Lec 01- Overview of Immune Responses Flashcards
How can microbes survive in animals?
grow extracellular (immersed in nutrients)
How can intracellular microbes survive?
replicate utilizing host-cell energy sources
What is immunity?
defense mechanisms providing protection from infectious disease
self vs. non-self
Noninfectious foreign substances
antigens (Ags)
An immune response against microbes that causes tissue injury
Immunopathology
Collateral damage
Antigens
substances which induce an immune response
What do antigens include?
- proteins
- carbs
- lipids
- nucleic acids
Smallest unit of an antigen
antigenic determinant
How many amino acids/sugar residues are there in the smallest unit that an antibody can make?
3-6 amino acids
5-6 sugar residues
Which molecules are multi determinant (multiple epitomes)?
All large structures of antigens
What binds to conformational antigenic determinants?
Antibodies (dependent on folding of the molecule)
What can recognize linear amino acid sequences?
T cell receptors
What are antigens that can stimulate an immune response called?
Immunogens
All _____ are antigens but not all antigens are ______.
All IMMUNOGENS are antigens but not all antigens are IMMUNOGENS
Which molecules can bind to Ab’s or TCR’s, but not initiate an immune response?
Haptens
Which type of immunity is the first line of defense against infection?
Innate immune system
The innate immune system gives rise to ______.
acute inflammatory response
What type of immunity has some specificity for microbes, but no memory?
innate immune system
What type of immunity takes longer to develop?
adaptive immune system
What type of immunity is highly specific and shows memory?
adaptive immune system
2 other names for innate immunity
natural immunity
native immunity
What type of immunity responds rapidly to infections and exists even before infection?
innate immunity
What type of immunity doesn’t distinguish fine differences between microbes?
innate immunity
3 principal components of innate immunity
1- physical and chemical barriers
2- phagocytic cells (macrophages/neutrophils), dendritic cells, natural killer cells, other innate lymphoid cells
3- blood proteins (complement system and other mediators of inflammation)
Timing differences of innate and adaptive immunity?
- Innate immunity = hours
- Adaptive immunity = days, weeks
Innate immunity component examples:
Cellular and chemical barriers
- skin
- mucosal epithelia
- antimicrobial molecules
Innate immunity component examples:
Blood proteins
- complement
- acute phase proteins
- cytokines
- others
Innate immunity component examples:
Cells
- phagocytes (macrophages, neutrophils)
- dendritic cells
- natural killer cells
- innate lymphoid cells
Adaptive immunity component examples:
Cellular and chemical barriers
- lymphocytes in epithelia
- antibodies secreted at epithelial surfaces
Adaptive immunity component examples:
Blood proteins
- antibodies
- cytokines
Adaptive immunity component examples:
Cells
B and T lymphocytes
Specificity of innate immunity
- Molecules shared by groups of related microbes
- Molecules produced by damaged cells
Specificity of adaptive immunity
microbial and nonmicrobial antigens
Diversity of innate immunity
limited
germline encoded
Diversity of adaptive immunity
- very large
- receptors produced by somatic recombination of gene segments
Reactivity to self?
Innate = none
Adaptive = none
What type of immunity is also a “decision-making stage” of an immune response?
innate immune system
Innate immunity ________ the invader in the context of intracellular vs. extracellular microbes. It then sends the instructions to adaptive immunity.
evaluates
Cells communicate through what type of contact?
direct cell-to-cell contact
cytokines and chemokines
What proteins regulate and coordinate many activities of the cells of innate and adaptive immunity?
cytokines
Each cell expresses a set of ___________________________ for several cytokines.
specific signaling receptors
What is the function of cytokines?
- growth and differentiation of all immune cells
- activation of effector functions of lymphocytes and phagocytes
What large subset of cytokines regulate cell migration and movement?
chemokines
2 type of lymphocytes
B and T cells
Interactions between _____ and ____, and between ____ and ____ are critical to the development of specific immunity
T and B cells
T cells and Antigen-presenting cells (APCs)
Where do the T cells mature?
thymus
Where do the B cells mature?
bone marrow
T cell maturation is stimulated by what?
antigens
What type of immunity do T cells give rise to?
cellular immunity
What type of immunity do B cells give rise to?
humoral immunity
What type of pathogens for T cells and B cells?
T cells = Intracellular pathogens
B cells = Extracellular pathogens
Humoral immunity produces which soluble molecules?
immunoglobulins
What did Paul Ehrlich hypothesize?
- immune cells use receptors to recognize toxins
- secrete receptors to combat microbes
What term did Paul Ehrlich coin?
antibodies = serum proteins that bind toxins
Ehrlich’s concepts = what model?
Function of B cells in humoral immunity
Humoral adaptive immunity is mediated by what?
antibodies in:
- blood
- mucosal secretions
What do B lymphocytes (B cells) produce?
antibodies in blood and mucosal secretions
3 functions of antibodies (Abs)
- RECOGNIZE microbial antigens
- NEUTRALIZE the infectivity of microbes
- TARGET microbes for elimination by various effector mechanisms
What is the principal defense mechanism against extracellular microbes and their toxins?
Humoral adaptive immunity
-Abs bind and eliminate them
Elie Mechnikoff was considered the father of what?
Cell-mediated immunity
Cellular theory of immunity states____?
host cells are the principal mediators of immunity
What did Metchnikoff discover at Pasteur in 1883?
phagocytes
What was Metchnikoff unable to prove?
that specific immunity to microbes could be mediated by cells
Cellular theory of immunity became re-established when ______.
resistance to an intracellular bacterium could be transferred with cells but not serum
Specificity and mediation of cell-mediated immunity is due to _______.
T lymphocytes
T lymphocytes work in concert with _______ to eliminate microbes.
phagocytes
T lymphocytes mediate defense against _______.
intracellular microbes that are inaccessible to circulating Abs
- viruses
- some bacteria
Function of cell-mediated immunity
- destruction of microbes residing in phagocytes
- killing of infected cells to eliminate reservoirs of infection
Function of T helper cells
eradication of extracellular microbes by helping B cells make effective Abs
Humoral immunity:
Microbe = Extracellular Microbes
1) Responding lymphocytes?
2) Effector mechanism?
3) Transferred by?
4) Functions?
1) B lymphocyte
2) Secreted antibody
3) Serum
4) Block infections and eliminate extracellular microbes
Cell-Mediated Immunity:
Microbe = Phagocytosed microbes in macrophage
1) Responding lymphocytes?
2) Transferred by?
3) Functions?
1) Helper T cells
2) Cells (T lymphocytes)
3) Activate macrophages to kill phagocytosed microbes
Cell-mediated Immunity:
Microbe = Intracellular microbes replicating within infected cell
1) Responding lymphocytes?
2) Transferred by?
3) Functions?
1) Cytotoxic T cells
2) Cells (T lymphocytes)
3) Kill infected cells and eliminate reservoirs of infection
What ensures that the immune response to a microbe (or non microbial antigen) is targeted to that microbe or antigen?
specificity
What enables the immune system to respond to a large variety of antigens?
diversity
What increases the ability to combat repeat infections by the same microbe?
memory
What increases the number of antigen-specific lymphocytes to keep pace with microbes?
clonal expansion
What generates responses that are optimal for defense against different types of microbes?
specialization
What allows the immune system to recover from one response so that it can effectively respond to newly encountered antigens?
contraction and homeostasis
What prevents injury to the host during responses to foreign antigens?
nonreactivity to self
When Ag is introduced and lymphocytes with receptors for Ag seek and bind it, they are triggered to _____.
proliferate and differentiate
gives rise to clones of cells that are specific for the Ag
Cells that seek and bind the Ag, react with the Ag to ______.
neurtralize or eliminate the Ag
Ag-specific cells late in the immune response are responsible for________.
memory in adaptive immunity
What did Dr. Jerne and Dr. Burnet suggest?
Clonal selection hypothesis
Ag-specific clones of lymphocytes develop before and independent of exposure to Ag
What is a clone?
A lymphocyte of one specificity and its progeny
4 steps of the Hypothesis of Clonal Selection
1) MATURE – Lymphocyte clones mature in generative lymphoid organs (in absence of antigens)
2) ENTER – Clones enter lymphoid tissue
3) ACTIVATED – Clones activated (selected) by antigens
4) RESPONSE – Antigen-specific immune responses occur
5 Phases of Adaptive Immune Responses
1) Antigen recognition
2) Lymphocyte activation (clonal expansion and differentiation)
3) Antigen elimination (antibodies and effector T cells)
4) Contraction/Homeostasis (apoptosis)
5) Memory
Primary vs. Secondary Adaptive Immune Response
Secondary response = more rapid and larger than primary response (memory)
In what phase do the expanded lymphocyte clones die?
contraction phase
homeostasis is then restored
Which English physician was the first to successfully vaccinate against smallpox?
Edward Jenner
Cowpox material»_space; 8 y.o. boy»_space; no disease developed when inoculated with smallpox later
Who is the father of immunology?
Dr. Pasteur
developed vaccines
What is active immunity?
- Conferred by a host response to a microbe or microbial Ags
- Provides resistance to infection
- Generates immunologic memory
What is passive immunity?
- Conferred by adoptive transfer of Abs or T cells specific for the microbe
- Provides resistance to infection
Which type of immunity generates immunologic memory (active or passive)?
Active immunity
B lymphocytes
1] Antigen recognition
2] Effector functions
1] Recognize soluble Ags and develop into Ab-secreting cells
2] Functions:
- Neurtalize microbe
- Phagocytize
- Complement activation
T helper lymphocytes
1] Antigen recognition
2] Effector functions
1] Recognize Ags on surface of Ag-presenting cells and secrete cytokines –> stimulate different immunity and inflammation
2] Functions:
- Activation of macrophages
- Inflammation
- Activation (proliferation and differentiation) of T and B cells
Cytotoxic T lymphocytes
1] Antigen recognition
2] Effector functions
1] Recognize Ags on infected cells
2] Function:
-Kill infected cells
Regulatory T cells
1] Antigen recognition
2] Effector functions
1] Self antigens
2] Functions:
-Suppress of other lymphocytes to prevent immune responses (to self antigens)
8 Cells of Innate Immunity
- neurtophil
- eosinophil
- basophil
- mast cell
- monocyte
- macrophage
- dendritic cell
- natural killer cell
WBC
- Normal range
- Mean
4,500-11,000
7,400
Neutrophils
- Normal range
- Mean
1,800-7,700
4,400
Eosinophils
- Normal range
- Mean
0-450
200
Basophils
- Normal range
- Mean
0-200
40
Monocytes
- Normal range
- Mean
0-800
300
Lymphocytes (T and B cells)
- Normal range
- Mean
1,000-4,800
2,500
Phagocyte function
Scavenger function
- ingest and destroy microbes
- get rid of damaged tissues
What cells are phagocytes?
- neutrophils
- macrophages
4 Steps of Phagocyte Response
- RECRUITMENT of cells to infection site
- RECOGNITION of and activation by microbes
- INGESTION of microbes by phagocytosis
- DESTRUCTION of ingested microbes
Activated phagocytes also secrete _____ to promote or regulate immune responses
cytokines
What are polymorphonuclear leukocytes?
- Neutrophils in normal blood
- Nucleus = segmented into 3-5 connected lobules
- Most abundant population of circulating WBC
- Diameter = 12-15 um
Polymorphonuclear leukocyte (neutrophils) function
mediate the earliest phases of inflammatory reactions
Where are neutrophils produced?
bone marrow
pleuripotent stem cells
Neutrophils arise from precursors that also give rise to _______.
Mononuclear phagocytes
What stimulates the production of neutrophils?
Granulocyte colony-stimulating factor (G-CSF)
a cytokine
How many neutrophils does an adult human produce daily?
1 x 10^11
How long does a neutrophil circulate in the blood?
- hours or a few days
- function in tissues for 1-2 days, then die
What stain is used for neutrophils?
neutral dyes
What stain is used for eosinophils?
eosin
What stain is used for basophils?
basic dyes
What are azurophilic granules?
- Lysosomes
- Contain enzymes and other microbicidal substances
What happens after neutrophils bind and internalize yeast cells via phagocytosis?
- yeast is sequestered in phagosomes
- fuse with azurophilic granules
What contributes to the killing of the phagosome?
- the production of ROS
- the release of enzymes (neutrophil elastase) into the phagosome
What happens when neutrophils encounter hyphae?
- not able to internalize them
- azurophilic granules = free to deliver their contents into the nucleus
- triggers chromatin decondensation and NET release
What do NET contribute to?
immobilization and killing of extracellular organisms
COST = some tissue damage
NET formation characteristics
- rapid, active process (minutes)
- mediated by cell death-dependent process (NETosis)
- composed of DNA (from mitochondria) and histones
- decorated by proteins from 1’ and 2’ granules
NETosis
- chromatin decondensation
- nuclear membrane disintegration
What is NET formation associated with?
- bacterial clearance
- thrombosis
- sepsis
- SLE
What protects against helminthes and reactions that cause allergic diseases?
- mast cells
- basophils
- eosinophils
Mast cells
- Filled with?
- Stained with?
- Histimines and other mediators
- Giemsa»_space; PURPLE
Blood basophils
Stained with?
Giemsa»_space; BLUE
Eosinophil granules
- Filled with?
- Stained with?
- basic proteins
- eosin (acidic dye)»_space; RED
8 Functions of Mast Cells
- Recruitment and activation of monocytes and macrophages
- Migration and activation of dendritic cells
- Recruitment and activation of T cells
- Recruitment and activation of neutrophils, basophils, and eosinophils
- Phagocytosis and/or antimicrobial activity
- Effects on epithelial cells, tight junction proteins, etc…
- Degradation of endogenous toxic mediators
- Degradation of snake venom components
Where are mast cells commonly found?
- sites that are exposed to the external environment (skin)
- close to BV
Mast cells can regulate ____ and _____.
regulate vascular permeability and effector-cell recruitment
The mononuclear phagocyte system includes _____ and _____.
- Circulating monocytes
- Resident tissue macrophages
What type of immunity do macrophages play a role in?
Innate & Adaptive immunity
Where do cells of macrophage lineage arise from?
Committed precursor cells in bone marrow
What stimulates macrophage formation?
Monocyte/Macrophage colony-stimulating factor (M-CSF)
Monocyte pathway
1- Bone marrow 2- Activated 3- Maturation 4- Enter blood circulation 5- Migrate to tissues 6- Mature into macrophages (especially during inflammation)
Fetus Mononuclear Phagocyte pathway
1- (Yolk sac) Hematopoietic stem cell 2- Embryonic tissue macrophage precursor 3- Blood 4- Differentiation in tissues > Brain = Microglial cells > Liver = Kuppfer cells > Liver = Alveolar macrophage > Spleen = Sinusoidal macrophages
Adult Mononuclear Phagocyte pathway
1- (Bone marrow) Hematopoetic stem cell 2- Monocyte/dendritic cell precursor 3- Monoblast 4- Blood 5- Monocyte 6- Macrophage activation in tissues
Mononuclear Phagocytes (Bone Marrow»_space; Peripheral Blood)
Bone Marrow: > HSC > GM-CFU > M-CFU > Monoblast > Pro-monocyte
Peripheral Blood:
> Inflammatory monocyte
> Resident monocyte
Monocyte Differentiation Options
-Bone = osteoclast
-CNS = microglial cells
-Lung = Alveolar macrophage
-Liver = Kupffer cells
-Connective tissue = Histiocyte
-Spleen =
> White pulp macrophage
> Red pulp macrophage
> Marginal zone macrophage
> Metallophilic macrophage
6 Functions of Monocytes/Macrophages
1- Activation 2- Chemotaxis, tissue inflammation 3- Phagocytosis, scavenger function, tissue repair 4- Effector function 5- Antigen presentation 6- Immunomodulation
MO present Ags to helper T cells at the sites of infection that leads to ______.
- T cell activation
- Activation of cytokines»_space; Activation of MO
- Eradication of phagocytized microbes that are resistant to killing
Common dendritic cell precursors
ADULTS:
-Pre-classical DC»_space; Classical DC
- Plasmacytoid DC»_space; Plasmacytoid DC (pDCs)
- Monocyte»_space; Inflammatory DC
FETUS:
-Embryonic tissue precursor»_space; Langerhans cells