Chapter 1: Overview of the Immune System

Chapter 1:Overview of the Immune System • Innate (Non-Specific) Immunity • Anatomic barriers • Physiologic barriers • Endocytic barriers • Phagocytic barriers • Inflammatory response barriers • Adaptive (Specific) Immunity • Properties • Specificity • Diversity • Memory • Self/non-self recognition

Major organs of the immune system 1° organs 2° organs Major cells of the immune system B lymphocytes T lymphocytes Antigen presenting cells (APCs) Humoral immunity Cell-mediated immunity Compare and Contrast Cell-mediated vs. humoral immunity Acquired vs. innate immunity

Recognition of Ag by B and T lymphocytes • Lymphocyte specificity and diversity • Role of the major histocompatibility complex (MHC) • Processing and presentation of Ags • Specificity of receptors • Instructional theory • Clonal selection theory • 1° immune response • 2° immune response • Cellular interactions required for generation of IRs • Generation of the humoral response • Generation of the cell-mediated response • end of outline

OVERVIEW OF THE IMMUNE SYSTEM IS = immune system IR = immune response Definitions Immunity state of protection from infectious disease Immune Latin immunis (exempt) antigen foreign substance (non-self) (Ag) Two Types of Immunity Innate (non-specific) Adaptive (specific)

INNATE IMMUNITY(NON-SPECIFIC) • {Review Table 1-2 next } • Anatomic Barriers • Skin • Mucous Membranes • Physiologic Barriers • Temperature • pH • Endocytic barriers {Figure 1-3} • Phagocytic barriers • Inflammatory response barriers {Figure 1-4} • Collaboration between Innate and Adaptive Immunity

Endocytic barriers • - pinocytosis - macromolecules internalized via non-specific membrane envagination (sipping) • - receptor-mediated endocytosis - macromolecules selectively internalized via specific receptors • endocytic vesicles • (fuse) • endosome + 1° lysosome • (fuse) • 2° lysosome • (endolysosome) •  • digestion Figure 1.3 next

Figure 1.3 phagosome + 1° lysosome  (fuse) 2° lysosome (phagolysosome)  digestion {Fig. 1-3*}

Phagocytic barriers • - foreign material ingested • - cell membrane expands to form phagosome • -specialized cells only • - neutrophils • - blood monocytes • - tissue macrophages

Inflammatory Response Barriers • inflammation regulated by cytokines • cardinal signs of inflammation • 1. rubor(redness) • 2. tumor (swelling) • 3. calor(heat) • 4. dolor (pain)

Figure 1.4

major events of inflammation • 1. vasodilation • - redness • -  temperature • 2. capillary permeability • - influx of fluid (exudate) • - swelling • 3. influx of phagocytes • - phagocytose bacteria • - release lytic enzymes • - can damage healthy cells (pain)

Collaboration between Innate and Adaptive Immunity • Innate • Microbes generate “danger or warning” signals (LPS, microbial products etc.) • Increase ability of macrophages of macrophages to take up and present antigens to IS. • Stimulate secretion of cytokines. • Adaptive • When activated produce cytokines to increase effectiveness of innate immunity • Antibodies mark pathogens for destruction by complement

Adaptive IMMUNITY(SPECIFIC) Focus of course Properties antigen specificity diversity of B and T cells immunologic memory self/non-self recognition Theme of course Remember specificity diversity memory self/non-self recognition

ANTIGEN SPECIFICITY • IS can distinguish subtle differences among Ags • Sensitive to 1 a.a. difference • DIVERSITY • ability to recognize billions of foreign Ags • B cell diversity via immunoglobulins (Igs) • T cell diversity via T cell receptors (TCRs)

IMMUNOLOGIC MEMORY • IMMUNE SYSTEM remembers 1st Ag encounter • 2nd encounter with same Ag •  • heightened response • can confer life-long immunity • SELF/NON-SELF RECOGNITION • IS distinguishes self from non-self Ags • governed by MHC molecules • response to non-self Ags  normal IR • response to self Ags  autoimmune disease

MAJOR ORGANS OF THE IMMUNE SYSTEM 1° ORGANS · Bone Marrow - gives rise to B and T cells - B cell maturation · Thymus - T cells migrate from bone marrow - T cell maturation - thymic selection 2° ORGANS · Spleen - filter for blood - traps Ag - Ag interacts with Ag-specific cells · Lymph Nodes - filter for lymph - traps Ag - Ag interacts with Ag-specific cells

MAJOR CELLS OF THE IMMUNE SYSTEM {Figure 1-5} B CELLS T CELLS ANTIGEN PRESENTING CELLS (APCs) NOTE CD = Cluster of Differentiation (proteins expressed on cell surface) (a.k.a. protein “markers”)

B cells • responsible for humoral IR • originate and mature in bone marrow (bursa of Fabricius - chicken) • immunoglobulins (Ig) - (Ab is general term) • -Ag receptor (“recognition”) • -membrane-bound (mIg) » BCR • -soluble (sIg)

maturation • - Involves Ig gene rearrangements (>108combinations) (>108combinations) • - self-reactive B cells eliminated • mature B cells • -immunocompetent (Ag-specific) • -circulate in blood and lymph • -activated by Ag-binding to mIg

mature B cell + specific Ag • ê • clonal selection / expansion • í î • memory B cells plasma cells • long-lived - effector B cells • - remember Ag - short-lived • -2° response faster - secrete sIg • sIg + Ag • ê • Ag-Ab complex • ê • elimination

T CELLS • responsible for cell-mediated IR • originate in bone marrow • mature in thymus

·T cell receptor (TCR) - associated with CD3 - Ag receptor (“recognition”) - dimer ( or )

· maturation -involves TCR gene rearrangements (>1015 combinations) - self-reactive T cells eliminated • mature T cells • - immunocompetent (Ag-specific) • - circulate in blood and lymph • - activated by TCR recognition of Ag • + MHC

sub-populations • T helper cells (TH) • - CD3+, CD4+, CD8- • - recognize Ag + MHC II • - activation leads to cytokines (“help”) • T cytotoxic cells (TC) • - CD3+, CD4-, CD8+ • - recognize Ag + MHC I • - activation è differentiation to CTL • - cytotoxic T lymphocyte • - armed effector cell • -kills target cell

ANTIGEN PRESENTING CELLS (APCs) • internalize Ag by phagocytosis or endocytosis • present Ag + MHC II to TH cells • {Figure 1-6} • TH cells produce cytokines • cytokines required by T and B cells • T cells (cell-mediated immunity) • B cells (humoral immunity) • APCs • - macrophages (Ms) • - B cells • - dendritic cells

Figure 1.7

HUMORAL IMMUNITY • Latin humor (body fluid) • B cell response • plasma cells are effector cells

Igs (Abs) are effector molecules • - neutralize Ag • - facilitate Ag elimination • Ag elimination • - Ab-Ag complexes more palatable to Macrophages • - Ab-pathogen complexes activate • complement (C’) system  pathogen lysis • -Ab-toxin complexes  neutralization

CELL-MEDIATED IMMUNITY • T cell response • effector cells • -THè cytokines • -CTL è cell lysis • cytokines • - activate phagocytes • - induce TC differentiation • TC è CTL (effector) • -support B cell differentiation • B cell è plasma cell (effector)

CELL-MEDIATED vs HUMORAL IMMUNITY TH cell cytokine production supports both B cell (humoral) and T cell (cell-mediated) IRs. {Review Figure 1-7}

ADAPTIVE vs INNATE IMMUNITY (SPECIFIC) (NON-SPECIFIC) • work together to eliminate foreign invader • examples • - phagocytes augment specific IR • - cytokines augment non-specific phagocytosis • - inflammatory cytokines attract and coordinate cells  specific IR ; more cytokine production

RECOGNITION OF Ag BY B AND T CELLS • Ags- large and complex • B and T cells recognize epitopes • - antigenic determinants • - bind to TCRs or BCRs (mIg) • B cells • - humoral immunity • - recognize epitopes alone

T cells • - cell-mediated immunity • - recognize epitopes + MHC molecules on the surface of • - altered self-cells (virus / cancer) - MHC I • - self-cells (APCs) - MHC II • - Class II MHC molecules (APCs only)

LYMPHOCYTE SPECIFICITY AND DIVERSITY SPECIFICITY ·B cells  mIg (BCR) ·T cells  TCR

DIVERSITY • B cells • - generated by random gene rearrangements • during maturation • - self-reactive B cells eliminated (clonal deletion) • - >108 antigenic specificities • - ~105 mIg/B cell with same specificity • (“antigenically committed”) • T cells • - generated by random gene rearrangements • during maturation • - self-reactive T cells eliminated (thymic selection) • - >1015 antigenic specificities • - ~105 TCRs/T cell with same specificity • (antigenically committed)

ROLE OF MAJOR HISTOCOMPATABILITY COMPLEX (MHC) {Figure 1-8} ·multi-allelic family of proteins with multiple loci ·two major classes - MHC I - MHCII

MHC I- glycoproteins; single chain (a) • - always associated with 2-microglobulin • - loci • - humans (3) - A, B, C • - mice (2) - K, D • - all nucleated cells • - identify unique “self” • - Ag + MHC I TC recognition • MHC II • - heterodimeric glycoproteins ( +  chain) • - loci • - humans (3) - DR, DP, DQ • - mice (2) - IA, IE • - APCs only • - Ag + MHC II  TH recognition

MHC and antigen recognition MHC binds to a “spectrum” of antigenic peptides MHC distal regions - wide variation in a.a. sequences - form cleft that holds antigenic peptides - present Ag to T cells

PROCESSING AND PRESENTATION OF Ags (Fig. 1-9) Exogenous From the outside Endogenous From the inside

Endogenous Ag • from within • e.g. cancerous and virally-infected cells (altered self-cells) • processed and presented with MHC I via • cytosolic pathway • TC recognition • Exogenous Ag • from outside, • e.g. bacteria,foreign proteins • processed and presented with MHC II via • endocytic pathway • TH recognition

SPECIFICITY OF RECEPTORS (Ab and TCR) What is the mechanism? Two Major Theories Instructional Theory Clonal Selection Theory

INSTRUCTIONAL THEORY • (supported by Linus Pauling) • Ag exists prior to Ab • Ag acts as template • Ag instructs formation of specific Abs

CLONAL SELECTION THEORY • {Figure 1-10} • early version: side chain theory (lock & key) (Paul Erlich ~1900) • Ag-specific B cells exist prior to Ag • Ag encounter causes proliferation of specific B cell clones

Therefore, antigen specificity exists prior to exposure to the antigen.

1° IMMUNE RESPONSE • {Figure 1-11} • ·1st encounter with Ag • selection of B cell clones • clonal expansion (proliferation/differentiation) • ê î • plasma cells memory B cells • ê • IgM • (low affinity) • lag period ~ 5-7 days • peaks @ ~14 days

2° IMMUNE RESPONSE • Figure 1-11a • 2nd encounter with Ag • activation of memory B cells • clonal expansion (proliferation/differentiation) •  • plasma cells more memory B cells •  • IgG • (high affinity) • lag period ~ 1-2 days • peaks @ ~7 days

CELLULAR INTERACTIONS REQUIRED FOR GENERATION OF IMMUNE RESPONSES • TH cells required for both humoral and cell-mediated Irs • Ag + MHC II  TH activation • activated TH cells  cytokines necessary for activation of B cells and TC cells • TH cytokines also regulate proliferation and differentiation of non-specific effector cells(e.g. NK cells and Ms) • memory TH cells important for 2° IR {Figure 1-13}

GENERATION OF THE HUMORAL RESPONSE B cell recognizes soluble Ag AND some Ag internalized, processed, and presented with MHC II by APC ê soluble Ag cross-links mIgs (BCRs) on B cell AND Ag-MHC II binds TCR on Ag-specific TH cell ê Ag-specific TH activation, proliferation, differentiation, and cytokine secretion memory TH cells ê TH cytokines support B cell proliferation and differentiation í î sIg producing memory B cells plasma cells

GENERATION OF THE CELL-MEDIATED RESPONSE endogenous Ag processed and presented as Ag-MHC I AND some soluble Ag internalized, processed, and presented as Ag-MHC II by APCs ê Ag-MHC I binds TCR on Ag-specific TC cell AND Ag-MHC II binds TCR on Ag-specific TH cell ê Ag-specific TH cell activation, proliferation, differentiation and cytokine secretion (esp. IL-2) memory TH cells ê TH cytokines (esp. IL-2) support TC cell proliferation and differentiation í î cytotoxic T lymphocytes memory TC cells (CTLs)

CELL-MEDIATED vs HUMORAL IMMUNITY TH cell cytokine production supports both B cell (humoral) and T cell (cell-mediated) IRs. {Review Figure 1-7}

Chapter 1: Overview of the Immune System