Principles of Immunology Prince Agri-Products & Phibro Animal

HealthTraining Seminar – Atlanta, Georgia

July 17-18, 2006

Immunity: security against a particular disease; nonsusceptibility to the invasive or pathogenic effects of foreign microorganisms or the toxic effect of antigenic substances.

Innate Immune System: consists of physical, chemical, enzymatic barriers and activity of phagocytic cells (neutrophils) which are associated w/ a signaling system

Adaptive (antibody-mediated) Immune System: consists of two components Humoral (antibody production

in response to antigen, medicated by B-lymphocytes)

Cell-mediated (production of specific killer cells in response to an antigen, mediated by T-lymphocytes)

Innate Immune Response -Neutrophils, first line of defense

Phagocytes: first to arrive at the site of infection

Function to contain infections, provide time for adaptive system to develop

200 billion in adult cow, 50% in circulation, remainder in bone or attached to vessel walls

Life span of 1-2 days Contain a protein

component: L-Selectin, index of innate immunity

Neutrophil recognition of pathogen

Neutrophil Pathogen

Pathogen-associated molecular Patterns: PAMPs)

Receptors on surfaceof neutrophil

Phagocytosis

Bacterium

Recognition

Inactive neutrophils Activated neutrophils with NETs

Source: Brinkmann et al., 2004

+ interleukin-8 (IL-8)

Production of NETS by neutrophils

Association of neutrophil “NETs” with bacteria

S. aureus (gram +) Salmonella (gram -) Shigella (gram -)

Neutrophils: a first line of defense

- tethering via L-selectin (A)

-shedding L-selectin (B)

- Interleukin-1- pro-inflammatory (C)

-migration toward “signals” (D)

-phagocytosis (F)

-pathogensSource: Burton and Erskine, 2003

Example of relationship between stress and immunity

Cortisol - Adrenal hormone • released in response to a

stressful event• needed by uterus at time

of calving• aids in intiating milk

secretion by the mammary gland

• elevated blood Cortisolcause neutrophils to lose their ability to migrate from blood into tissue by interfering with L-selectin synthesis

Source: Burton and Erskine, 2003

Cortisol Response Relative to Parturition

TRANSITION COW TRIAL - CORTISOL

0

2

4

6

8

10

12

14

16

-7 -6 -5 -4 -3 -2 -1 0 1 7 14

Co

rtis

ol

(ug

/dL

)

Hospital Cows

All Cows

Puntenney & French 2003

Effect of stress on neutrophils

Normal Stress

Proliferation and invasionof pathogens

L-selectin and interleukin

Take home on neutrophils First line of defense against

bacteria and molds L-selectin (tethering/rolling/

“surveillance”) (A/B) IL-8 (signal from infection

site) (D) IL-1β (access infection site/

“diapedesis”) (C) Free-flowing blood neutrophil

(E) Killing mechanisms

(digestion and NETs) (F)

Pluripotent hematopoeitic stem cell(Self-renewing, white blood cell producing)

Common lymphoid Progenitor

(lymph tissue)

Common myeloid Progenitor

(bone marrow)

B cells T cells NK cells White blood Red blood Megakaryocytes cells cells

-Adaptive

-Innate

Monocyte Neutrophil Eosinophil Basophil Dendritic cell

MacrophageJaneway et al., 2005

Platelets

Phases of an infection 1. Entry of pathogen 2. encounter a macrophage/dendritic cell 3. macrophage recruits neutrophils via IL-8

4. macrophage (phagocytic cell) and dendritic cells (antigen-presenting cells) migrate to lymph tissue where they encounter naïve B and T lymphocyte

5. B and T lymphocytes clonally expand and differentiate and make antibodies

Inna

teA

cqui

red

Linkage of innate and adaptive immunity

1. Activated macrophages and dendritic cells with ingested pathogen present antigen to T-lymphocytes

2. Chemokines, secreted by macrophages, enhance tissue permeability and influx of T-lymphocytes into an infection site (IL-1B)

3. Macrophages and neutrophils produce activating molecules (e.g., IL-1β and IL-6)

Activated neutrophil

B and T lymphocytes

IL-1β

+

Janeway et al., 2005

4. Activated T-cells, in turn, activate macrophages

Review

Terms Pathogen: disease-causing infectious agent Antigen: any molecule that stimulates the immune

response (pathogen proteins or carbohydrates) Phagocytes: cells attracted to site of infection to destroy

pathogens (not antigen-specific, part of innate system) Neutrophils Eosinophils Monocytes/macrophages Natural Killer Cells (virus-infected and cancer cells)

Review

Terms Leukocytes: white blood cells Adaptive Immunity: response to repeat infection

Synthesis of antibody to bind antigen and promote elimination

T cell killing of virus-infected cells T cell activation of macrophages to destroy

phagocytosed pathogens that are resistant to destruction

Review Terms

Innate Immunity: defense system that can recognize “generic danger” and responds by walling off and engulfing foreign organisms Barriers - skin, mucous membranes Mechanical – cilia, blinking, sneezing, coughing, vomiting Chemical – HCl in stomach, digestive enzymes in tears,

mucus Phagocytes – Neutrophils, eosinophils, macrophages, M

cells, monocytes Natural Killer Cells – kill virus/cancer cells

Review Terms

Apoptosis: programmed cell death Macrophages: innate immune cell, binds pathogens,

produce cytokines to attract other phagocytic cells and make blood vessels leaky, may present antigen to stimulate T cell activation (adaptive)

Dendritic cells: innate immune cell, may be phagocytic and may present antigen to simulate T cell activation (adaptive immune system)

Lymphocytes: antigen-specific white blood cells responsible for adaptive immunity

Review Terms

Natural Killer (NK) Cells: large lymphocytes that lack specific antigen receptors but respond to altered tissue typing in virus-infected and cancer cells

Cytokines: small proteins produced by macrophages in response to bacterial antigens; signal other white blood cells; act by binding to specific membrane receptors to signal the cell to alter its behavior (gene expression) Lymphokine (lymphocytes), monokine (monocytes),

chemokine (chemotactic activity), interleukin (made by one leukocyte and acting on others)

Review Terms

Antibody: antigen receptor on B cells and is also secreted to bind and remove antigen from the body

Immunoglobulins: antibodies that are antigen-binding proteins (IgG, IgM, IgD, IgA, IgE)

Interleukin-1: cytokines produced by macrophages which activate nearby vascular endothelium to promote leukocyte movement into the tissue (extravasation)

Interlukin – 8: chemokines which recruit leukocytes and attract them to site of infection

L-selectin: neutrophil-adhesion molecule that initiates binding between leukocytes and endothelium