INNATE IMMUNITY Our Non-Specific Defenses References: 1. Immunology by Kuby 2. Microbiology by Tortora 3. Essentials of Immunology by Roitt Marilen M. Parungao-Balolong 2011 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE • The 2011 Nobel Prize in Physiology or Medicine was awarded to Bruce Beutler at the Scripps Research Institute in California, Jules Hoffmann at the French National Center for Scientific Research and Ralph Steinman at The Rockefeller University in New York City. Beutler and Hoffman helped to elucidate innate immunity, the non-specific array of initial responses by the body’s immune system that can recognize invading microorganisms as being foreign and try to destroy them. DR.T.V.RAO MD 2 • The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity" . THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 2011 DR.T.V.RAO MD 3 • We are constantly being exposed to infectious agents and yet, in most cases, we are able to resist these infections. It is our immune system that enables us to resist infections. The immune system is composed of two major subdivisions, the innate or non-specific immune system and the adaptive or specific immune system OVERVIEW OF THE IMMUNE SYSTEM DR.T.V.RAO MD 5 5 5 WHAT YOU NEED TO KNOW Differentiate innate from adaptive immunity Define important terms related to innate immunity Be familiar with the 4 types of defense/ barriers in innate immunity Be familiar with cells of the innate immunity and their important roles First line of defense • Intact skin • Mucous membranes and their secretions • Normal microbiota Second line of defense Third line of defense • Specialized lymphocytes: T cells and B cells • Antibodies • Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages • Inflammation • Fever • Antimicrobial substances Players in the immune response
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140422 Innate Immunity.pdfReferences:
Marilen M. Parungao-Balolong
2011 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE
• The 2011 Nobel Prize in Physiology or Medicine was awarded to Bruce Beutler at the Scripps Research Institute in California, Jules Hoffmann at the French National Center for Scientific Research and Ralph Steinman at The Rockefeller University in New York City. Beutler and Hoffman helped to elucidate innate immunity, the non-specific array of initial responses by the body’s immune system that can recognize invading microorganisms as being foreign and try to destroy them.
DR.T.V.RAO MD 2
• The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity".
THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 2011
DR.T.V.RAO MD 3
• We are constantly being exposed to infectious agents and yet, in most cases, we are able to resist these infections. It is our immune system that enables us to resist infections. The immune system is composed of two major subdivisions, the innate or non-specific immune system and the adaptive or specific immune system
OVERVIEW OF THE IMMUNE SYSTEM
DR.T.V.RAO MD 5 55
Define important terms related to innate
immunity
barriers in innate immunity
immunity and their important roles
First line of defense
Second line of defense Third line of defense
• Specialized lymphocytes: T cells and B cells • Antibodies
• Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages • Inflammation • Fever • Antimicrobial substances
Players in the immune response
Recall: the Lymphatic System
Q: Why do you
Anatomic/Physical
Physiologic
Phagocytic
Inflammatory
Serves as a Physical Barrier
Epidermis consists of tightly packed cells with KERATIN, a protective protein
Normal Microbiota:
Anatomic:
Mucous
Membranes
away from the lungs
Lacrimal apparatus: Washes eye
Saliva: Washes microbes off
Lysozyme in
perspiration, tears,
Gram-negative endotoxin cause phagocytes to release interleukin–1 (IL–1)
Hypothalamus releases prostaglandins that reset the hypothalamus to a high temperature
Body increases rate of metabolism and shivering which raise temperature
When IL–1 is eliminated, body temperature falls (crisis)
Physiologic:
CELLS OF INNATE IMMUNITY
DR.T.V.RAO MD 19 19191991919191911
1. Neutrophils: Phagocytic 2. Basophils: Produce histamine 3. Eosinophils: Toxic to parasites and some
phagocytosis 4. Dendritic cells: Initiate adaptive immune
response 5. Monocytes: Phagocytic as mature
macrophages a. Fixed macrophages in lungs, liver,
and bronchi b. Wandering macrophages roam
tissues 6. Lymphocytes: Involved in specific
immunity
Adaptive
Immunity
Phagocytosis
• Greek: Phagos (eat), cyte (cell) • Ingestion of a substance/ microbe by a cell • Phagocytes – Cells that perform phagocytosis – Leukocytes and/or derivatives
SEM of a neutrophil phagocytosing
Aspergillus spores
• Neutrophils: early during infection – First phagocytes at site of infection
• Monocytes – Morph into Macrophages when infection
progresses – Fixed v/s Wandering Macrophages • Non-motile; Specifically present in tissues/ organs
– Lymph nodes, bone marrow, spleen, liver
• Roaming through tissue, gather at site of inflammation
• Blood - Called monocytes (1-6% WBC)
• Tissues - Called macrophages
• mature form of monocytes
• normally found in tissues such as gastrointestinal tract, lung, liver and spleen
• Functions:
• Phagocytose and kills after bactericidal mechanisms are activated (T cells)
• Produce cytokines/chemokines (initiates inflammation)
MACROPHAGES (MQ)
• Not normally present in tissues
• Short lifespan - 12 hours • Functions:
• First at the site of infection/injury
• Ingest and kill microbes after bactericidal mechanisms are activated (binding to pathogen)
NEUTROPHILS (PMN)
• 2-6 x 103 cells/μL
• 40 –75 % of leukocytes
HUMAN NEUTROPHIL
– Cytokines (released from other WBCs) – Cell damage – Microbial products
• Adherence: attachment to microbial surface – Toll-like receptors (TLRs) – Pathogen associated Molecular Patterns (PAMPs) – Opsonins: proteins that coat microbe
• Ingestion: pseudopodia engulf microbe into phagosome • Digestion: fusion of phagosome with lysosome
– Enzymes digest microbe – Residual body excreted
Mechanism of Phagocytosis
Antimicrobial Substances
Complement system = defensive system of >30 proteins produced in the liver that circulate the blood & tissues
• “Complements” the action of immune cells Destroy microbes by: 1. Cytolysis 2. Inflammation 3. Phagocytosis
• Act in a cascade with one reaction triggering another
Activated by one of 3 possible pathways
The Complement Cascade
2. C3b coats the microbe to promote phagocyte attachment (opsonization)
3. C3b initiates formation of membrane attack complex (MAC) on invading cell
4. MAC causes cytolysis = bursting of invading cell due to inflow of extracellular fluid
5. C3a and C5a bind mast cells stimulate release of histamine increase blood vessel permeability • C5a also attracts phagocytes
Complement-induced cytolysis
1. Antibodies bind antigens antigen-antibody complexes activate C1
2. Active C1 splits (activates) C2 and C4 into C2a, C2b, C4a, C4b
3. C2a and C4b combine and split C3 into fragments C3a and C3b Active fragments initiate the complement cascade
Complement activation: classical pathway
Steps: 1. C3 combines with factor B, D and P
(complement proteins) on the surface of a microbe
2. C3 splits into C3a and C3b complement cascade
• No antibodies involved • Direct contact between
complement proteins and pathogen
Complement activation: alternative pathway
Lectins = proteins produced by the liver that bind carbohydrates Mannose binding lectin (MBL) = binds mannose (in bacterial cell walls and some viruses)
Steps: 1. MBL binds an invader 2. Activates C2 and C4 3. C2a and C4b combine and
activate C3 complement cascade
Some Bacteria Can Evade
Interferons Interferons = class of cytokines produced by certain animal cells after viral stimulation • Interfere with viral multiplication
Three types in humans: Alpha and Beta interferon = produced by infected host to induce antiviral protein synthesis in neighboring cells
• Oligoadenylate synthetase = degrades viral mRNA • Protein kinase = inhibits viral protein synthesis
Gamma interferon = produced by lymphocytes; induces neutrophils and macrophages to kill invaders; suppresses tumor cell proliferation
Interferons
Interferon complications: • Stable for only short time periods • Side effects of injection:
- Nausea, fatigue, vomiting, fever • Toxic in high concentrations
- heart, kidneys, liver, red bone marrow
Medical usage: • Limited or no effect on tumors in clinical trials • Alpha interferon some virus-associated disorders
• Kaposi’s sarcoma • Chronic Hepatitis B and C
Interferons Iron-binding proteins Humans use iron in many ways: • component of cytochromes in the ETC • cofactor of many enzymes • component of hemoglobin
Iron-binding proteins = transport and store iron Transferrin = blood and tissue fluids Lactoferrin = milk, saliva, mucus Ferritin = liver, spleen, red blood marrow Hemoglobin = red blood cells deprives pathogens of available iron!
Iron-binding proteins
Siderophores = proteins released into the medium by bacteria to capture iron from transport proteins • Forms iron-siderophore complex, recognized by
bacterial receptors and taken into cell • Splits iron from siderophore and utilizes it
Other mechanisms of obtaining iron: • Release toxins when iron is low
Kills host cells, releasing their iron Ex) Strep pyogenes • Hemolysins lysis of red blood cells • Hemoglobin broken down to capture iron
Antimicrobial Peptides Antimicrobial peptides (AMPs) = short chains of amino acids synthesized on ribosomes • Synthesized by neutrophils when TLRs contact PAMPs
- Broad spectrum killing of bacteria, viruses, fungi - Attract other phagocytes - Sequester endotoxins
What makes them interesting? • Work together with other antimicrobials (synergy) • Stable over a wide range of pH • Microbes don’t develop resistance
To Summarize....
Marilen M. Parungao-Balolong
2011 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE
• The 2011 Nobel Prize in Physiology or Medicine was awarded to Bruce Beutler at the Scripps Research Institute in California, Jules Hoffmann at the French National Center for Scientific Research and Ralph Steinman at The Rockefeller University in New York City. Beutler and Hoffman helped to elucidate innate immunity, the non-specific array of initial responses by the body’s immune system that can recognize invading microorganisms as being foreign and try to destroy them.
DR.T.V.RAO MD 2
• The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity".
THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 2011
DR.T.V.RAO MD 3
• We are constantly being exposed to infectious agents and yet, in most cases, we are able to resist these infections. It is our immune system that enables us to resist infections. The immune system is composed of two major subdivisions, the innate or non-specific immune system and the adaptive or specific immune system
OVERVIEW OF THE IMMUNE SYSTEM
DR.T.V.RAO MD 5 55
Define important terms related to innate
immunity
barriers in innate immunity
immunity and their important roles
First line of defense
Second line of defense Third line of defense
• Specialized lymphocytes: T cells and B cells • Antibodies
• Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages • Inflammation • Fever • Antimicrobial substances
Players in the immune response
Recall: the Lymphatic System
Q: Why do you
Anatomic/Physical
Physiologic
Phagocytic
Inflammatory
Serves as a Physical Barrier
Epidermis consists of tightly packed cells with KERATIN, a protective protein
Normal Microbiota:
Anatomic:
Mucous
Membranes
away from the lungs
Lacrimal apparatus: Washes eye
Saliva: Washes microbes off
Lysozyme in
perspiration, tears,
Gram-negative endotoxin cause phagocytes to release interleukin–1 (IL–1)
Hypothalamus releases prostaglandins that reset the hypothalamus to a high temperature
Body increases rate of metabolism and shivering which raise temperature
When IL–1 is eliminated, body temperature falls (crisis)
Physiologic:
CELLS OF INNATE IMMUNITY
DR.T.V.RAO MD 19 19191991919191911
1. Neutrophils: Phagocytic 2. Basophils: Produce histamine 3. Eosinophils: Toxic to parasites and some
phagocytosis 4. Dendritic cells: Initiate adaptive immune
response 5. Monocytes: Phagocytic as mature
macrophages a. Fixed macrophages in lungs, liver,
and bronchi b. Wandering macrophages roam
tissues 6. Lymphocytes: Involved in specific
immunity
Adaptive
Immunity
Phagocytosis
• Greek: Phagos (eat), cyte (cell) • Ingestion of a substance/ microbe by a cell • Phagocytes – Cells that perform phagocytosis – Leukocytes and/or derivatives
SEM of a neutrophil phagocytosing
Aspergillus spores
• Neutrophils: early during infection – First phagocytes at site of infection
• Monocytes – Morph into Macrophages when infection
progresses – Fixed v/s Wandering Macrophages • Non-motile; Specifically present in tissues/ organs
– Lymph nodes, bone marrow, spleen, liver
• Roaming through tissue, gather at site of inflammation
• Blood - Called monocytes (1-6% WBC)
• Tissues - Called macrophages
• mature form of monocytes
• normally found in tissues such as gastrointestinal tract, lung, liver and spleen
• Functions:
• Phagocytose and kills after bactericidal mechanisms are activated (T cells)
• Produce cytokines/chemokines (initiates inflammation)
MACROPHAGES (MQ)
• Not normally present in tissues
• Short lifespan - 12 hours • Functions:
• First at the site of infection/injury
• Ingest and kill microbes after bactericidal mechanisms are activated (binding to pathogen)
NEUTROPHILS (PMN)
• 2-6 x 103 cells/μL
• 40 –75 % of leukocytes
HUMAN NEUTROPHIL
– Cytokines (released from other WBCs) – Cell damage – Microbial products
• Adherence: attachment to microbial surface – Toll-like receptors (TLRs) – Pathogen associated Molecular Patterns (PAMPs) – Opsonins: proteins that coat microbe
• Ingestion: pseudopodia engulf microbe into phagosome • Digestion: fusion of phagosome with lysosome
– Enzymes digest microbe – Residual body excreted
Mechanism of Phagocytosis
Antimicrobial Substances
Complement system = defensive system of >30 proteins produced in the liver that circulate the blood & tissues
• “Complements” the action of immune cells Destroy microbes by: 1. Cytolysis 2. Inflammation 3. Phagocytosis
• Act in a cascade with one reaction triggering another
Activated by one of 3 possible pathways
The Complement Cascade
2. C3b coats the microbe to promote phagocyte attachment (opsonization)
3. C3b initiates formation of membrane attack complex (MAC) on invading cell
4. MAC causes cytolysis = bursting of invading cell due to inflow of extracellular fluid
5. C3a and C5a bind mast cells stimulate release of histamine increase blood vessel permeability • C5a also attracts phagocytes
Complement-induced cytolysis
1. Antibodies bind antigens antigen-antibody complexes activate C1
2. Active C1 splits (activates) C2 and C4 into C2a, C2b, C4a, C4b
3. C2a and C4b combine and split C3 into fragments C3a and C3b Active fragments initiate the complement cascade
Complement activation: classical pathway
Steps: 1. C3 combines with factor B, D and P
(complement proteins) on the surface of a microbe
2. C3 splits into C3a and C3b complement cascade
• No antibodies involved • Direct contact between
complement proteins and pathogen
Complement activation: alternative pathway
Lectins = proteins produced by the liver that bind carbohydrates Mannose binding lectin (MBL) = binds mannose (in bacterial cell walls and some viruses)
Steps: 1. MBL binds an invader 2. Activates C2 and C4 3. C2a and C4b combine and
activate C3 complement cascade
Some Bacteria Can Evade
Interferons Interferons = class of cytokines produced by certain animal cells after viral stimulation • Interfere with viral multiplication
Three types in humans: Alpha and Beta interferon = produced by infected host to induce antiviral protein synthesis in neighboring cells
• Oligoadenylate synthetase = degrades viral mRNA • Protein kinase = inhibits viral protein synthesis
Gamma interferon = produced by lymphocytes; induces neutrophils and macrophages to kill invaders; suppresses tumor cell proliferation
Interferons
Interferon complications: • Stable for only short time periods • Side effects of injection:
- Nausea, fatigue, vomiting, fever • Toxic in high concentrations
- heart, kidneys, liver, red bone marrow
Medical usage: • Limited or no effect on tumors in clinical trials • Alpha interferon some virus-associated disorders
• Kaposi’s sarcoma • Chronic Hepatitis B and C
Interferons Iron-binding proteins Humans use iron in many ways: • component of cytochromes in the ETC • cofactor of many enzymes • component of hemoglobin
Iron-binding proteins = transport and store iron Transferrin = blood and tissue fluids Lactoferrin = milk, saliva, mucus Ferritin = liver, spleen, red blood marrow Hemoglobin = red blood cells deprives pathogens of available iron!
Iron-binding proteins
Siderophores = proteins released into the medium by bacteria to capture iron from transport proteins • Forms iron-siderophore complex, recognized by
bacterial receptors and taken into cell • Splits iron from siderophore and utilizes it
Other mechanisms of obtaining iron: • Release toxins when iron is low
Kills host cells, releasing their iron Ex) Strep pyogenes • Hemolysins lysis of red blood cells • Hemoglobin broken down to capture iron
Antimicrobial Peptides Antimicrobial peptides (AMPs) = short chains of amino acids synthesized on ribosomes • Synthesized by neutrophils when TLRs contact PAMPs
- Broad spectrum killing of bacteria, viruses, fungi - Attract other phagocytes - Sequester endotoxins
What makes them interesting? • Work together with other antimicrobials (synergy) • Stable over a wide range of pH • Microbes don’t develop resistance
To Summarize....
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