Introduction to immunology, Science of Immunity

Introduction to ImmunologyScience of Immunity

How we are ProtectedDr.T.V.Rao MD

1Dr.T.V.Rao MD

Immunology• Immunology is the study of our

protection from foreign macromolecules or invading organisms and our responses to them.

• Host – e.g. me!!!!• Foreign macromolecule, antigen –

e.g. virus protein, worm, parasite (Everything that should not be in my body) 2Dr.T.V.Rao MD

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Immunology

• Contains Basic science• Clinical Application Host defense reactions to foreign

Antigen Substance is not self Antigen recognizing Cell Mediated Host defense functions

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Definitions• Immune system = cells, tissues, and

molecules that mediate resistance to infections

• Immunology = study of structure and function of the immune system

• Immunity = resistance of a host to pathogens and their toxic effects

• Immune response = collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system 6Dr.T.V.Rao MD

Role of the immune system

• Defense against microbes• Defense against the growth of tumor

cells–kills the growth of tumor cells

• Homeostasis–destruction of abnormal or dead cells

(e.g. dead red or white blood cells, antigen-antibody complex)

Jenner - Smallpox vaccine

• Noticed that milkmaids that had contracted cowpox did NOT get smallpox

• Test on an 8 year old boy, injected cowpox into him (NOT very nice……)

• Follwed by exposure to smallpox• Vaccine was invented (latin vacca

means ”cow”)

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First insights into mechanics of immunity…

1880’s- Metchnikoff discovered phagocytic cells that ingest microbes and particles

cells conferred immunity

1890- von Behring and Kitasato discovered blood sera could transfer immunity

liquid of blood conferred immunity

Q: Which confers immunity… cells or serum?

Emil von Behring

S. Kitasato

Elie Metchnikoff9Dr.T.V.Rao MD

Louis Pasteur watching as Joseph Meister receives attenuated rabies vaccine (1885)

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Subjects In Immunology

• Cell mediated host defense functions• Antibody related defense mechanisms• Hypersensitivity reactions ( Including

Allergy )• Auto Immunity• Immunodeficiency• Transplantation

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• Protect against pathogens

• Eliminate damaged or malignant cells

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What is Response to Infection

• Immunity can be Innate ( Nonadapative )

• Adaptive - Acquired.

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Immunology is a ComplexSubject

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Two types of immunity 1. Innate (non-adaptive)

– first line of immune response– relies on mechanisms that exist before

infection

2. Acquired (adaptive)– Second line of response (if innate fails)– relies on mechanisms that adapt after

infection – handled by T- and B- lymphocytes– one cell determines one antigenic determinant 15Dr.T.V.Rao MD

Distinction Between Innate and Adaptive Immune Responses

• Innate immunity is non-adaptive and helps to initiate adaptive immune responses (= first line of defense – but LIMITED)– Immediate (0-4 hours)

• Adaptive immunity provides a more universal line of defense and has long-lived memory to provide protection upon re-infection– Second line of defense– Generation of Ag-specific effector cells– Early (4-96 hours)– Late (>96 hours) 16Dr.T.V.Rao MD

THE EVOLUTION OF IMMUNITY

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Immunity

Innate immunity Acquired immunity

Non-specific SpecificImmediate onset Delay onset

Humoral Immune Response

Cellular Immune Response

Antibodies production T-cell activationDr.T.V.Rao MD

Basic classification of Immunity

Designed by Dr.T.V.Rao MD 18

Different types of Immunity

A - Non specific 1 Species 2 Racial 3 Individual

B Specific 1.Species 2 Racial 3 Individual

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The immune system

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Immune system

• Anatomic barriers (Skin, mucous membranes)

• Physiological barriers (temperature, pH)

• Phagocytic Barriers (cells that eat invaders)

• Inflammatory barriers (redness, swelling, heat and pain)

• Antigen specificity • Diversity • Immunological memory • Self/nonself recognition

Innate (non-specific) immunityAdaptive (specific) immunity

Dr.T.V.Rao MD

Innate, Surface Defenses• Skin

– physical barrier to microbes– Keratin resistant to most bacterial enzymes & toxins– secretions are acidic pH 3-5

• Mucosa – physical barrier & produces a variety of protective

chemicals• Gastric mucosa

– very acidic & produces proteolytic enzymes• Saliva & lacrimal fluid contain lysozyme• Mucous

– traps bacteria & moves them away from epithelial surface

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Different types of Immunity

A - Non specific 1 Species 2 Racial 3 Individual

B Specific 1.Species 2 Racial 3 Individual

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Types of Immunity

Acquired Immunity A Active Natural Artificial B Passive Natural Artificial

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Resistance to Infectious Disease

• Innate immunity (nonspecific resistance) protects us against all pathogens: “over-the-counter defenses”

• Adaptive immunity (specific resistance) is defenses against specific pathogens: “prescription defenses”

Innate Immunity

Innate Immunity is resistance that is preexisting and is not acquired through contact with a foreign substance known as antigen

Individual has innate Immunity by genetic or constitutional Make Up

Non related to prior contact with Microorganisms or Immunization

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Physical and Chemical Barriers

• Skin, mucus membranes• Cilia, mucus, reflexes• pH, lysozyme, fatty

acids, defensins• Normal flora• Genetic resistance

– species differences– individual differences

It is Dependent on

• Species• Race

( Racial )• Individual

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Species and Immunity

• Immunity refers to total resistance to a Pathogen by all members of the species

• Eg Human do not get plant diseases Humans do not get some animal diseases• Dependent on Human configuration

physiology ? Biochemical difference29Dr.T.V.Rao MD

Race - Immunity

• Genetic resistance Plasmodium falciparum malaria resistance in Africa

• In sickle cell anemia immune to malaria

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Individual - Immunity

• Twins homozygous twins exhibit similar resistance

• Susceptibility similar in Leprosy

• Tuberculosis similar resistance

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Factors Influencing Innate Immunity

• Placenta prevent infection

• But still can infected with Toxoplasmosis, Rubella, CMV and Herpes infection.

• Can produce congenital malformations

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Immunity In Adults

• Polio infection , and Chickenpox highly severe in adults.

• Enlargement of prostate lead to UTI

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Hormonal Influence on Immunity

• Diabetes mellitus• Hypothyroidism in

adults• Adrenal

dysfunction• Stress increases

steroids predisposes to Infection

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Nutrition

•Some protection in some diseases

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Mechanism's of Immunity

• Epithelial surfaces

Skin and Epithelial surfaces cover the body and protects the individuals

Healthy skin poses bactericidal influence, salt, drying sweat , Long fatty acids

Wet hand predisposes to Mycotic and pyogenic infections

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Mucous Membranes

•Respiratory tract Shape of Nose, Nasal orifice 37Dr.T.V.Rao MD

Mechanism's of Immunity• Epithelial surfaces Skin and Epithelial surfaces cover

the body and protects the individuals

Healthy skin poses bactericidal influence, salt, drying sweat , Long fatty acids

Wet hand predisposes to Mycotic and pyogenic infections 38Dr.T.V.Rao MD

• Cilia in Respiratory tract

• Propel the foreign particles

• Respiratory secretion contain 39Dr.T

.V.Rao MD

Oral Cavity• Saliva• Stomach HCl• Large

intestine large number of bacteria

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Conjunctiva• Contain lachrymal

secretions• Tears contains

antibacterial substances

• Lysozyme present except in CSF, Sweat, Urine

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Other Mechanisms

• Flushing action of urination drives out Microbes in the Urethra

• Spermine in Semen

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Innate, Internal Defenses

• Phagocytes– Macrophages: derived from monocytes

• Free Macrophages: roam through tissues• Fixed Macrophages: Kupffer cells (liver) &

microglia (brain) • Ingest cellular debris, foreign material, bacteria,

fungi

– Neutrophils: ingest pathogens– Eosinophils: weakly phagocytic of pathogens.

Attack parasites (degranulation)– Mast Cells: phagocytic of various bacteria

Antibacterial Substances

• May be present Blood as Complement

• Antibacterial substances in Blood

Betalysin,

Leukin

Lactoperoxidase in Milk

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Interferon's in Immunity• Interferon's (IFNs) are natural proteins

produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, parasites and tumour cells. Interferon's belong to the large class of glycoproteins known as cytokines

• Interferon's are more useful than Antibodies

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Microbial AntagonistsNormal flora Help us

• Normal Microbial flora

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Normal flora Helps Us• We harbour near 1014 bacteria. This group

of organisms, traditionally referred to as "normal flora" (although they are not plants) is composed of a fairly stable set of genera, mostly anaerobes. While each person has a relatively unique set of normal flora, members of the Streptococcus and Bacteroides make up a large percentage of the inhabitants. These organisms contribute to our existence in several ways’ 47Dr.T.V.Rao MD

Other Normal Flora

• Streptococcus and Bacteroides make up a large percentage of the inhabitants. These organisms contribute to our existence in several ways’

• Help us by competing with pathogens such as Salmonella

• Help us by providing vitamins or eliminating toxins (e.g. Bacteroides)

• Harm us by promoting disease (e.g. dental caries) • Cause neither help nor harm (e.g. "commensals").

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Normal Bacterial Flora of Conjunctiva

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Cellular Factors in Innate Immunity

• Metchnikoff 1883• Cells called as Phagocytic cells Microphages, MacrophagesMicrophages Polymorph nuclear neutrophilsMacrophages Histiocytes wandering Amoeboid

cellsMonocytes in BloodCells in Reticuloendothelial System These cells remove foreign particles

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Phagocytes• Phagocytes = eating cells

–Neutrophils (PMNs) are present in the highest numbers in blood

–Macrophages (“big eaters”) in the tissues encounter the pathogen first•Secrete cytokines ---> inflammation, systemic responses

How Phagocytes act• Phagocytic cells

reach the site o Inflammation

• Attracted by Chemo tactic substances

• Ingest particle material

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Cellular and Inflammatory Components of Innate Immunity

• Cellular–Phagocytic

cells• Inflammatory

–Vasodilation–Capillary

permeability53Dr.T.V.Rao MD

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Phagocytosis

Capsule In Innate immunity

• Some bacteria have capsules

• Streptococcus pneumonia

• Klebsiella pneumonia• Bacteria with capsules

are not ingested by Phagocytes unless in the presence of opsonins

• Bacteria are fixed against fixed surface such as alveoli

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Mechanism of Phagocytosis

• Bacteria are phagocycosed into vacuole (Phagosome)

• Forms phagolysosome

• Lytic enzymes destroy the Bacteria

• Brucella and Leprosy

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Natural Killer cellsNK cells

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Mediators of inflammationVasodilation, smooth muscle contractionIncreased vascular permeabilityEdema, extravasation

(histamines, prostaglandins, kinins)ExtravasationChemo taxis

(cytokines, chemokine's, complement)Systemic response- fever, acute-phase proteins

C-reactive protein

Interferon and Function

Anti-Viral Interferons• IFNa and IFNb made by virus-

infected cells• Not virus-specific• Bind neighboring host cells and

induce synthesis of anti-viral proteins to block virus replication

Natural Killer Cells

• All nucleated cells in body have membrane MHC = tissue typing antigens

• In virus-infected cells, MHC is reduced in amount or contains virus peptides

• NK cells recognize this ‘altered’ MHC and kill virus-infected cells (also tumor cells)

Role of Natural killer Cells

• Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitute a major component of the Innate immune system. NK cells play a major role in the rejection of tumours and cells infected by viruses. The cells kill by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis

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Inflammation• Tissue Injury• Irritation• Arterioles constrict initially and then

dilate• Slow the Blood flow and Margi nation

of Leucocytes • Escape into tissues by diapedesis

and accumulate in large numbers64Dr.T.V.Rao MD

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Inflammation

• Outpour plasma, and dilute the toxic material

• Produce fibrin barrier and localized the infection

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Fever• Natural defense

Mechanisms• Destroy infectious

agents• Therapeutic –

Trepanoma palladium• Production of

Interferon's

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Antibacterial substances in Blood and Tissues

• The complement system possess bacterial activity and plays role in the bactericidal activity and destroys the pathogenic bacteria

• Betalysin – anthrax• Leukins and Plakins• Lactic acid found in muscles • Lacto peroxidase in milk

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Acute Phase proteins too play a great role in Immunity

• Infection and Injury produces Acute phase proteins

• C- Reactive proteins CRP• Mann in binding proteins• CRP activates alternative pathway• Increases host defenses• Prevents issue injury• Repair inflamed lesions.

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Acute Phase proteins

• Infection and Injury produces Acute phase proteins

• C- Reactive proteins CRP• Mann in binding proteins• CRP activates alternative pathway• Increases host defenses• Prevents issue injury• Repair inflamed lesions.

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Adaptive immunity: second line of response

• Based upon resistance acquired during life• Relies on genetic events and cellular growth • Responds more slowly, over few days • Is specific

– each cell responds to a single epitope on an antigen

• Has anamnestic memory– repeated exposure leads to faster, stronger response

• Leads to clonal expansion

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Adaptive immunity: mechanisms

• Cell-mediated immune response (CMIR)– T-lymphocytes– eliminate intracellular microbes that survive

within phagocytes or other infected cells• Humoral immune response (HIR)

– B-lymphocytes– mediated by antibodies– eliminate extra-cellular

microbes and their toxins Plasma cell

(Derived from B-lymphocyte, produces

antibodies)

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Cell-mediated immune response

1.T-cell – recognizes peptide

antigen on macrophage in association with major histo-compatibility complex (MHC) class

– identifies molecules on cell surfaces

– helps body distinguish self from non-self

2. T-cell goes into effectors cells stage that is able to kill infected cells

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Cell mediated immune response

Primary response – production of specific clones of effector T cells

and memory clones– develops in several days – does not limit the infection

Secondary response – more pronounced, faster – more effective at limiting the infection

Example - cytotoxic reactions against intracellular parasites, delayed hypersensitivity (e.g., Tuberculin test) and allograft rejection

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Humoral immune response1. B lymphocytes recognize

specific antigens – proliferate and

differentiate into antibody-secreting plasma cells

2. Antibodies bind to specific antigens on microbes; destroy microbes via specific mechanisms

3. Some B lymphocytes evolve into the resting state - memory cells

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Antibodies (immunoglobulin's)•Belong to the gamma-globulin fraction of serum proteins•Y-shaped or T-shaped polypeptides

–2 identical heavy chains–2 identical light chains

• All immunoglobulin's are not antibodies•Five kinds of antibodies

– IgG, IgM, IgA, IgD, IgE

Measurement of Immunity

• It is not possible to measure the immunity accurately

• Detection of antibodies• Detected by agglutination tests,

Precipitation tests, complement fixation HI ELISA

• Skin Tests, Schick test , Dick Tests• Tuberculin Test – Delayed Hypersentivity

tests in TuberculosisDr.T.V.Rao MD 77

Local Immunity

• Can be produced by Oral Vaccines• Sabin's vaccine for polio given orally X

Salk will not protect Local Immunity but produces systemic Immunity

• Locally produced Antibodies IgA protect the gut from entry of pathogens

• Local immunity antigen protects the individuals

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Herd Immunity• This indicates the overall level in the

community and important in control of infections in the community (HERD )

• When Herd immunity is low epidemics occur.

• Eradication of communicable diseases depends on the development of high level of herd immunity rather than high level of Individual Immunity

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• Programme Created by Dr.T.V.Rao MD for Medical and Paramedical Students

in the Developing World • Email

• [email protected]

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