Polymorphonuclear Neutrophils start life in the bone marrow and constantly circulate in the blood stream until they are called to action. They are the first to act (30min to response) and increase in number when infection is present.

Easy to identify due to the two lobes.

Most abundant in puss

Lysosomes attach to cell wall to destroy pathogen

Macrophages

Type of mononuclear phagocytic cells

Naming depend on the location in inhabits (know the different macrophages)

Kupffer Cell (in the liver)

Function is to remove old RBC through phagocytosis and present antigens to T-Cells

(Slow to action)

Cells can be stationary or can travel

Dendritic Cells

Originate in bone marrow

Function is similar to macrophages by performing phagocytosis and present antigens to T-cells

Long, membranous extension

Reside within tissues waiting for exposure to foreign pathogens

How phagocytic cells detect pathogens

They have Pattern Recognition Receptors (PRR) on their surface

PRRs detect the Pathogen-Associated Molecular Patterns (PAMPs) on the microorganism

Once PRR binds to a PAMP the phagocytic cells activate

Phagocytic cell secretes cytokines (calls for backup)

The four PRR are

TLR (Toll-like receptor) (remember this one)

CLR (C-type lectin receptor), NLR (NOD-like receptor), RLR (RIG-I-like Receptor)

Inflammation (Natural Immunity)

Purpose is to maintain stability and restore function after an injury

Mobilize and attract immune component to site of injury

Repair tissue damage and clear away harmful substances

Destroy microbes and block further invasion

What are the signs/symptoms of inflammation? Sign can be seen, Symptom is felt

Redness, Heat, pain, swelling, loss of function

The 4 stages of inflammation are: Vascular permeability, phagocytic migration of neutrophils, phagocytic migration of macrophages, cellular proliferation and repair

Vascular Permeability

Endothelial cells smooth muscle contract allowing cells to separate creating gaps

Fluids and PMNs can move through gaps into tissue

Prostaglandin and Histamine are released by mast cells

causes capillaries to dilate resulting in large pores and release of phagocytes and clotting factors to site

Blood vessels dilation increases blood and fluid volume accumulation (transudation) to site producing signs of inflammation- redness and heat

Increased vessel permeability causes water to leak out of blood vessels which produces tissue swelling and edema pressure triggers pain receptors

Fibrinogen is converted to fibrin

Neutrophils

Chemotaxis (messenger) attracts neutrophils to the site

Endothelial cells become sticky; PMN adhere resulting in the formation of pus and allows cell to stay in the area

Arrive quickly (30-60 min) and stays for 24-48h depending amount of chemotactic factors (C5a attracts neutrophils to site)

Neutrophils are major type of cell in acute inflammation

Macrophages (clean up crew)

Macrophages are stimulated to produce IL-1 (interleukin 1)

Direct stimulation: phagocytosis of debris

Indirect stimulation: through products of phagocytosis and degranulation

IL-1 is a cytokine (chemical messenger) which attracts other monocytes/macrophages and lymphocytes

Also causes fever and pain

Macrophages clean up all the debris and dead neutrophils

Arrives in 4h and peaks at 16-24h

Cellular Proliferation and Repair

Fibroblast proliferation occurs

Produces acidic mucopolysaccharides that neutralize some chemical mediators

Begins around 18h and peaks 48-72h later

Tissue repair occurs and function is restored

Occasionally, a granuloma is formed

Contains/Quarantines infection it cannot get rid off

Phagocytosis Phase (MEMORIZE)

Chemotaxis - chemicals like Cytokines and C5a call phagocytic cell to the site

Adherence - chemotactic factor cause phagocytic cell to adhere to endothelial cell

Locomotion - Phagocytic cells send out pseudopods to locomot toward target

Diapedesis - Phagocytic cells insert pseudopods between endothelial cells to escape the blood vessel and into surrounding

Ingestion - Cell walls of the phagocyte surround and encapsulate the target. Phagosome (vesicles) form around target, Opsonin a serum protein binds to target to make it susceptible to phagocytosis (IgG, C3b)

Degranulation - intracellular granules (PMN) fuse with phagosomes. Granule contents (enzymes) are released into the phagosome or outside the phagosome. Contain myeloperoxidase which when mixed with hydrogen peroxide kills microorganism

Digestion - target is exposed to the lytic action of the enzymes and is digested

Excretion - release of debris outside of the cell

Complement

Part of innate immunity when activated by the alternative or lectin pathways

Composed of groups of protein that work in a cascade fashion to destroy microorganism

The 3 pathways are

Classical

Alternative

Lectin

Natural Killer Cells

5% of lymphocytes; originate in bone marrow

1st line of defense against virally infected cells, tumor cells and cell infected with intracellular pathogens

Function

Release cytolysin (perforin) which lyse virally infected cells/tumor cells by direct cell to cell contact (cytolysis)

No prior exposure to target required

Detects whether the target has MHC 1 proteins if they don't then they will attack said cells

REMEMBER 6 most important acute phase plasma proteins, CRP next most ordered test

Acute Phase Plasma Proteins

After an injury, infection or trauma the synthesis of plasma proteins increases. This is a non-specific indicator of an inflammatory process.This is generally produced within 12-24 h in response to increased cytokines. Made in the liver. These proteins are believed to play a major role in wound healing.

The Following are the six acute phase plasma proteins

C-Reactive Protein (CRP)

Fastest responding, most sensitive indicator of acute inflammation

Increases dramatically during bacterial infections or trauma

Promote phagocytosis by acting as an opsonin

Clinical Application: monitoring infection, autoimmune disorders or healing after myocardial infarction

Haptoglobin

Binds and removes free hemoglobin

Protects kidney from damage

Prevents iron loss by urinary excretion

Increases 2-10x in concentration during infection

Fibrinogen

Converts to fibrin (clot) to seal off wound

Clot traps pathogen and acts as barrier against further invasion

Involved in coagulation pathway

Alpha-1 Antitrypsin

Inhibits proteases released from leukocytes, especially elastase, therefore limiting tissue damage

“Mop-up” or Counteract neutrophil invasion effects during inflammatory response

Concentration in the bloodstream increases when stimulated by inflammation

Ceruloplasmin

A protein in blood that transports copper in blood

Required for collagen formation

Increases due to inflammation

Serum Amyloid A

Causes adhesion and chemotaxis of phagocytes and lymphocytes

Binds lysosomal enzymes released during inflammation

Can increase almost 1000X

What is Adaptive Immunity

3rd line of defense aka specific immunity

Specific: recognize,remember and responds to specific stimulus

Lag Period: it takes time to detect response to first exposure (5-7 days)

Time decreases with each exposure

Key player: lymphocyte

After initial infection, the body retains a memory of the invader

Memory allows for a more rapid response

Lymphocyte function may be cell-mediated (T-cell) or humoral (B-cell)

Works together with macrophages

Obstination the appeal f

Phase 1: Development of the Lymphocyte System

All lymphocyte develop from same basic stem cell type in the bone marrow and develops into 2 distinct types within the Primary Lymphoid organs

B Lymphocytes (B-Cells) develop in bone marrow

T Lymphocytes (T Cells) develop in thymus

Lymphocytes mature and migrate via the blood to the secondary lymphoid organs

Secondary Lymphoid Organs are;

Lymph Nodes, Spleen, Tonsils, Appendix, Mucosal Associated Lymphoid Tissues (MALT)

B Cells (Humoral Immune Response)

Mature in bone marrow

5-15% of lymphocytes

Differentiate into plasma cells and memory B cells

Secrete antibodies (protein that bind to a foreign antigen)

Responsible for humoral immunity

T Cells (cellular Immune Response)

Mature in the Thymus

Differentiate into Helper T Cells (TH) and Cytotoxic- T Cells (TC)

80% of lymphocytes

Attack target cells and secrete cytokines

Cytokines: small protein that acts as a chemical messenger

Cell-mediated immunity

Surface Markers

Proteins on the cell surface used to differentiate cells

Consists of glycoprotein with additional carbohydrate components

Gives cells identify and specificity

Functions

Perceive and attach to antigens

Self recognition

Communication to other cells by chemical messengers

Aid in cellular maturation

Each protein surface marker is classified by a Cluster of Differentiation (CD) and a number

Each cell may display several markers:

All T-cells carry CD2+ and CD3+

All B-cells carry CD19+ and CD20+

Major Histocompatibility Complex (MHC)

A set of genes that code for surface marker

Also called human leukocyte antigen(HLA)

MHC are proteins whose main function is antigen presentation

A B-Cell will be stimulated to attack right away

A T-Cell will analyze the antigen before deciding to attack

MHC are found on all nucleated cells of the body (basically all WBC have it) specifically Class 1

Genes that code for MHC are located on the 6th chromosome and form 3 clusters

Class I, Class II, Class III

Everyone has DP, DQ, DR but they will be in different configuration for each person

MHC Class I (inside the cell) endogenous

Genes found at 3 loci on chromosome 6: HLA-A, HLA-B, HLA-C

Human leukocytes Organs (HLA)

Glycoproteins found on all nucleated cells

Assists in elimination of transplanted cells, virus infected cells and tumor cells

Cytotoxic T-cells (CD8+) recognize antigens presented by Class 1

MHC CLass II (outside the cell) Exogenous

Genes found at 3 different loci on chromosome 6: HLA-DR, HLA-DQ, HLA-DP

Found primarily on Antigen Presenting Cells(APC) (macrophages, B-cells, Epithelial Cells and dendritic cells) REMEMBER the APC

Help immune cells to communicate with one another

Helper T-cells (CD4+) recognize antigens present by Class II

MHC Class III (just know they exist for test purpose)

Genes found between class 1 and 2 loci on chromosome 6 which code for C2,C4, Factor B, cytokines

Also, encode various secreted proteins that have immune functions involved in complement system and inflammation

Not expressed on cell surface

The main function of class 1 and class 2 MHC molecules is antigen presentation. The MHC molecules combine with degraded virus proteins and roam around and to interact with roaming T-cells. Both Helper T cell and Cytotoxic T cell are MHC restricted. A diverse MHC allows for better defense against viruses

Phase 2: Entrance and Processing of Antigens

Cells work in harmony to screen, trap and eliminate foreign invaders

1st Responder: Natural Killer Cells and macrophages (innate immunity)

Macrophages initiate adaptive immunity by antigen presentation via MHC and release of cytokines (IL1 and IL6)

IL1 is responsible for the onset of fever associated with infection, also call CD4 cells

IL6 activate production of acute phase plasma protein from liver, proliferation of T and B cells and enhances antibody production

B and T cells must recognize that foreign antigen is present in order for adaptive immune response to occur

B cells can recognize antigen in its natural form

T cells need antigen presented through MCH

Antigen Presenting Cells (APC): process and present exogenous (bacterial) antigens

macrophages , dendritic cells, B lymphocytes and epithelial cells

Antigen Receptors

B cells have B Cell Receptors (BCR) and T cells have T Cell Receptors (TCR)

Determine specificity of each cells

Present in thousands of identical copies at the cell surface

Made before encountering an antigen

Have unique binding sites

Phase 3: Activation of Lymphocytes and Clonal Expansion

When TH (Helper T cells) attach to an antigen they are stimulated to secrete cytokines

Cytokines initiate the humoral (B-cell) and cellular (T-cell) adaptive immune responses

Cytokines recruit and activate inflammatory WBC

B and T cells will multiply and mature producing a group of genetically identical cells called clones

Some develop into memory cells which recognize previously encountered antigens and can provide long-lasting immunity

Phase 3: Activation of Lymphocytes and Clonal Expansion

Clonal Selection Theory

One uniquely specific receptor must exit for each different antigen in the immune system

Lymphocyte have a pool of 500 genes that are shuffled into unique combination for each type of receptor

Each genetically distinct group of lymphocytes that produces the same specificity is called a clone

Each lymphocyte expresses only a single specificity

Specificity is pre-programmed during maturation/ differentiation

Tolerance to self

Lymphocytes that attacks self antigens are eliminated or suppressed

Phase 4: Humoral Immunity

The immunity of a child following chicken pox is ACTIVE immunity and NATURALLY acquired.

The immunity of a child following a pertussis vaccine is ACTIVE immunity and ARTIFICIALLY acquired

The immunity from an injection of tetanus immune globulin is PASSIVE immunity and ARTIFICIALLY acquired

The immunity of a newborn to infectious microbes is PASSIVE immunity and NATURALLY acquired.

Phase 4: Humoral Immunity

Initiation involves macrophages, helper T cells and B cells

Immunoglobulin receptors on the B cell surface react specifically with antigens

Immunoglobulin receptors on B cells in peripheral blood are IgD, IgM and receptors for complement

Immunoglobulin receptor on B cells in MALT (mucosal associated lymphoid tissue) are primarily IgA

Once a B cell is bound to the antigen it is now committed to produce that specific antigen as a result it is immunologically committed.

Helper T cells release IL4 (B cell growth factor) and IL2 which stimulate differentiation of B cells into plasma cells clones and memory cells

Plasma cells secrete antibodies into tissue fluids and die but antigen will now be floating in body fluids

Ab attach to Ag → Ag is marked for destruction/neutralization → complement may be activated

The antigens circulate freely in the body humors (tissue fluids, lymph, blood) hence humoral immunity

Memory cell produced by activated B cells retain memory of specific antigen

When the antigen is reintroduced the Memory B cell turns into plasma cells to produce antibodies

Antibody-mediated immunity works mainly against

Antigens present in body fluids

Extracellular pathogens, which include any virus, bacteria, or fungi that are outside cells

Antibodies are the effector of humoral immunity

Effector cell has the ability to remove antigens from body without differentiation

Phase 5 Cellular Immunity

Once cell is infected intracellularly the humoral response can no longer detect it

Direct involvement of T lymphocytes are required

Antibody plays a subordinate role now

Characterized by direct cell to cell interaction or the effects of chemical mediators (cytokines)

Note T Cell DO NOT produce antibodies

T cells are divided into cytotoxic T cells and helper T cells

Cytotoxic T cells destroy cells infected with intracellular pathogen

Kills cells by releasing cytotoxic granules

Recognizes cells through interaction of TCR with antigens presented on MHC Class I

Helper T cells do not kill directly but release cytokines IL2 and IL4

IL2 → T cell growth factor; growth and differentiation of T and B cells and enhances lytic activity of NK cells

IL4 → B cell growth factor

The main components of cellular immunity are:

Effector cells

Kills target by direct cell contact eg cytotoxic cells

Cytokines

Have direct cytolytic or enhanced activity of effector cells (NK, macrophage)

Memory Cells

Immediate response to any future exposure to the specific antigen; persist after suppression of immune response

In cell-mediated immune response (cellular immunity) antigen presenting cells (APC) present antigen to T cell during induction phase and become activated in response to cytokines (IL1) during effector phase.

Cellular Immunity is particularly effective against

Intracellular pathogens (virus, bacteria, fungi)

Some cancer cells

Foreign tissue transplants

Always involves cell attacking cells

LO1.4

Cytokine: chemical messenger that helps regulate immunity by influencing the innate and adaptive immune response. Cytokines have the ability to instruct the cell reviewing the signal to proliferate, differentiate, secrete additional cytokines, migrate, or die. After release they are quickly broken down by extracellular environments which help limit their influence. Note they induce inflammatory response therefore excessive contact is bad for the body.

Cytokines are pleiotropic and redundant

Pleiotropy activity allows a single cytokine to have many different action

Eg IL II (excite T (itself) and B cells)

Redundant refers to different cytokine influencing the same cell

Two principal producers of cytokines are helper T cells and macrophages

All cytokines have a matching cell surface receptor and attachment with this receptor results in cascades of signals inside the cell which change the function

Cytokine activities are classified according to the distance traveled between producing cell and its target

Autocrine signaling

Refers to cytokine which bind to receptors on the same cell which produced it

Paracrine signaling

Refers to cytokines which act on the tissue region surrounding the cellular source

Endocrine signaling

Refers to cytokines which diffuse into the bloodstream and influence cells far from their source

Autocrine and Paracrine are considered localized activity

Types of Cytokines are Interleukins, Tumor Necrosis Factor (TNF), Interferon, Chemokines

Interleukins

Produced by WBC to communicate with each other

There are currently 37 interleukins. REMEMBER Chart

Know that IL-5 is activator of eosinophils (for allergic reactions)

Tumor Necrosis Factor (TNF)

Kills tumor cells and promotes inflammation

Overproduction can lead to autoimmune diseases

The two main type are TNF-α and TNF-β REMEMBER TABLE

Interferon REMEMBER TABLE

Released due to presence of viruses

Can interfere with viral replication

When infected with a virus cells synthesize interferon which bind to uninfected neighbouring cells to create zone around viral infection to restrict its spread

Chemokines

Influences motility and migration of target cells

Cells follow a signal of increasing chemokine concentration towards the source

Immune cells are strongly influence by chemokines which attract the cells to areas of infection and inflammation

EG. C5a which calls the neutrophils to the site of infections

REVIEW

Innate Immunity: Non-specific attack

Time to attack

Cells Involved

Internal Barriers

External Barriers

Adaptive Immunity: Specific attack