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, it does 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 na ï ve (but motivated) student, you’re heading in the right direction. Therefore: learn what questions to ask.

Immunology-- The Whirlwind Tour

Time Course of the Primary 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 nodes and spleen Step 4. Lymphocytes exit the lymph nodes and spleen and 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: CD2 CD4 and CD8 CD3 and the TCR Thymocyte Education: Selection of the T cell repertoire Negative Selection Positive Selection What Happens in the Thymus?

Thymic Development Periphery Bone marrow “ Educated, but na ï ve ”

What Happens During a Primary 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-loaded APC Naïve T-cell Effector or Memory T-cell

The Clonal Selection Theory    Naïve state Ag encounter Clonal expansion

Functions of MHC I and II

N 11 2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 Molecules and Peptide Defines MHC Restriction Polymorphisms within the MHC account for the variability of the immune response between individuals

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

1. Bound antigen is internalized and presented to T cells. 2. Bound antigen triggers signals in the B cell to proliferate and differentiate. The B Cell Receptor for Antigen (BCR) Two Major Functions:

The “Immunologic Synapse”

The Two-Signal Theory of T-cell Activation APC = Antigen-presenting cells TCR = T-cell receptor for antigen DC = Dendritic cell CD80 = Co-stimulatory receptor No response or Anergy Activation

   V  C  C  V    peptide CD3 TCR CD4 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 Lck 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 cells Ag presentation IFN-  secretion Help to CD8 T cells Cytokine secretion Macrophages activation Innate immunity T cells Major Lymphocyte Subsets in Peripheral Blood and Selected Effector Functions

Immunity Tolerance Autommunity Immunodeficiency Activation Suppression Regulation of the Immune Response: a Conceptual View

Systemic Lupus Erythematosis (SLE): AnAutoimmune Disease

Clinical Manifestations of Rheumatoid Arthritis