Immunology Course-General Principles

1. Repetition is good, especially in different contexts.

2. As good students, you are accustomed to mastering “the syllabus.”At least in this course, you can’t. The syllabus is an illusion, itdoes not truly exist.

3. It is important to learn the basics, the “party line.”

4. There is no party line; it keeps changing.

Immunology Course-General Principles

“Do I know the material?”

Simple test to determine whether you have mastered the material:

If you can explain the underlying concepts to the naïve (but motivated)student, you’re heading in the right direction. Therefore: learn whatquestions to ask.

Immunology--The Whirlwind Tour

Time Course of thePrimary Immune Response

Innate immunity

Acquired immunity

Ontogeny of the Acquired Immune System

Step 1. Lymphocytes develop in the bone marrow and thymus

Step 2. Naïve lymphocytes circulate in the blood and lymph

Step 3. The primary immune response occurs in the lymph nodesand spleen

Step 4. Lymphocytes exit the lymph nodes and spleenand become effector lymphocytes--they produce antibody (B cells) or become competent to kill (CD8+ T cells)

Stages in the Development of a Primary Immune Response

Step 1. The immune repertoire develops Lymphocytes develop early in life in the 1° lymphoid organs (bone marrow and thymus) and are competent to respond to a broad array of antigens. This process is first stochastic in nature and then becomes regulated by the MHC through positive and negative selection.

Ig Maturation

Antibodies: Secreted or Transmembrane (BCR)

TCR: Transmembrane

Antibody (Ig) and TCR are the Only Genes that Undergo Somatic Cell Recombination

Journey of a B Cell

Ordered TCR gene rearrangement and TCR expression

Ordered expression of surface molecules:CD2CD4 and CD8CD3 and the TCR

Thymocyte Education: Selection of the T cell repertoireNegative SelectionPositive Selection

What Happens in the Thymus?

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Thymic Development

Periphery

Bone marrow

“Educated, but naïve”

What Happens During aPrimary Immune Response?

The Primary Immune Response--Input (APCs) and Output

(Lymphocytes et al.)

Three Types of APCs

The Itinerant Dendritic Cell

Functional Anatomy of a Lymph Node

Ag-loadedAPC Naïve

T-cell

Effector orMemory T-cell

The Clonal Selection Theory

Naïve state

Ag encounter

Clonal expansion

Functions of MHC I and II

N

1

2

Structure of Peptide-binding Class I MHC Domains

Contact Between the TCR and MHC/peptide:

Not All Peptides are Created Equal

Contact Between the TCR and MHC/peptide:

Not All MHC Molecules are Created Equal

Polymorphisms

The “Fit” Between MHC Moleculesand Peptide Defines MHC

Restriction

Polymorphisms within the MHC account forthe variability of the immune response between individuals

AntigenRecognition

T Cell Receptor for Antigen (TCR):One TCR is Specific for One Antigen

T cellActivation

1. Bound antigen is internalizedand presented to T cells.

2. Bound antigen triggers signals in the B cell to proliferate anddifferentiate.

The B Cell Receptor for Antigen (BCR)

Two Major Functions:

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The “Immunologic Synapse”

The Two-Signal Theory of T-cell Activation

APC = Antigen-presenting cellsTCR = T-cell receptor for antigenDC = Dendritic cellCD80 = Co-stimulatory receptor

2 1 1 2

No responseNo response

or AnergyActivation

V

C C

V

peptide

CD3

TCRCD4

MHC II

V

C C

V

CD3

TCR

MHC I

CD8

(1) Interacts with MHC class II expressing cells (APCs)

(2) Helps B cells to synthesize antibody(3) Induces and activates macrophages(4) Secretes cytokines

(1) Interacts with MHC class I-expressing cells (all nucleated cells)

(2) Kill MHC class I-expressing target cells(3) Secretes cytokines

CD4+ T cell CD8+ T cell

peptide

Two Major Functional T Cell Subsets

LckLck

APC APC

CD4+ T Cells Activate Macrophages and B cells

CD8+ CTLs Kill Viral-infected Cells

B cells CD8 CD4

Ab production Cytotoxicity Cytotoxicity Help to B cellsAg presentation IFN- secretion Help to CD8 T cells

Cytokine secretion Macrophages activationInnate

immunity

T cells

Major Lymphocyte Subsets in Peripheral Blood and Selected Effector Functions

ImmunityImmunity Tolerance Tolerance

AutommunityAutommunity ImmunodeficiencyImmunodeficiency

Activation Suppression

Regulation of the Immune Response:

a Conceptual View

Systemic Lupus Erythematosis (SLE): AnAutoimmune Disease

Clinical Manifestations of Rheumatoid Arthritis