pbh162A Wk#5+#6: Adaptive + Innate Immunity

Innate Immunity

Timing: rapid (m-h)

Specificity: Germline encoded

Cell 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

3 Roles of Professional Phagocytes

Kill pathogens - primarily neutrophils, macrophages

Initiate inflammatory response - macrophages, DC

Initiate and influence adaptive - macrophages, DC

How the lysosome kills pathogens

Phagocytes traffic phagocytosed and endocytosed particles to the lysosome

Lysosome

- Slightly acidic pH activates enzymes (hydrolases) that will digest the lysosome's contents and activates antimicrobial peptides

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

Macrophages and Neutrophil Similarities

- Degradation by phagocytosis & lysosome

- Oxidative burst

- Creates reactive oxygen species (ROS)

- NADPH oxidase induces oxidative burst

Macrophages and Neutrophils Differences

Neutrophils utilize *NETosis*, macrophages do not

- Production of nets of antimicrobial proteins & DNA that trap pathogens

Complement System Definition

Proteins in the blood that combat pathogens through

Complement Pathways

1) Alternative pathway

- C3b binding to microbial invaders

2) Lectin pathway

- Mannose-binding lectin (MBL) binding

3) Classical pathway

Antibodies binding

Complement System: 3 Functions

1) Leading to an inflammatory response

2) Lysis of foreign cells

3) Opsonization: pathogen is coated with proteins that leads it to get recognized by a phagocyte for phagocytosis and death

Key features of Inflammation

increased blood flow (vasodilation): redness, heat

increased vascular permeability: swelling

This allows for immune cells to reach to site of infection faster

TLRS: Toll Like Receptors

Receptors on host cell membranes (extracellular and within endosomes/lysosomes) that can recognize PAMPS

- Lead to the production of cytokines (soluble proteins that activate other cells, enhance immune response)

- Recognition of viral PAMPs → activates Type I interferon (IFN) → activates Natural Killer (NK) cells (induce self-death in infected cells)

- Inflammatory cytokine: TNF-alpha

- autoimmune disease: could be excess TNF-α)

Type I Interferon

Produced as an "alarm signal" by cells infected with a virus

- Warn neighbouring cells to enter an antiviral state

- harder for virus to spread

- Buys time for immune system to mount a stronger defense

Innate Response: Bacteria

Macrophages and neutrophils

Innate Response: Virus

NK cells

Innate Response: Worms

Macrophages, mast cells, eosinophils

"Weep and Sweep" Mucus production

Cytokines

proteins in blood that promote inflammation to activate other immune cells

PAMPS: Pathogen Associated Molecular Patterns

Invariant components of pathogens recognized by the innate immune system

Features of PAMPS

- Conserved among many pathogens

- Pathogen specific (not found on human cells)

- Difficult for the pathogen to alter

- Alert the immune system that a microbe is present

Recognition of viral PAMPS

Recognition of viral PAMPs → activates Type I interferon (IFN) → activates Natural Killer (NK) cells (induce self-death in infected cells)

Antimicrobial peptides

Short peptides produced in response to protein and sugar molecules on microbes

Inhibit cell wall synthesis

Form pores in the plasma membrane

Broad spectrum of activity

NADPH oxidase

multisubunit enzyme that produces superoxide radicals and contributes to the killing of internalized pathogens in neutrophils

Neutrophil NETs

Event where neutrophils commit suicide by releasing histones, myeloperoxidase, defensins, and elastase that entraps and kills microbes. This process is called Netosis

TNF-α

- Inflammatory cytokine: TNF-alpha

- autoimmune disease: could be excess TNF-α

Opsonization

Pathogen is coated with proteins that leads it to get recognized by a phagocyte for phagocytosis and death

Humoral Arm

antibody-mediated immunity (B cells)

Cellular Arm

T cell mediated immunity

T cells: Origin and Development

Originate: hematopoietic stems cells in bone marrow

Develop: in thymus

T Cell Activation

Each T-cell has a unique receptor with specificity for a particular peptide-antigen presented by a particular type of MHC

Inactive T-cells specific for an antigen circulate until they encounter their antigen/MHC presented by a dendritic cell (in lymph node), then they clonally expand

T Cell Functions

CD8 → kills infected cells

CD4 → Activate macrophages to produce cytokines

Required to produce antibodies

Aid in activation of immune effector cells

Help activate CD8 T cells

Activate B cells so plasma cells make antibodies

CD8 T Cells

Kills cells infected with virus (virus replicates in cytosol)

MHC I presents antigens from cytosol

CD4 T Cells

Activates macrophages and B-cells (important for extracellular pathogens)

MHC II presents antigens from endocytosis

MHC II only present on dendritic cells, B cells, and macrophages

Clonal expansion

Most naive T cells never encounter antigen that bind their receptor

The few that do are triggered to proliferate and travel to the site of infection

Same thing for B-cells except B- cells usually stay in the lymph node after activation

B Cells: Origin and Development

Originate: hematopoietic stems cells in bone marrow

Develop: in bone marrow

B cell Activation/differentiation

Activation: (recognizes different antigen epitopes)

Signal 1: Binds a specific antigen using BCR

Signal 2: T cell recognizes antigen presented by B cell and sends signal

*Both required for optimal B cell activation*

Differentiates: differentiate into plasma cells + makes antibodies (+ into memory cell)

Antigen Epitopes

B-cell receptor / antibodies recognize different antigen epitopes (i.e proteins, carbohydrates, nucleic acid, toxins etc)

Lymphocyte circulation

Naive lymphocytes recirculate in search of a threat (antigen that matches their receptor)—receptors are are incredibly diverse

Circulate between the blood and the lymphatic system

Antibody

Soluble version of a B-cell receptor (BCR)

BCR and antibodies are highly specific (lock and key model)

Antibody Functions (3)

1) Neutralize → bind to toxins/microbes, prevent them from initiating an infection

Opsonize → antibodies coat the pathogen to help phagocytes recognize pathogens for phagocytosis

Activate Complement →leads to lysis and phagocytosis of the pathogen + inflammatory response

Antibody Classes/Types

5 types: IgG, IgA, IgM, IgE, IgD

IgM = first antibody made

IgA = localized to mucosal surfaces

- Helps prevents bacteria from colonizing mucosal surfaces

Fc Region Antibody

The constant region (Fc) determines antibody class

- Also determines where the antibody circulates in body/function

Antigen

A protein that, when introduced in the blood, triggers the production of an antibody

MHC class I

Expressed on all nucleated cells in the body

Presents antigens from intracellular pathogens (in the cytosol) to CD8 T-cells

MHC class II

Expressed on dendritic cells, macrophages, and B-cells

Presents antigens from extracellular antigens (in the endosomal/lysosomal network) that have been phagocytized to CD4 T-cells

VDJ recombination

Variable - diversity - joining rearrangement

Process where T and B cells mix and match pieces of DNA called variable (V),

diversity (D), and joining (J) segments to build unique receptors

Allows T and B cells to recognize millions of different antigens

Somatic Hypermutation (SHM)

A process that occurs in activated B cells where random point mutations are

introduced in the variable region of the BCR at a very high rate to improve

antibody affinity for an antigen

Primary infection

= first exposure

The adaptive immune response takes 5-7 days to initiate during a primary infection. The T and B cells against antigens of a pathogen must be activated and expanded (proliferate) in spleen or lymph node and then spread throughout body to fight the pathogen

Secondary infection

= any subsequent exposure

The second time you are exposed to a pathogen, the adaptive immune response happens more quickly (1-3 days) because of adaptive immune memory cells. The more rapid immune response in a secondary exposure is because you have memory T cells and memory B cells which can be activated more quickly when they recognize the pathogen.

Organs of the immune system

bone marrow, thymus gland, spleen, lymph nodes, tonsils, appendix