SERO_MTAP

Edward Jenner

smallpox vaccination

Louis Pasteur

father of immunology

Louis Pasteur

Discovered the first attenuated vaccine against cholera

Attenuation

altering the pathogen to make it less virulent through the use of:

• Heat 

• Aging 

• Chemical modification

• Attenuation – altering the pathogen to make it less virulent through the use of:

1888; Ellie Metchnikoff; starfish larvae

1894; Jules Bordet

Year & Person	Phagocytosis (_ _ was used)
Year & Person	Complement

1897; Robert Kaus

1901; Emil Von Behring

Year & Person	Precipitins
Year & Person	Serum antitoxins

1984

1987; Susumu Tonegawa

Tak Wah Mak Mark M. Davis Year?	T cell receptor gene
Year & Person	Antibody diversity Nobel Prize Awardee

2025; Sakaguchi, Brunkow, & Ramsdell

Year & Person

Nobel Prize in Medicine

Innate/Natural Immunity

resist infection by normally present immune function; non-specific

Adaptive Immunity

specificity for a pathogen and has memory which contributes to an increased response with repeated exposure

External Defense System

Physical

Biochemical

Normal Flora

_ (First line of defense)

Anatomic barriers (ex: skin) Divided into three components: _ _ _

Internal Defense System

Cellular

Humoral

_ (Second line of defense)

_ – phagocytes, NK cells _ – non-cellular Acute phase reactants (APR) Inflammation Complement

Acute Phase Reactants

Enhance the phagocytic process

C-Reactive Protein (CRP)

cardiovascular disease

Acute Phase Reactants

Marker for acute inflammation

Capable of opsonization, agglutination, precipitation, and complement activation

Increase in CRP = increased risk for ?

Serum Amyloid A

Acute Phase Reactants

High affinity for HDL

Complement

Acute Phase Reactants

Serum proteins that are capable of opsonization, chemotaxis, and cell lysis

C3

Acute Phase Reactants

Most abundant complement

C4

Acute Phase Reactants

2nd most abundant complement

a1-antitrypsin

Acute Phase Reactants

Major component of alpha-1 band in electrophoresis

“Mop-up” the effects of neutrophils during inflammation

Haptoglobin

Acute Phase Reactants

Binds irreversibly to free hemoglobin

Fibrinogen

Acute Phase Reactants

Increases the strength of a wound and is involved in the coagulation pathway

Ceruloplasmin

Acute Phase Reactants

Copper-transporting protein and is also an enzyme that oxidizes iron

a2-macroglobulin, fibrinogen, ceruloplasmin

Acute Phase Reactants

Components of A2 band

4-6

0.5

1000

Protein	Response Time	Normal Value (mg/dL)	Increase
C-Reactive Protein
Serum Amyloid A	24	5	1000x
a1-antitrypsin	24	200-400	2-5x
Fibrinogen	24	200-400	2-5x
Haptoglobin	24	40-290	2-10x
Ceruloplasmin	48-72	20-40	2x
C3	48-72	60-140	2x

24

5

1000x

Protein	Response Time	Normal Value (mg/dL)	Increase
C-Reactive Protein	4-6	0.5	1000x
Serum Amyloid A
a1-antitrypsin	24	200-400	2-5x
Fibrinogen	24	200-400	2-5x
Haptoglobin	24	40-290	2-10x
Ceruloplasmin	48-72	20-40	2x
C3	48-72	60-140	2x

Neutrophils

Internal Defense System (Cellular Components)

• First responder to infection

• Phagocytosis

• Most abundant in adults

• Reaches site of infection in 30-60 mins

Eosinophils

Internal Defense System (Cellular Components)

• Neutralize basophil and mast cell products

• Mast cell regulator

• Kills parasites

• Greatest eosinophilia in man is caused by the muscle worm

Basophils

Internal Defense System (Cellular Components)

• Induce and maintain allergic reaction

• Stimulates IgE production

Mast Cell

Internal Defense System (Cellular Components)

• Distributed to different tissue sites (skin, CT, etc.)

• Similar to basophils but longer life span and different lineage

acid phosphatase, alkaline phosphatase, protease, and histamine

Internal Defense System (Cellular Components)

Mast Cell

• Enzymes include (4)

Monocytes

Internal Defense System (Cellular Components)

• Largest WBC

• Migrates to tissue to become a macrophage

Macrophage

Internal Defense System (Cellular Components)

• Antigen presentation

• Kill intracellular parasites

• Phagocytosis

Dendritic Cells

Internal Defense System (Cellular Components)

• Most potent antigen presenting cell

• Most effective antigen presenting cell

Natural Killer (NK) Cells

CD16

CD56

• _ (+), (+)

• First line of defence against intracellular organisms and tumor cells

• Releases perforins and granzymes

• Bridges the innate and adaptive immune system

Perforins

Granzymes

NK Cells

• _ – perforate cell wall

• _ – enzyme packets which kill the microorganisms inside

Bone Marrow

Thymus

Primary Lymphoid Organs (2)

Spleen

Lymph Nodes

Tonsils

Appendix

Peyer’s Patches

Adenoid

MALT

GALT

BALT

Secondary Lymphoid Organs (9)

Inflammation

• Defined as the body’s overall reaction to injury or invasion by an infectious agent

• Attract cells to the site infection and remove pathogens by phagocytosis

• Rubor (redness)

• Calor (heat)

• Tumor (swelling)

• Dolor (pain)

• Functio laesa (loss of function)

Five cardinal signs of inflammation

Adherence

Phagocytosis

• Mediated by chemotaxis

  • Attraction of cells to the site of infection by chemical substances such as APRs or soluble bacterial components

• When a NEUT encounters the site of injury or infection, it attaches to the endothelial cells and moves to the tissue

Engulfment

Phagocytosis

• Outflowing of cytoplasm to surround the microorganism by pseudopodia (endocytosis)

Phagosome Formation

Phagocytosis

• The pseudopodia will fuse and enclose the pathogen to form the phagosome

• The phagosome will then travel towards the center of the cell

Granule Contact

Phagocytosis

• Lysosomal granules migrate and fuse with the phagosome

Phagolysosome Formation

Phagocytosis

• Contents of the lysosome are fused into the membrane bound space

• The granules contain lysozymes, myeloperoxidase, and other proteolytic enzymes

Digestion

Phagocytosis

• Divided into:

  • Oxygen-independent pathway

  • Oxygen-dependent pathway

    • This process produces reactive oxygen species (ROS) that are highly toxic to the microorganism and damage proteins irreversibly

Superoxide (O2)

peroxide (H2O2)

hydroxyl (OH)

hypochlorite (OCl; most potent ROS)

Phagocytosis

• Digestion

  • ROS (4)

NADPH Oxidase Complex (NOC)

Phagocytosis

• Digestion

  • Key action in the oxygen-dependent pathway

Excretion

Phagocytosis

• Contents of the phagolysosomes are expelled outside the cell by exocytosis

Chronic Granulomatous Disease

• Affects phagocytic capability of neutrophils

• Impaired NADPH oxidase

Nitroblue Tetrazolium (NBT) Test

Chronic Granulomatous Disease

• Checks for enzymatic function of NADPH Oxidase

Blue

Yellow

• Nitroblue Tetrazolium (NBT) Test

  • Checks for enzymatic function

  • (+) NADPH oxidase: _ (d/t formazan)

  • (-) NADPH oxidase: _ (d/t tetrazolium)

Adaptive Immunity

• Specificity for each individual pathogen or microbial agent

• The ability to remember a prior exposure

• An increased response to that pathogen upon repeated exposure

B lymphocytes and T lymphocytes

Adaptive Immunity

• Key Cells

Double Negative (DN) Stage

T Lymphocytes (Development and Differentiation)

• Lacks CD4 and CD8

• Proliferates under the influence of IL-7 in the outer cortex of the thymus

IL-7

Double Negative (DN) Stage

Proliferates under the influence of _ in the outer cortex of the thymus

Double Negative (DN) Stage

T Lymphocytes (Development and Differentiation)

• Rearrangement of the genes that code for the T-cell receptor (TCR)

7

14

Double Negative (DN) Stage

• Rearrangement of the genes that code for the T-cell receptor (TCR)

  • Beta chain is coded on chromosome _

  • Alpha chain is coded on chromosome _

Double Positive Stage

T Lymphocytes (Development and Differentiation)

• CD4 and CD8 are expressed

Positive selection

thymic cortex

T Lymphocytes (Development and Differentiation)

• Double Positive Stage

  • CD4 and CD8 are expressed

  • __ - checks for TCR function; occurs in the ?

Positive selection

apoptosis

negative selection

T Lymphocytes (Development and Differentiation)

• Double-positive thymocyte

  • CD4 and CD8 are expressed

__ - checks for TCR function; occurs in the thymic cortex

• Strong binding or no binding to MHC I/II → _ (death by neglect)

• Intermediate binding → ?/SP Stage (Single Positive)

Negative selection

T Lymphocytes (Development and Differentiation)

• _ – checks for reaction with self-peptides; occurs in the thymic medulla and corticomedullary region

apoptosis

T Lymphocytes (Development and Differentiation)

• Self-peptide/antigen reaction = _

Clonal deletion

T Lymphocytes (Development and Differentiation)

• _ _ – process of elimination of clones of T cells that would be capable of an autoimmune response

Mature T Cells

T Lymphocytes (Development and Differentiation)

• exhibit only one type of marker (CD4 or CD8)

2/3

1/3

T Lymphocytes (Development and Differentiation)

Mature T Cells

• _% of the peripheral T cells express the CD4 antigen 

• _% of the peripheral T cells express the CD8 antigen

1:2

T Lymphocytes (Development and Differentiation)

Mature T Cells

• CD8:CD4 ratio = _

CD2

CD3

T Lymphocytes (Development and Differentiation)

• _ – earliest T cell marker

• _ – most specific cell marker

Double Negative Stage

C7

C14

T Lymphocytes (Development and Differentiation)

• _

  • Rearrangement of genes

  • Beta = _

  • Alpha = _

Double Positive Stage

CD8 (Tc)

CD4 (Th)

T Lymphocytes (Development and Differentiation)

• _

  • Checks TCR function against MHC I and II

  • MHC I: _

  • MHC II: _

Negative Selection

Apoptosis

Mature T cell

T Lymphocytes (Development and Differentiation)

• _

  • Checks for reaction against self-peptides

    • (+): _

    • (-): _

Th1

T-helper (Th) Cell Subtypes

• produces IFN-γ, IL-2, and TNF-α

  • Activates cytotoxic lymphocytes and macrophages

Th2

T-helper (Th) Cell Subtypes

• produces interleukins (IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13)

  • Helps B cells produce antibodies against extracellular pathogens

  • Regulate B-cell activity

Treg cell

4

25

T-helper (Th) Cell Subtypes

• suppress the immune response to self-antigens

  • CD_ (+) and CD_ (+)

Th17 cell

T-helper (Th) Cell Subtypes

• proinflammatory and associated with autoimmune diseases

  • Releases IL-17 and IL-22

Th9 cell

T-helper (Th) Cell Subtypes

• proinflammatory and stimulate hematopoietic cell growth

Th1, Th9

Th2, Th17

Cell-Mediated Immunity
Humoral Immunity

bone marrow

B Lymphocytes (Development and Differentiation)

B cells remain in the ?

Pro-B Cell

Pre-B Cell

Immature B Cell

Mature B Cell

B Lymphocytes (Development and Differentiation)

• Antigen-Independent Phase (4)

Pro-B Cell

B Lymphocytes (Development and Differentiation)

• Antigen-Independent Phase

  • Rearrangement of genes that code for the heavy and light chains of antibody molecule (sIg)

  • Heavy chain rearrangement occurs at chromosome 14

  • Differentiation of pro-B cells into pre-B cells occurs upon successful rearrangement of heavy-chain gene at either chromosome 14

Pre-B Cell

B Lymphocytes (Development and Differentiation)

Antigen-Independent Phase

• Synthesis of the heavy chain begins (starts with the μ chain)

• μ chains accumulate at the cytoplasm or;

• May be expressed on the cell surface with a surrogate light chain to form a pre-B cell receptor

Immature B Cell

B Lymphocytes (Development and Differentiation)

Antigen-Independent Phase

• Appearance of the complete IgM antibody

• μ chains are no longer detectable in the cytoplasm

CD21 (+)

Central tolerance

B Lymphocytes (Development and Differentiation)

Antigen-Independent Phase

• Immature B Cell

  • _ –  receptor for C3d

  • _ _ – elimination of immature B cells that bear self-reactive receptors

  • Leave the bone marrow to mature in the spleen

Marginal B cell

Follicular B cell

• IgD

B Lymphocytes (Development and Differentiation)

Antigen-Independent Phase

• Mature B Cell

  • Two types:

    • _ _ _ – blood-borne pathogen

    • _ _ _ – lymph nodes and other secondary lymph organs

  • Exhibit IgM and IgD on the surface nodes

  _ – prolongs the life span of mature B cells

Plasma Cell

B Lymphocytes (Development and Differentiation)

Humoral Phase

• Most fully differentiated lymphocyte

• Antibody production

• Not normally found in the blood

CD10

CD19

Protein	Pro-B Cell	Pre-B Cell	Immature B Cell	Mature B Cell	Plasma Cell
CD Markers	_ _	CD10 CD19 CD20	CD10 CD19 CD20 CD21 CD40	CD19 CD20 CD21 CD40	CD138
B-Cell Receptor	–	Pre-BCR: Immunoglobulin (Ig) heavy chain Surrogate light chain	Functional BCR: Immunoglobulin M (IgM) heavy chains and κ or λ light chains	Functional BCR: Immunoglobulin D (IgD) or IgM heavy chains and κ or λ light chains	–
MHC II	+	+	++	++	-

CD10

CD19

CD20

Immunoglobulin (Ig)

Surrogate light

Protein	Pro-B Cell	Pre-B Cell	Immature B Cell	Mature B Cell	Plasma Cell
CD Markers	CD10 CD19	(3)	CD10 CD19 CD20 CD21 CD40	CD19 CD20 CD21 CD40	CD138
B-Cell Receptor	–	Pre-BCR: _ heavy chain _ _ chain	Functional BCR: Immunoglobulin M (IgM) heavy chains and κ or λ light chains	Functional BCR: Immunoglobulin D (IgD) or IgM heavy chains and κ or λ light chains	–
MHC II	+	+	++	++	-

CD10

CD19

CD20

CD21

CD40

Immunoglobulin M (IgM)

Kappa or lambda

Protein	Pro-B Cell	Pre-B Cell	Immature B Cell	Mature B Cell	Plasma Cell
CD Markers	CD10 CD19	CD10 CD19 CD20	(5)	CD19 CD20 CD21 CD40	CD138
B-Cell Receptor	–	Pre-BCR: Immunoglobulin (Ig) heavy chain Surrogate light chain	Functional BCR: _ heavy chains and (2) light chains	Functional BCR: Immunoglobulin D (IgD) or IgM heavy chains and κ or λ light chains	–
MHC II	+	+	++	++	-

CD19

CD20

CD21

CD40

Immunoglobulin D (IgD) or IgM

Kappa or lambda

Protein	Pro-B Cell	Pre-B Cell	Immature B Cell	Mature B Cell	Plasma Cell
CD Markers	CD10 CD19	CD10 CD19 CD20	CD10 CD19 CD20 CD21 CD40	(4)	CD138
B-Cell Receptor	–	Pre-BCR: Immunoglobulin (Ig) heavy chain Surrogate light chain	Functional BCR: Immunoglobulin M (IgM) heavy chains and κ or λ light chains	Functional BCR: _ or _ heavy chains and (2) light chains	–
MHC II	+	+	++	++	-

CD138

Protein	Pro-B Cell	Pre-B Cell	Immature B Cell	Mature B Cell	Plasma Cell
CD Markers	CD10 CD19	CD10 CD19 CD20	CD10 CD19 CD20 CD21 CD40	CD19 CD20 CD21 CD40	(1)
B-Cell Receptor	–	Pre-BCR: Immunoglobulin (Ig) heavy chain Surrogate light chain	Functional BCR: Immunoglobulin M (IgM) heavy chains and κ or λ light chains	Functional BCR: Immunoglobulin D (IgD) or IgM heavy chains and κ or λ light chains	–
MHC II	+	+	++	++	-

Cell Flow Cytometry

Laboratory Identification of Lymphocytes

• identifying cells based on the scattering of light as cells in a stream of fluid flow in single file by a laser beam

Rosette Test

Laboratory Identification of Lymphocytes

• uses sheep or rabbit red blood cells to identify lymphocytes

1.077

Laboratory Identification of Lymphocytes

• Ficoll-Hypaque Test

  • Ficoll-Hypaque has a specific gravity of ?

Antigen

Antigens and Similar Substances

• substance that reacts with an antibody or sensitized T cells but may not be able to evoke an immune response in the first place

Immunogen

Antigens and Similar Substances

• capable of triggering an adaptive immune response by inducing the formation of antibodies or sensitized T cells in an immunocompetent host

Macromolecular size

Foreignness

Chemical composition/molecular complexity

Ability to be processed by MHC

Antigens and Similar Substances

Immunogen

• Characteristics (4)

Macromolecular size

Antigens and Similar Substances

Immunogen

• An antigen can only be considered an immunogen if its size reaches at least 10,000 daltons (10 kilodaltons)

Foreignness

Antigens and Similar Substances

Immunogen

• The more distant taxonomically the source of the immunogen is from the host

Chemical composition/molecular complexity

Antigens and Similar Substances

Immunogen

• Proteins – most effective immunogens due to their inherent structural complexity

• Carbohydrates – less effective than proteins because of their simpler structure; occur in the form of glycolipids or glycoproteins

• Lipids and nucleic acids – not immunogenic in their pure form but must be attached to a carrier molecule to elicit an immune response

Epitope

Antigens and Similar Substances

• antigenic determinants that are recognized by the lymphocytes