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ELIAS BONYA

B-TECH

2014

NORMAL IMMUNE RESPONSE

OBJECTIVES

• Discuss history of Immunology

• Explain what an antibody is

• Differentiate between internal and external defense systems

• Distinguish natural from acquired immunity

• Discuss the role of acute phase reactants in innate or natural

immune response

• Discuss the types of white blood cells involved in phagocytosis

OBJECTIVES

• List the steps in the process of phagocytosis.

• Explain the importance of phagocytosis in both natural and acquired

immunity.

• Discuss the intracellular mechanism for destruction of foreign particles

during the process of phagocytosis.

• Describe the process of inflammation.

• Recognize false-positive and false-negative reactions in latex

agglutination test for C-reactive protein.

• Determine the significance of abnormal levels of acute phase reactants.

Thought

Learning is finding out what you already know.

Doing is showing that you know it.

Teaching is letting others know that they know it just as well

as you do. Richard Bach (Illusions)

HISTORY OF IMMUNOLOGY

• Immunology is the study of host’s reaction when foreign

substances are introduced into the body

• An immunogen induces immune response – usually an

antigen

• Immunity is the condition of being resistant to infection


• First written records date back to 1500s – the Chinese inhaled

scabs of small pox powder to defend themselves from the

small pox – variolation

• In 1700s Edward Jenner discovered relationship between

exposure to cowpox and immunity to small pox – origin of the

term vaccination (Vacca – for cow) by Pasteur

• Cross-immunity – exposure to one agent produces protection

from another


• Louis Pasteur – generally considered to be the “Father of

Immunology” – discovered attenuated vaccine

• 430 BC – Thucydides recorded during plague in Athens

discovered that after exposure, individuals recovered in the

subsequent exposure

• England adopted variolation in 1740 after Charles Maitland

performed the “Royal Experiment”.

JENNER'S DRAWING OF COW POX LESION FROM

WHICH HE CREATED HIS VACCINE

• Elie Metchnikoff discovered

phagocytosis (1886 –

1887) at Louis Pasteur

Institute – “cellularist”

• Paul Ehrlich predicted the

existence of antibodies –

“Humoralist”

HISTORY OF IMMUNOLOGYEhrlich’s drawing of a “haemopoietic” cell bearing

“side chains” (receptors) and releasing “immune bodies”

(antibodies).

CLONAL SELECTION THEORY

• Discovered in 1950s by Burnet

• States that:

Animals contain numerous cells called lymphocytes

Each lymphocyte is responsive to a particular antigen by virtue of

specific surface receptor molecules

Upon contacting its appropriate antigen, the lymphocyte is stimulated

to proliferate (clonal expansion) and differentiate

The expanded clone is responsible for secondary response while the

differentiated (effector) cells secrete antibody.

CLONAL SELECTION THEORY

OTHER ADVANCES

• Chemokines discovered in 1989 by Leonard, et al

• 1997 Toll, a transmembrane protein discovered by Janeway

and Medzhitov – conferred resistance to lipopolysaccharide

• Acquired immunity

• Acute-phase reactant

• Antibody

• Antigen

• Chemotaxin

• Complement

• C-reactive protein

• Cross-immunity

• Diapedesis

• External defense system

• Humoral immunity

• Immunity

KEY TERMS

• Immunology

• Inflammation

• Internal defense system

• Natural immunity

• Opsonin

• Phagocytosis

• Phagolysosome

• Phagosome

• Respiratory burst

• Toll-like receptors

KEY TERMS

CHARACTERISTICS OF THE IMMUNE SYSTEM

• Specificity

• Memory

• Mobility

• Replicability

• Cooperation between different cells or cellular products

NATURAL OR INNATE IMMUNITY

• Individual resists infection by means of normally present body

functions

• Non-adaptive and nonspecific

• No prior exposure required

• Factors like nutrition, age, fatigue, stress, and genetic

determinants influence the mechanisms

ACQUIRED IMMUNITY

• Characterized by specificity for each pathogen

• Ability to remember prior exposure – an increased response

upon repeated exposure

• Acquired immunity and natural immunity operate in concert,

and are dependent on one another for maximal protection

• Natural immunity is categorized into external defense and

internal defense

EXTERNAL DEFENSE

• Keeps microbes from entering the body

• Composed of structural barriers that prevent most infectious

agents from entering the body

• Intact skin, mucous membranes, acid pH (lactic acid in sweat,

fatty acids from sebaceous glands maintain a pH of about 5.6)

EXTERNAL DEFENSE

• Unique mechanisms for each organ

Mucous and cilia movement in the respiratory tract

Flushing action of urine plus slight acidity

Lactic acid in the vagina – pH 5

Low pH in stomach – pH 1

Lysozyme in tears and saliva

Earwax (cerumen) protects auditory canals

EXTERNAL DEFENSE

• Competitive exclusion – presence of normal flora

• Competitive exclusion is readily demonstrated by

looking at side effects of antibiotics – growth of

Candida albicans

THOUGHT

• Concentrate all your thoughts upon the work at hand. The sun’s rays do not burn until brought to a focus.

Alexander Graham Bell

INTERNAL DEFENSE SYSTEM

• Cells and soluble factors play a role

• Designed to recognize molecules unique to specific

microorganisms

• Involves recognized a CHO such as mannose found on

microorganisms and not evident on human cell

• Phagocytosis – most important in internal defense system

• Phagocytosis is enhanced by acute-phase reactants

CELLULAR VERSUS HUMORAL IMMUNITY

• Cellular immunity – cells involved (mediated)

• Humoral immunity – antibodies and other soluble,

extracellular factors in the blood and lymphatic fluid.

• All these are found in both innate and adaptive

immunity

SUMMARY OF NATURE OF IMMUNITY

Immunity

External

Natural Adaptive

Cellular

Cellular

Internal Humoral

Humoral

• Complement

• Lysozyme

• Interferon

• Mast cells

• Neutrophils

• macrophages

COMPONENTS OF THE NATURAL IMMUNE SYSTEM

CELLULAR HUMORAL

ACUTE-PHASE REACTANTS

• Normal serum constituents

• Increase rapidly (at least 25%) due to infection, injury, or

trauma

• Examples are C-reactive protein, serum Amyloid A,

complement components, mannose-binding protein, alpha1-

antitrypsin, haptoglobulin, fibrinogen, and celuroplasmin.


• Produced primarily by hepatocytes within 12 – 24

hours

• Production signaled by cytokines

• Most notable examples of cytokines are interleukin-1β

(IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-

alpha (TNF-α) that are produced by monocytes and

macrophages at the sites of inflammation

C-REACTIVE PROTEIN

• Trace constituent of serum

• Originally thought to be an antibody to the c-

polysaccharide of pneumococci

• Increases rapidly within 4 – 6 hours following infection,

surgery, or trauma

C-REACTIVE PROTEIN

• Levels increase dramatically (100 – 1000 times) and

peak within 48 hours

• Levels decline with cessation of stimulus

• Half-life of about 19 hours

C-REACTIVE PROTEIN

• Elevated levels are found in bacterial infections,

rheumatic fever, viral infections, malignant

diseases, tuberculosis, and after a heart attack

• The median CRP value increases with age

NATURE OF C-REACTIVE PROTEIN

• Homogenous molecule

• Molecular weight of 118,000 D

• Pentamer – identical units held together by

noncovalent bonds


• Member of the pentraxins

• Acts somewhat like an antibody

• Capable of opsonization, agglutination, precipitation,

and activation of complement by classical pathway


• Binding is calcium-dependent and non-specific

• Main substrate is phosphocholine, a common

constituent of microbial membranes

• Also binds to small ribonuclear CHONs,

phospholipids, peptidoglycan, an other constituents

of fungi, bacteria and parasites


• Binds to specific receptors on monocytes

macrophages, and neutrophils – promoting

phagocytosis

• Most widely used indicator of acute inflammation

• Used for monitoring malignancy therapy and

organ transplantation, prevention of hear attack or

stroke

SERUM AMYLOID A

• Lipoprotein, normal circulating levels approximately 30

μg/ml

• Synthesized in the liver

• Molecular weight – 11,685 D

• Associated with HDL cholesterol in plasma

SERUM AMYLOID A

• Cleanses site of tissue injury – removes cholesterol

form cholesterol-filled macrophages

• Facilitates recycling of membrane cholesterol for

formation of new cells required during acute

inflammation

• Increases significantly more in bacterial infections than

viral infections

COMPLEMENT

• A series of normally present serum CHONs

• Overall function is to mediate inflammation

• Activated by antibody binding in a sequence known as

classical cascade (9 CHONs)

• Additional number triggered by microorganisms in alternative

pathway

• Function in opsonization, Chemotaxis, and lysis of cells

MANNOSE-BINDING PROTEIN

• MPB – also called mannose-binding lectin (MBL

• Trimer

• Acts as an Opsonin

• Calcium-dependent

• Able to recognize CHOs such as mannose, and other sugars

found on bacteria, some yeasts, viruses, and several

parasites

MANNOSE-BINDING PROTEIN

• Widely distributed on mucosal surfaces throughout the

body

• Similar to complement component C1q – binding

activates complements, and promotes phagocytosis

• Normal plasma concentrations are up to 10 μg/ml

• Lack of MPB is associated with recurrent yeast

infections

ALPHA1-ANTITRYPSIN

• (AAT)

• Major component of alpha band when serum is

electrophoresed

• Inhibits proteases from leukocytes, especially elastase

• Counteracts effects of neutrophil invasion during inflammation

• Regulates production of proinflammatory cytokines such as

TNF-α, IL-1β, and IL-6

• Deficiency can lead to premature emphysema

BIOLOGY OF AAT

• At leas 17 gene alleles code for AAT that are associate with

low production of the enzyme

• One particular variant gene is associated with lack of AAT –

individuals at risk of liver disease and emphysema

• Homozygous inheritance of this most severe variant gene

may lead to cirrhosis, hepatitis, or hepatoma in early

childhood

HAPTOGLOBIN

• An alpha2-globulin

• 100,000 D

• Binds irreversibly to free hemoglobin released by

intravascular hemolysis

• Once bound, the complex is cleared rapidly in Kupffer cells

and parenchymal cells in liver – preventing loss of free

hemoglobin

HAPTOGLOBIN

• Two fold or ten fold increase can be seen in

inflammation, stress or tissue necrosis

• Normal plasma levels – 49 – 290 μg/dl

• Protects the kidney from damage

• Prevents urinary loss of iron

• Prevents aggregation of damaged CHONs in the blood

FIBRINOGEN

• Most abundant of the coagulation factors – forms fibrin

clot

• 340,000 D

• Normal levels in serum = 100 – 400 mg/dl

• Small portion cleaved by thrombin to make fibrin clot

• Increased levels contribute to an increased risk of

coronary heart disease, especially in women

CERULOPLASMIN

• Single polypeptide chain with molecular weight of

132,000 D

• Principal copper-transporting protein in human plasma

• Acts as a feroxidase – thus releasing iron from ferritin

for binding to transferrin

• Depletion is found in Wilson’s disease

CELLULAR DEFENSE MECHANISMS

• Five principal types of leukocytes

Neutrophils

Basophils

Eosinophils

Lymphocytes

Monocytes

NEUTROPHILS

• Polymorphonuclear neutrophilic leukocyte (PMN)

• Represents 50% – 70% of peripheral blood leukocytes

• 10 - 15μm in diameter, with a nucleus having two to five lobes

• Azurophilic (primary) granules contain enzymes such as

myeloperoxidase, elastase, proteinase 3, lysozyme, cathepsin

G, and defesins, small proteins having antibacterial activity

NEUTROPHILS

• Secondary granules contain collagenase, lysozyme,

lactoferrin, NADPH oxidase, and other membrane

proteins normally associated with the plasmalema

• Tertiary granules contain gelatinase and plasminogen

activator

• Acid hydrolases are found in lysosomes

NEUTROPHILS

• Half of the population is in the marginal pool, the rest flow freely in blood

6 – 10 hours

• Margination allows Diapedesis

• Selectins make neutrophils sticky – enhance adherence to endothelial

cells

• Chemotaxins enhance direction of the neutrophils

• Have life span of about 5 days in tissues

EOSINOPHILS

• 12 – 15 μm in diameter

• 1 – 3 % of the circulating WBCs

• Number increases in allergic reactions or parasitic infections

• Nucleus usually bilobed or ellipsoidal

• Take up acid eosin dye – large orange to reddish

EOSINOPHILS

• Primary granules contain acid phosphatase, and arylsulphatase

• Eosinophil-specific granules contain major basic protein,

eosinophil cationic protein, eosinophil peroxidase, and eosinophil-

derived neurotoxin

• Involved in phagocytosis but less sufficient due to low numbers

• Neutralizes basophil and mast cell products

• Kill certain parasites

BASOPHILS

• Found in smaller numbers - >1% of circulating WBCs

• Smallest of the granulocytes – 10 – 15 μm in diameter

• Contain coarse, densely staining deep-bluish-purple

granules that often obscure the nucleus

• The granules contain histamine, small amount of

heparin, and eosinophil chemotactic factor-A –

inducing and maintaining immediate hypersensitivity

reactions

• Exist only for a few hours in the blood stream

MAST CELLS

• Resemble basophils but are connective tissue cells of mesenchymal

origin

• Widely distributes throughout the body

• Larger than basophils, with a small round nucleus and more granules

• Life span 9 – 18 months

• The enzyme content helps distinguish them form basophils – contain

acid phosphatase, alkaline phosphatase, and protease

• Paly a role in hypersensitivity by binding to IgE

MONOCYTES

• Mononuclear cells

• Largest cells in peripheral blood (12 – 22 μm in diameter)

• Irregular or horseshoe-shaped nucleus occupies almost half

of the total cell volume

• Abundant cytoplasm staining dull grayish blue

• Cytoplasm has ground grass appearance due to fine dust-like

granules

MONOCYTES

• Granules contain peroxidase, acid phosphatase, and

arylsulphatase

• Other type of granules contain β-glucuronidase, lipase, and

lysozyme but not alkaline phosphatase

• Digestive vacuoles may be observed in the cytoplasm

• 4 – 10% of circulating WBCs

• Stay in peripheral blood up to 70 hours, then enter tissues

and become macrophages

TISSUE MACROPHAGES

• Arise from monocytes

• 25 – 80 μm in diameter

• Contain no peroxidase

• Have specific names according to tissue location

Kupffer cells in liver

Histiocytes in connective tissues

Microglial cells in brain

TISSUE MACROPHAGES

• Have slow motility

• Life span of up to months

• Monocyte-macrophage system plays important role in

microbial killing, tumoricidal activity, intracellular parasite

eradication, phagocytosis, secretion of cellular mediators, and

antigen presentation

• Macrophages are activated by cytokines produced by T

lymphocytes

DENDRITIC CELLS

• Covered with long membranous extensions

• Phagocytose antigen and present it to helper T lymphocytes

• Believed to descend from myeloid line

• Langerhans cells are found on skin and mucous membranes

• Interstitial dendritic cells populate in liver, heart, lungs, kidney and the GIT

• Interdigitating cells are found in T lymphocyte areas of lymphoid tissue and the thymus

• Most potent phagocytic cells in the tissue

TOLL-LIKE RECEPTORS (TLRS)

• Toll – CHON originally discovered in Drosophila

• Similar molecules are found on human leukocytes and other non-leukocyte

cells

• Highest concentration occurs on macrophages, monocytes, and neutrophils

• 11 slightly different TLRs in humans

• Each of the receptors recognize different microbial product

• TLR2 recognizes techoic acid and peptidoglycan found on gram positive

bacteria

• TLR4 recognizes lipopolysaccharide found on gram-negative bacteria

TOLL-LIKE RECEPTORS

PHAGOCYTOSIS

• Has four main steps:

Physical contact between white cell and foreign particle

Formation of Phagosome

Fusion with cytoplasmic granules to form

Phagolysosome

Digestion and release of debris to the outside

PHAGOCYTOSIS

PHAGOCYTOSIS

• Enhanced by opsonins – neutralizes surface charge on

foreign particle

• Respiratory or oxidative burst helps in destroying the microbe

• Phagosome formed – cell pseudopods enclose microbe in

vacuole

• Phagolysosome formed – Phagosome and granules fuse

• Granules release their contents and digestion occurs

• Exocytosis – undigested materials

PHAGOCYTOSIS

• Resting cells get energy anaerobically

• During phagocytosis respiratory bursts provides energy

• The hexose monophosphate shunt oxidizes NADP to NADPH

• NADPH reduces O2 by NADPH oxidase which is only activated by

conformational change triggered by microbes themselves – superoxide

(O2–) produced

• Other radicles are produced, hydroxyl, hypochlorite

• Radicles digest the microbes

PHAGOCYTOSIS

• NADPH oxidase may depolarize the membrane, allowing

hydrogen and potassium ions to enter the vacuole.

• When hydrogen combines with the superoxides, the pH

increases, which in turn activates proteases that contribute to

microbial killing.

PRODUCTION OF RADICLES

INFLAMMATION

• The overall reaction of the body to injury or invasion by an infectious

agent is known as inflammation.

• Both humoral and cellular mechanisms are involved

• Four cardinal signs are:

Hyperemia

Increased capillary permeability – swelling

Migration of white cells especially neutrophils

Migration of macrophages to the injured area

INFLAMMATORY RESPONSE

LOOK UP!

• Serology and Immunology - Christine Stevens

• http://www.nature.com/scitable/topicpage/toll-like-receptors-sensors-that-detect-

infection-14396559

• Microbiology, principles and explorations – Jaquelyne Balack, Eigth edition

• Cellular and Molecular Immunology – Abul K Abbas et al sixth edition

http://www.nature.com/scitable/topicpage/toll-like-receptors-sensors-that-detect-infection-14396559

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