion, activated cells multiply producing effector and memory cells

Y- shape with two identical arms (Fab regions) that bind to antigen and a stem (Fc region) that marks the antigen for elimination by immune cells

prevents toxins and viruses from bindint to host cells

enhances phagocytosis

triggers the classical pathway

interferes with bacterial motility and adherence

links antigens together

targets cells for destruction by NK cells

short amino acid sequences or three dimensional shapes recognized by antibodies

possess numerous different epitopes

membrane bound antibody composed of two heavy chains and two light chains forming a Y shaped structure.
variable region: binds to specific antigen
constant region: anchors receptors to cell membrane

B cells encounter antigens in secondary lymphoid organs and upon binding antigen internalizes and processes it, presenting fragments on MHC Class II molecules. Helper T cells then recognize these fragments and activate the B cel via cytokine delivery, leading to proliferation and differentiation

variable region conferrs antigen-binding specificity while constant region determines antibody class and function

first produced during primary response
pentamer
efficient in complement activation

most abundant immunoglobulin class
provides long term protection
crosses placenta
found in Colostrum

dimer
important in mucosal immunity
found in secretions

involved in antibody response development
function in serum is unclear

bound to basophils and mast cells
important in allergic reactions and parasite defenses

B cells with higher affinity for antigen binding proliferate

B cells switch to producing one class of immunoglobulin to another (ex IgM to IgG) to ehance the immune response

slower and less efficient
takes 10-14 days; produces IgM first

faster, mediated by memory cells
produces IgG or IgA
eliminates pathogens before harm

presents endogenous antigens
recognized by CD8+ cytotoxic T cells

presents exogenous antigens
recognized by CD4+ helper T cells

release perforin and proteases to induce apoptosis in infected cells

deliver cytokines to activate B cells and macrophages

induce apoptosis in antibody-bound "self" cells and cells lacking MHC class I molecules

NK cells recognize and kill cells coated with antibodies

exaggerated immune response that damages host tissue

misdirected immune response that damages host tissue

lack of adequate immune responses

immediate IgE-mediated
allergic reactions

antibodies react to molecules on cell surfaces leading to cell death via complement activation or antibody-dependent cellular cytotoxicity (ADCC)

example: hemolytic transfusion

immune complex-mediated
caused by formation of immune complexes bw antibodies and soluble antigens. large complexes are removed while smaller ones can lodge in blood vessels, activate complement, and trigger inflammation

ex: lupus, infective endocarditis, glomerulonephritis

localized immune complex reaction after infection of antigen into a previously immunized individual

systemic immune complex disease caused by passive immunization with animal antibodies

delayed-type cell-mediated
mediated by antigen-specific T cells and peaks 2-3 days after exposure

common causes: nickel, cosmetics, latex, poison ivy
mechanism: dendritic cells present hapten-peptide complexes to T cells, leading to activation, proliferation and differentiation. memory T cells respond to subsequent exposures causing inflammation and rash

allografts: most common
autografts and isografts avoid rejection
xenografts evoke strong immune responses

maintained by negative selection (apoptosis) of self-reactive lymphocytes and development of regulatory T cells (Treg) that inhibit responses to autoantigens (one's own cells)

congenital / genetic

acquired after birth
ex. AIDS

hives: skin condition with wheal and flare; blocked by antihistamines
hay fever: teary eyes, sneezing and runny nose; blocked by antihistamines
asthma: bronchial spasms, mucus; antihistamines not effective

alters immune response by inducing IgG production against allergens
IgG competes with IgE for binding, reducing allergic reactions
Omalizumab binds Fc portion of IgE, blocking its attachment to mast cells and basophils

occurs when Rh-negative mother carries an Rh-positive fetus
if fetal RBCs enter the mother's circulation, she may develop anti-Rh antibodies. in subsequent pregnancies, maternal IgG antibodies can cross placenta and destroy fetal RBCs

treatment; RhoGAM

first antibiotic discovered by Fleming
effective against many bacteria
Chain and Florey purified penicillin and tested it clinically in 1941
WWII accelerated research and mass production

greater harm to microbes than hunan cells

lowest dose toxic to patient divided by the dose that is used for therapy

range bw therapeutic and toxic dose

medications too toxic for systemic use can be used topically

inhibit bacterial growth
host defenses must eliminate pathogens

kill bacteria
effectiveness may depend on drug concentration and microbial growth stage

affect a wide range of organisms
useful for acute life threatening diseases; may disrupt microbiome

affect limited range of organisms
require pathogen identification and are less disruptive to microbiome

medications inhibit the effects of one another

medications enhance each other's effects

combined effect equals sum of individual effects

imbalance in microbiome
ex. bacterial overgrowth

certain antibiotics degrade peptidoglycan

inhibit penicillin-binding proteins (PBPs) that catalyze peptide bridge formation between glycan strands

bind to amino acid side chains of NAM molecules, blocking cross-link formation

interferes with transport of peptidoglycan precursors across cytoplasmic membrane; used topically

differing in side chains influences spectrum and resistance properties

grouped by side chain modifications
natural penicillins are narrow-spectrum and susceptible to penicillinases

developed to counter resistance in S. aureus

resistant to some B-lactamases; later generations more effective against Gram-negatives and MRSA

Lincosamides, oxazolidinones, streptogramins, pleuromutilins, chloramphenicol, macrolides

aminoglycosides, tetracyclines, glycylcyclines

structurally similar to PABA; competitively inhibit enzyme in folate synthesis

inhibits later step in folate synthesis
little effect on human enzymes

co-trimoxazole (trimethoprim + sulfonamide) enhances efficacy

enzymes such as penicillinase and extended-spectrum B-lactamases degrade antibiotics

structural changes prevent antibiotic binding

changes in porin proteins block antibiotic entry

efflux pumps remove antibiotics from cell