micro 405: immunology

what is immunology?

the study of physiological mechanisms that humans and other animals use to defend bodies from invasion by other organisms

a historical perspective of immunology and vaccinations

• Dr. Edward Jenner observed that dairy farmers were immune to smallpox

• smallpox disease is highly contagious and often deadly, whereas _____ is a mild form of smallpox

  • inoculation with it was done to prevent humans from contracting smallpox

cowpox

what are the main components of immunology?

innate and adaptive immunity

overview of immunologic networks

1. pathogens enter the body through mucosal surfaces or skin

2. the pathogen is detected by resident phagocytic cells (yellow), triggering ______

innate immunity

overview of immunologic networks

3. free pathogen and some phagocytic cells that have engulfed the pathogen flow or migrate through lymphatic vessels toward ______ (e.g. lymph nodes)

secondary lymphoid structures

overview of immunologic networks

4. they intersect with lymphocytes entering from the blood

5. ______ is initiated in secondary lymphoid tissues, where T helper cells (blue), T cytotoxic cells (red), and B cells (green), which result in proliferation and differentiation

adaptive immunity

overview of immunologic networks

6. T and B cells migrate out of the lymph node

7. as they identify areas of infection, they migrate toward the infection, where they can help and destroy any remaining pathogen (the ____ phase)

8. _____ are generated

effector, memory cells

how do we generate immune cells?

• ______

  • the process by which hematopoietic stem cells (HSCs) differentiate into mature blood cells

• stems cells are defined by two capacities:

  • the ability to regenerate or “self-renew”

  • the ability to differentiate into diverse cell types

hematopoiesis

generation of immune cells (hematopoiesis)

• ______ generate lymphocytes

common lymphoid progenitor

generation of immune cells (hematopoiesis)

• _______ generate myeloid cells

common myeloid progenitor

generation of immune cells (hematopoiesis)

• myeloid cells are _____

innate

generation of immune cells (hematopoiesis)

• lympoid cells are _____

adaptive

the myeloid lineage: innate cells

• what are the innate cells?

granulocytes and phagocytes

the myeloid lineage: innate cells

_______

• include neutrophils, eosinophils, basophils, and mast cells

• first responders to multiple extracellular pathogens, including bacteria/parasitic worms

• when activated, they release contents of _____, which directly and indirectly impair pathogen activity

• also release ______ that influence adaptive immune response and are potent contributors to allergic respones

granulocytes, granules, cytokines

the myeloid lineage: innate cells

_______

• include macrophages and dendritic cells

• when activated by an _____, they can activate T lymphocytes

• dendritic cells are the most potent antigen-presenting cell for naive T cells

phagocytes, antigen

the myeloid lineage: innate cells

• what are the granulocytes?

neutrophils, eosinophils, basophils, and mast cells

the myeloid lineage: innate cells

• what are the phagocytes?

macrophages and dendritic cells

the myeloid lineage: innate cells

• granulocytes

  • _____: phagocytosis and activation of bactericidal mechanisms

neutrophil

the myeloid lineage: innate cells

• granulocytes

  • ______: killing of antibody-coated parasites

eosinophil

the myeloid lineage: innate cells

• granulocytes

  • ______: promotion of allergic responses and augmentation of anti-parasitic immunity

basophil

the myeloid lineage: innate cells

• granulocytes

  • ______: release of granules containing histamine and active agents

mast cell

the myeloid lineage: innate cells

• phagocytes

  • _____: phagocytosis and activation of bactericidal mechanisms (antigen presentation)

macrophages

the myeloid lineage: innate cells

• phagocytes

  • _____: antigen uptake in peripheral sites (antigen presentation)

    • most potent antigen-presenting cells for naive T cells

dendritic cells

the myeloid lineage: innate cells

• what do granulocytes release to trigger allergic responses?

cytokines

lymphocytes are mediators of adaptive immunity

1. lymphocytes include B cells and T cells which are the principal players in the adaptive immune response and the source of _____

2. B and T cells express unique ______ on their surfaces: the B-cell receptor (BCR) and the T-cell receptor (TCR)

3. activated B cells can present antigens to T cells

4. B cells ultimately differentiate into antibody producing cells called _______

5. T lymphocytes include CD4+ helper T cells and CD8+ cytotoxic T cells

6. natural killer (NK) cells can kill some infected and tumor cells

immune memory, antigen receptors, plasma cells

lymphocytes are mediators of adaptive immunity

• what are the lymphocytes?

B and T cells

lymphocytes are mediators of adaptive immunity

• what are B cells that have differentiated into antibody-producing cells called?

plasma cells

lymphocytes are mediators of adaptive immunity

• what are the T lymphocytes?

CD4+ helper T cells and CD8+ cytotoxic T cells

lymphocytes are mediators of adaptive immunity

• what T lymphocyte recognizes peptides bound to MHC class II?

CD4+ helper T cell

lymphocytes are mediators of adaptive immunity

• what T lymphocyte recognizes peptides bound to MHC class I?

CD8+ cytotoxic cell

types of antigen receptors

• B cell receptors (BCR) are _____ and can be either cell-associated or soluble (antibodies)

  • they have 2 identical antigen-binding sites, and each B cell is specific for a single antigen

bivalent

types of antigen receptors

• B cell receptors (BCR)

  • antibody: _____

soluble

types of antigen receptors

• B cell receptors (BCR)

  • BCR: ______

membrane-bound

types of antigen receptors

• T cell receptor (TCR) are surface molecules. they have a ____ antigen binding site that is specific for the antigen that is presented in association with an MHC molecule

  • each T cell clone is specific for a single antigen/MHC combination

single

types of antigen receptors

• B cell and T cell each have one _____ specificity

antigen

B cells

• B cells (lymphocytes) develop in the bone marrow

• produce _____: proteins that bind to antigens

• each cell expresses a unique B cell receptor

antibodies

T cells

• development depends on the ____

• two kinds of T cells: helper cell with CD4 on surface and cytotoxic cell with CD8 on surface

• each cell expresses a unique T cell receptor

thymus

natural killer (NK) cells

• lymphocytes but participates in innate immunity

• provide defense against viruses, bacteria, and tumor cells

• are able to recognize and lyse target cells lacking _____

MHC class I

____: releases lytic granules that kill some virus-infected cells

natural killer (NK) cells

dendritic cells

• both myeloid and lymphoid

  • activate T cells as antigen presenting cells (APC)

  • ____ innate immunity to adaptive immunity

bridge

three phases of immune responses upon infection

• innate immunity

  • _____: 0-4 hours

  • infection → recognition by preformed,

  • nonspecific and broadly specific effectors → removal of infectious agent

immediate

three phases of immune responses upon infection

• _______

  • early: (4-96 hours)

  • infection → recruitment of effector cells → recognition of PAMPs. activation of effector cells and inflammation → removal of infectious agent

early induced innate response

three phases of immune responses upon infection

• _______

  • late: >96 hours

  • infection → transport of antigen to lymphoid organs → recognition by naive B and T cels → clonal expansion and differentiation to effector cells → removal of infectious agent

adaptive immune response

two arms of immunity

• innate immunity

  • immediate

  • constitutive

  • includes myeloid cells and NK cells, complement, and other factors

  • depend on the ability to distinguish molecules expressed by microbes

  • protection by ______ or destruction of non-self structures

neutralization

two arms of immunity

• adaptive immunity

  • delayed

  • inducible

  • includes T and B cells with specific receptors

  • depends on the _____ with specificity of the receptors on B and T cells

  • generates memory cells and responses

diversity

the immune system protects against four classes of pathogens

• what are they?

viruses, intracellular bacteria, extracellular bacteria, and parasitic worms

two different types of pathogen recognition by immune cells

• _______

  • innate cells (granulocytes, macrophages)

  • innate immunity

pattern-dependent recognition

two different types of pathogen recognition by immune cells

• _______

  • adaptive cells (B and T cells)

  • adaptive immunity

antigen-specific recognition

an example of pattern-dependent recognition: neutrophils and macrophages

• _____ express pattern recognition receptors for an initial discrimination between self and non self

sensor cells

an example of pattern-dependent recognition: phagocytes

• ______ agents produced by phagocytes after taking up microorganisms

bactericidal

what are the key features of the adaptive immune response?

specificity, diversity, self-tolerance, and memory

four characteristics of adaptive immune responses

• ______ of recognition by cells and molecules

  • the cells and molecules in the immune system recognize the particular antigen that they are selected for one million-fold better than (most) all other antigens

specificity

four characteristics of adaptive immune responses

• _____ of recognition

  • immune system can recognize ten million or more different antigens

diversity

four characteristics of adaptive immune responses

• ______

  • depending on how an antigen is encountered, the immune system can become nonresponsive to that antigen.

    • maammals and birds are tolerant to self-antigens

tolerance

four characteristics of adaptive immune responses

• _____ or secondary responses

  • the immune response upon a second encounter with an antigen is stronger, faster, and qualitatively different than the first encounter with an antigen

memory

lymphoid organs

• ______ lymphoid organs is where immune cells develop

primary

lymphoid organs

• _____ lymphoid organs are where immune response is initiated

  • lymph nodes, spleen

secondary

clonal selection

• clonal selection is the process by which individual lymphocytes are either activated to produce a clone (positive selection) or deleted to prevent a clone from developing (negative selection)

  • each lymphocyte expresses a single antigen specificity

  • recognition of that antigen results in lymphocyte activation

  • activation results in the _______ of that lymphocyte and the formation of a _____, all of which express the same antigen specificity

  • ______ lymphocytes are deleted during development and are not present in the circulation

proliferation, clone, self-reactive

clonal selection

• what is positive selection?

when an individual lymphocyte is activated to produce a clone

clonal selection

• what is negative selection?

when an individual lymphocyte is deleted to prevent a clone from developing

a _____ in the gut epithelial, secretes mucus to protect epithelial cells from microorganism invasion

goblet cell

key elements of innate immunity

• the first line of defense

  • physical and chemical barriers that prevent infection, provided by the _____ layers of the skin, _____ tissues (ex. gastro, respiratory, and urogenital tracts), and _____ tissues (ex. salivary and mammal glands)

epithelial, mucosal, glandular

what is included in the mucosal immunology?

skin, mouth, airway lung, large intestine, and small intestine

key elements of innate immunity

• the second line of defense

  • recognizes pathogen components and triggers a variety of cellular responses

  • pathogen recognition by these receptors activates some cells to ______ and degrade the pathogen

phagocytose

key elements of innate immunity

• activation of innate immune responses kills pathogens and produces _______ and _______ that recruit cells, molecules, and fluid to the site of infection, leading to swelling and other symptoms collectively known as ________

cytokines, chemokines, inflammation

two major components of innate immunity

• ____ mediators

  • anti-microbial peptides

  • cytokines and chemokines

  • complement

• ____ mediators

  • cell types: granulocytes, phagocytes, and NK cells

  • receptors in innate immunity

    • pathogen-associated molecular patterns (PAMPs) on microbes are recognized by pattern recognition receptors (PRRs) on host cells

    • PAMP-PRR interaction induces inflammation

soluble, cellular

two major components of innate immunity

• what are the soluble mediators of innate immunity?

antimicrobial peptides, cytokines/chemokines, and complements

two major components of innate immunity

• what are the cellular mediators of innate immunity?

granulocytes, phagocytes, NK cells, PAMPs, and PRRs

two major components of innate immunity

• cellular mediators

  • ______ interaction induces inflammation

PAMP-PRR

two major components of innate immunity

• pathogen-associated molecular patterns (PAMPs) on microbes are ______ by pattern recognition receptors (PRRs) on host cells

recognized

soluble mediators

• antimicrobial peptides

  • _______ produced by phagocytes after taking up microorganisms

    • macrophage products: cathelicidin, macrophage elastase-derived peptide

    • neutrophil products: lactoferricin, azurocidin, etc.

bactericidal agents

soluble mediators

• in response to invasion or threat, immune cells ______ with each other using chemical messengers such as cytokines and chemokines

communicate

soluble mediators

• cytokines

  • ____ that stimulate or inhibit the differentiation, proliferation, or function of cells

  • produced by immune and non-immune cells

  • one cell may produce many cytokines

  • one cytokines may be produced my many different cells

proteins

soluble mediators

• cytokines

  • ______: cytokines that act on leukocytes

    • IL-#, up to IL-1 up to IL-33

  • ______: cytokines that prevent (“interfere with”) viral infection

    • IFNs

interleukins, interferons

soluble mediators

• cytokines

  • what are cytokines that act on leukocytes?

interleukins

soluble mediators

• cytokines

  • what are cytokines that prevent (“interfere with”) viral infection?

interferons

soluble mediators

• _____: a family of structurally related cytokines that selectively induced chemotaxis and activation of leukocytes

chemokines

soluble mediators - introduction of the complement system

• activation by _____

  • by 3 different initiators that bind to pathogens:

    • classical pathway, lectin pathway, and alternative pathway

• _____

  • a cascade of proteolysis follows, generating the central proteins of the complement cascade, the C3 and C5 convertases

• three outcomes

  • opsonization

  • inflammation

  • cell lysis by the membrane attack complex (MAC)

microbes, proteolytic cascade

soluble mediators - introduction of the complement system

• proteolytic cascade

  • a cascade of proteolysis follows, generating the central proteins of the complement cascade, the _____

C3 and C5 convertases

soluble mediators - introduction of the complement system

• what are the three outcomes of the complement system?

opsonization, inflammation, and cell lysis by MAC

soluble mediators - introduction of the complement system

• ______: coating pathogen with antibodies and/or complement proteins → readily taken up by phagocytes

opsonization

cellular mediators

• sensor cells express ________ for an initial discrimination between self and non-self

  • ex. neutrophils and macrophages

    • macrophages also activate adaptive immunity, so a little different than neutrophils

pattern recognition receptors (PRRs)

characteristics of natural killer (NK) cells

• lymphocytes but participate in innate immunity

• provide defense against viruses, bacteria, and tumor cells

• recognize and lyse target cells lacking ______

• NK cell-mediated activation involves the secretion of cytokines, in particular, INF-𝛾 and direct ____-dependent cytolysis of target cells

• NK cell activity is controlled by an array of activating and inhibitory receptors

MHC class I, perforin

NK cell killing: a question of balance

• NK cell inhibition

  • MHC class I on normal cell is recognized by inhibitory receptors that inhibit signals from activating receptors → NK cell does not lyse normal cell

• NK cell activation

  • absent MHC class I cannot stimulate a negative response → activated NK releases granule contents, inducing _____

• virus-infected cells and tumor cells _____ MHC

apoptosis, downregulate

summary of NK cell killing

1. the major histocompatibility (MHC) is expressed by healthy cells as an indication of “self”

2. NK cells can recognize MHC markers on the surface of healthy cells, and these MHC markers serve as an _____ signal preventing NK cells from activation

3. to kill, NK cells need a second signal - called _______ - confirming that the target is altered meaning transformed or infected

4. NK cells synthesize (perforin and granzymes) stores in lytic granules.

   1. Cytotoxins are secreted upon receptor engagement

inhibitory, activating signal

how do innate immune cells sense pathogens?

• _______

  • pathogen-associated microbial patterns (PAMP)

  • the molecules expressed in microbes and recognized by innate immune cells

    • ex. cell wall carbohydrates, flagellin, non-methylated CpG

pathogens

how do innate immune cells sense pathogens?

• _______

  • pathogen recognition receptors (PRR)

    • the receptors expressed on host cells and recognize PAMPs and other microbial-associated molecules

      • ex. TLR, NLR, RLR

immune cells

pathogen-associated molecular patterns (PAMPs)

• PAMPs are signature molecules expressed only in _____ such as bacteria, viruses, fungi, but not in human cells

• PAMP are repeating ______ common to many microbes within the same group

• PAMP can be found on the surface of the pathogen (surface pattern) or inside the pathogen (intracellular pattern)

microbes, structural motifs

pathogen-associated molecular patterns (PAMPs)

• where can PAMPs be found on microbes?

surface of pathogen (surface pattern) and inside the pathogen (intracellular pattern)

examples of PAMPs

• bacteria

  • surface: cell wall components and _____

  • intracellular: unmethylated _____

flagella, CpG DNA

examples of PAMPs

• viruses

  • surface: cell surface proteins

  • intracellular: _____ and _____

ds-RNA, ss-RNA

examples of PAMPs

• fungi

  • surface: ______

  • intracellular: none

cell wall

pattern recognition receptors (PRRs) - sensors

• pattern recognition receptors (PRRs) are proteins capable of recognizing PAMPs

  • they emerged phylogenetically before the appearance of adaptive immunity and, therefore, are considered to be part of the innate immune system

• PRRs are associated with subcellular compartments, such as the cellular and ______ membranes, the _____, and extracellularly

• there are four major subfamilies of PRRs

  • toll-like receptors (TLR)

  • nucleotide-binding oligomerization domain NOD leucin-rich repeats containing receptors (NLR)

  • retinoic acid-inducible gene 1 RIG-1-like receptors (RLR)

  • cytosolic DNA sensor cGAS

endosomal, cytosol

pattern recognition receptors (PRRs) - sensors

• what are four major subfamilies of PRRs?

toll-like receptors (TLR), NOD-like receptors (NLRs), RIG-1-like receptor (RLR), and cyclic GMP-AMP synthase (cGAS)

toll-like receptors

• ______

• are found either on the surface cell or intracellularly

  • recognize different things bc different locations

TLR-1 → TLR 9

TLR signaling pathway in innate immune cells

• ______ signals send cascades to activate pro-inflammatory cytokines

  • IL-6, IL-1β, TNF-⍺

surface

TLR signaling pathway in innate immune cells

• what are the pro-inflammatory cytokines?

IL-6, IL-1β, TNF-⍺

TLR signaling pathway in innate immune cells

• _____ activates type I IFNs induces anti-viral infection on targets

  • IFN-⍺ and IFN-β

intracellular

TLR signaling pathway in innate immune cells

• what are the type I interferons?

IFN-⍺ and IFN-β

nucleic acid-binding TLRs can trigger interferon (IFN) production

• virus-infected host cells → produce IFN-⍺ and IFN-β → induce innate immune responses and activate ____ cells to kill virus-infected cells → recruit lymphocytes and induce _______

NK, adaptive immunity