Mechanisms of Immunity

Part One

Types of Immunity

CLS 420Clinical Immunology &Molecular Diagnostics

Objectives

1. Differentiate innate (natural) immunity and acquired (adaptive) immunity.

2. Describe the significance of the following factors included in the first line of defense:

a. Skin and mucous membranes

b. Age

c. Metabolism

d. Environment

e. Normal flora

f. Concomitant disease

Objectives

3. Compare specific versus non-specific immunity as it relates to:a. Phagocytosisb. Inflammationc. Cellular immunityd. Humoral immunitye. Memoryf. Opsonization

4. Differentiate humoral and cellular immunity.5. Compare active and passive immunity, including

examples of each.

Immunity

The state of protection from infectious disease.

Immunity

• Protection against:– Pathogens– Toxins – Tumors

• Recognition of foreign vs. self

• Two branches:– Innate– Adaptive (acquired)

Immune function is influenced by:

• Age • Nutritional status• Stress• Fatigue

What happens when foreign matter enters the body?

Innate ImmunityThe First Line Of Defense

Innate Immunity

• Available at birth (innate or natural).

• Generalized, nonspecific reaction.

• Response to invader is rapid.

• No prior exposure to foreign substance required.

• Response doesn’t change with further exposure.

Barriers

• Skin

• Tears, saliva, secretions

• Mucus

• Cough Reflex

Environment

• pH

• Normal flora

• Temperature

Pathogen Recognition

• Toll-like receptors

• Complement – Alternative Pathway

– Mannose Binding Lectin Pathway

Chemicals

• Chemicals include:– Complement– Histamine– Cytokines– Acute Phase Reactants– Kinins

• Destroy pathogens • Expand the immune response• Neutralize the effects of other chemicals

Inflammation

• Capillaries dilate and blood accumulates in the affected area.– Redness– Increased temperature

• Fluid accumulates in tissue (edema).

Inflammation

• Chemokines attract phagocytes into affected area.

• Phagocytes migrate into the tissue (extravasation) and destroy invading pathogens.

• Other chemicals are released that cause:– Fever– Increase WBC adhesion to vascular endothelium– Stimulate clotting/fibrinolysis cascades

Inflammation

• Pus formation

• Macrophages clean up debris.

• Release chemicals that enhance the inflammatory response.

• Growth factors rebuild tissue and blood vessels.

Inflammation – Acute vs. Chronic

• Well defined onset and resolution

• Mediated by macrophages– Fever– Increase WBC production– Acute phase reactants

released from liver

• Phagocytosis by neutrophils

• Ongoing inflammatory process

• Inability to clear pathogen• Less defined onset &

resolution• Macrophages and

lymphocytes involved• Loss of tissue function

– Granuloma formation– Scar tissue

PhagocytosisYUM

Phagocytes

• Dendritic cells

• Neutrophils

• Macrophages

• Monocytes

• Eosinophils

“Contact”

• Receptors on phagocyte make contact with foreign material.– May be enhanced

by opsonins• CRP• Complement• Antibodies

“Ingestion/Digestion”

• Phagocyte engulfs foreign material to form phagosome.

• Phagosome merges with granules in cytoplasm.

• Granules contain chemicals that digest foreign material.

Chemicals

• Respiratory burst – membrane bound oxidase converts oxygen to superoxide anion.

• Nitric oxide synthetase- oxides arginine releasing nitric oxide.

• Lysozyme- antimicrobial enzyme

• Defensins – cysteine rich peptides that attack bacterial cell membranes.

Exocytosis

• Waste material is expelled from phagocyte (exocytosis).

Cells Alive!

• Please go to http://www.cellsalive.com/ouch1.htm

• View “Anatomy of a Splinter”.

How can long-lasting protection be developed?

Acquired Immunity

a.k.a.

Adaptive Immunity

Characteristics• Forms only after exposure to foreign

substance.• Response is specific to the foreign

stimulus.• Recognizes self vs. non-self.• Displays memory.• 2 forms:

– Cell mediated– Humoral

Cell Mediated Immunity

• Controlled by T lymphocytes.– Influence other parts of the immune system

(including the humoral response) through the release of cytokines.

• Responsible for such processes as delayed hypersensitivity, transplant immunity, and tumor rejection.

Cell Mediated Process

• Foreign matter is broken down into small peptides.

• Peptides combine with the Major Histocompatibility Complex (MCH) molecules on the cell membrane.

Major Histocompatibility Complex

• Found on the membrane of every nucleated cell.

• Three classes:– I (A, B, C loci)– II (DR, DQ, DP loci)– III (complement , Tumor Necrosis Factor

[TNF])

• MHC has antigen binding groove which carries foreign peptides.

Major Histocompatibility Complex

Class I

Class II

Cell Mediated Process

• Class I MHC antigens bind peptides that are produced within the cell

• Class II MHC molecules are found on Antigen Presenting Cells (APC)– Monocytes, macrophages, dendritic cells, and

B lymphocytes

• Class II molecules bind foreign peptides that have been processed by the APC.

Recognition

• T lymphocytes possess receptors (TCR) that recognize foreign antigen when the antigen is bound to MHC antigen.

Signaling

• TCR is coupled to CD3.

• CD3 signals the interior of the T cell that antigen is present.

• T cell produces cytokines in response (effector cell).

• Some T cells mature into memory T cells.

T Lymphocyte Subsets

• T helper cells (TH)– Make up 2/3’s of the T cell population– CD4 positive– React with MHC class II proteins– Assist in initiating cytotoxic response– Stimulate humoral response

• T cytotoxic cells (TC)– CD8 positive– React with MHC class I proteins

Cytotoxic Response

• Tc cell recognizes foreign peptides associated with Class I MHC antigen.

• Cytotoxic T Lymphocyte (CTL) binds to target cell

• Release perforin and granzymes, leading to apoptosis of target cell.

• Cytokines TNF and interferon released to prevent spread of virus.– May injure healthy tissue.

Cells Alive!

• Please go to http://www.cellsalive.com/ctl.htm

• View “The Cytotoxic T Lymphocyte”.

Humoral Immunity

• Major cell involved is the B lymphocyte.– Develops into plasma cells and memory cells.

• Influenced by T helper cells.

Humoral Response

• Foreign antigen is introduced to host.

• APCs process antigen into peptide fragments, then present peptide to the TH lymphocyte.

• The TH recognizes the foreign antigen through its TCR and CD4.

Humoral Response

• The B cell has also recognized the foreign antigen via the B cell receptor (BCR), and processed the foreign antigen.

• Foreign peptide is then expressed on the surface MHC class II molecules.

Y

Humoral Response

• TH lymphocyte recognizes that the peptide seen by its TCR and the peptide presented by the B cell are the same.

• TH cell releases cytokines to stimulate B cell.

B Lymphocytes

• B cells divide into plasma cells or memory B cells.

• Plasma cells produce and secrete antibody.– The antibody produced is

specific for one epitope!

• Memory cells recall previous encounter with foreign antigen. – Respond quickly when

antigen is encountered again.

T Helper Lymphocytes

• Signals from the TH cell influence the class of immunoglobulin produced by the B cell and the ability to switch classes.– Interleukins– Transforming growth factor

Alternate Humoral Response

• B cells may be influenced to produce antibody independent of T cells.– Rapid response– Few memory cells – No switch to other classes of immunoglobulin– Additional nonspecific antibody may be

produced (autoantibody)

Cells Alive!

• Please go to http://www.cellsalive.com/antibody.htm

• View “Making Antibodies”.

Active vs. Passive Immunity

• In active immunity, the host produces an immune response to foreign matter following exposure.

• Long lasting.• Displays memory. • Examples include:

– Vaccinations– Immunity following infection

• In passive immunity, the host acquires antibody that was produced in another being.

• Short term protection.• No memory.• Examples include:

– Maternal transfer to fetus– Immune Serum Globulin

used to treat hypogammaglobulinemia

STRETCH

Take a break before moving on to Part II