pbh 162a Wk#5 - Innate Immunity

Challenges facing the immune system

- microbes replicate quickly

- microbes evolve quickly

- must react to every pathogen but not react to self

- must clear infected tissues without damaging self

Innate Immunity

Timing: rapid (m-h)

Specificity: Germline encoded

Cells involved: Most if not all cells

Functions: Hold pathogens in check, stimulate adaptive responses

Adaptive Immunity

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

Cells of immune system to know

common myeloid progenitor

- neutrophil

- monocyte (macrophage or dendritic cell)

from common lymphoid progenitor

-natural killer (NK) cell

need to know anatomy of immune system

bone barrow

thymus

spleen

lymph nodes

Cells that arise from Myeloid progenitor

Neutrophil: Phagocytosis and killing of microorganisms, oxidative burst (kill microbes by producing ROS), kill pathogens with extruded "nets" composed of DNA and protein

Monocyte:

Macrophage: Phagocytosis and killing of microsomes, traffic phagocytosed and endocytosed particles to the lysosome

Dendritic cells: Activation of T cells and initiation of adaptive immune response

Cells that arise from Lymphoid progenitor

Natural killer (NK(cell)

Anatomy of immune system: Bone marrow

site of hematopoiesis and B cell development

Anatomy of immune system: Thymus

site of T cell development

Anatomy of immune system: Spleen

where T cells and B cells are activated when infection is in the blood; also filters blood and removed damaged RBCs

Anatomy of immune system: Lymph nodes

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

Barriers to infection (3)

1) Mechanical:Skin, tight junctions, flow of fluid, flow of mucus (polysaccharide chains - hard to swim)

2) Chemical: acidity, enzymes

3) Microbiological: normal (commensal) flora

Responses caused by actions of innate immune system

bacterial pathogens: redness, swelling, pain, heat: inflammation

infleunza: fever, muscle aches: cytokines and prostaglandins

parasite in gut mucosa: abdominal cramping: smooth muscle contractions for parasite expulsion

Professional Phagocytes

the first cells to encounter pathogens

- Dendritic cells, macrophages, neutrophils

3 Roles of Professional Phagocytes

Kill pathogens (macrophages -> lysosomes, make holes in membrane)

Initiate inflammatory response

Initiate and influence adaptive immune response

Characteristics of Lysosomes

- Acidity activates hydrolases

- Proteases (digest cell wall proteins), Glycosidases (cleave cell wall sugars), Lipases (cleave cell wall lipids)

- Metabolite transporters: pump essential metals and other nutrients out of lysosome

- Antimicrobial peptides: found in lysosome and active at acidic pH, make holes in pathogen membranes

Oxidative burst

A large increase in the oxygen consumption of immune cells during phagocytosis of pathogens as the immune cells produce oxygen radicals to kill the pathogen.

- macrophages and neutrophils

macrophages

Found within the lymph nodes, they are phagocytes that destroy bacteria, cancer cells, and other foreign matter in the lymphatic stream.

Neutrophils

Most abundant white blood cell., The most abundant type of white blood cell. Phagocytic and tend to self-destruct as they destroy foreign invaders, limiting their life span to a few days.

- kills pathogens with extruded "nets" composed of DNA and protein

Bacterial Capsule

A way bacteria avoids phagocytosis (eaten by neutrophils)

Thick layer of polysaccharides

Complement System

A system of proteins in the blood that combat pathogens

Protein labels microbial invaders

Poke holes, decorate membranes, inflammatory response: signals for phagocytosis

Membrane attack complex

Regulation prevents host cells from activating complement system

What prevents host cells from activating the complement system

regulation

Complement pathways (3)

1) Alternative pathway

C3b binding to microbial invaders

2) Lectin pathway

Mannose-binding lectin (MBL) binding

3) Classical pathway

Antibodies binding

Inflammation

Increased blood flow: redness, heat

Increased vascular permeability: swelling

Promotes the entry of immune cells into infected tissues; Changes make it easier for plasma proteins and cells to pass out of the blood and into site of infection

2 strategies for sensing pathogens

damage model

self-nonself discrimination

damage model

sense damage or alterations to host physiology induced by pathogens

Self-Nonself Discrimination model

sense specific features on pathogens that are not present normally

Pathogen-associated molecular patterns (PAMPs)

Invariant components of pathogens recognized by the innate immune system

- Not found on human cells

- Conserved among pathogens

- Difficult for pathogen to alter

- Alert immune system

Toll-like receptors (TLRs)

Survey the extracellular space and endosomes/lysosomes

Cytokines

Soluble proteins that diffuse through blood and activate other cells

- Sensing PAMPs result in production of inflammatory cytokines

Canonical inflammatory cytokine: Tumor necrosis factor alpha (TNF-α)

Inflammatory Cytokines: Immune Response

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

Blood vessels become "sticky" for specific immune cells

Vasodilation increases blood flow to inflamed site

Blood vessels become leaky and plasma enters tissue (swelling)

Type I interferons

IFN-alpha and IFN-beta

Type I interferon Response

- recognition of viral PAMPs activates the interferon response

- transcriptional targets of Type I IFNs include intrinsic antiviral factors

1) induce resistance to viral replication in all cells

2) increase expression of ligands for receptors on NK cells

3) activate NK cells to kill virus-infected cells

innate response for multicellular pathogens (worms)

Recognition of components from worms (ex. chitin) initiate effector functions

- "weep and sweep": increased mucus production, smooth muscle contraction

macrophages:

- histamine

secrete chitinases and proteases

eosinophils

- degranulate toxic granules onto surface of the worm