Chapter 1

Introduction to the Immune System

Immune System
Physiologic functions
prevent infection eradicate established infections

Importance of the Immune System

Impact of Vaccination

Innate Immunity
Mediates the initial protection against infection Natural or NATIVE always present, prepared to block entry of microbes and eliminate them and consists of
epithelium acting as a barrier specialized cells phagocytes, NK cells, complement system antibiotics present in the epithelium

Doesnt respond to non-infectious agents Enhances the adaptive response

Adaptive Immunity
Specific or acquired Stimulated by microbes invading the tissue, evading the innate system Develops more slowly and more effective defense against infection is mediated by the innate system and consists of
lymphocytes and their products, antibodies (Ab) recognize antigens (Ag) different substances produced by pathogenic and non-pathogenic organisms

Enhances the innate response

Innate and Adaptive Immunity

Adaptive Immunity
There are 2 types of adaptive immunity
Humoral against extracellular microbes
recognizes proteins, carbohydrates and lipids Ab from the B-cell lymphocyte will prevent entry of the microbe and colonizing the host at mucosal surfaces and in the blood

Cell-Mediated against intracellular microbes

T-cell lymphocytes recognize microbial protein Ag only activates phagocytes macrophage kills infected cell that are harboring intracellular infections cytoplasm and in vacuoles

Humoral vs. Cell-Mediated

2 Mechanisms of Establishing Immunity

Active Immunity induced by infection or vaccination; protect from subsequent infection Passive Immunity transfer of Ab or lymphocytes from immunized individual; lasts as long as cells or proteins stay in the recipient
newborns get Ab from the placenta or breast milk

Adaptive Immune Response Properties

Specificity
Diverse lymphocyte repertoire for Ag recognition Express clonally distributed receptors for Ag each receptor is unique for each clone Get a heightened response on exposure to that Ag on next contact but not to almost identical Ag
1 Ag = 1 cell that recognizes it

Clonal Selection Theory

Many different clones
1 cell and its progeny arise before exposure to Ag

Each Ag elicits immune response by lymph activation after recognition Clonal expansion activated lymph undergoes proliferation and all progeny recognize same Ag

Memory Protects Long-term

Mount a larger and more effective response with each and every exposure to Ag
1 immune response comes after the first exposure of the nave lymphocyte, see the antigen for the first time 2 immune response happens when the lymphocyte sees the same Ag again, more rapid, larger, better at eliminating Ag
caused by the activation of memory cells that were made during the 1 response; more made during subsequent exposure

Immune response is self-limiting as it declines as the infection is cleared

1 and 2 Response

Cells of the Immune System

Lymphocytes
Only cell that has specific Ag receptor as distinguished by surface proteins - CD (cluster of differentiation, also have number designation) Key mediators of adaptive immunity B-cell has membrane-bound receptors on the surface of the cell and/or secretes Ab
humoral immunity

T-cell Ag receptor will bind protein fragments on a major histocompatibility complex (MHC) molecule on the Ag-presenting cell (APC)
cell-mediated immunity

T-Cell Types
Helper T-cell CD4+ cells
help B-cells make Ab and phagocytes to destroy ingested microbes special subset that prevent or limit the immune response = regulatory T-cell

Cytolytic or Cytotoxic T-cell CD8+ cells

kill cells harboring intracellular microbes

Natural Killer cells NK cells

Kill infected host cells but do not express clonally distributed receptor as B and T cells component of the innate immune system

Origin of Lymphocytes

All come from stem cells in bone marrow and mature in the generative lymphoid organs
B-cells mature in BM T-cells mature in thymus

~1012 lymphocytes in circulation and lymphoid tissue

Maturation of Lymphocytes

Antigen Presenting Cells

Specialized cells that capture Ag and transport to peripheral lymphoid tissues
dendritic cells best understood in presenting proteins to T-cells (chapter 3) macrophages can also present Ag to T-cells follicular dendritic cells inside follicle of peripheral lymph tissue to present Ag to B-cell

Cells that also present the 2nd signal to activate the lymphocyte are professional APC

Nave Lymphocytes
Recognize microbial Ag and get additional signals to proliferate and differentiate into effector and memory cells Move thru peripheral lymphoid tissues for weeks to months, no Ag recognition then die by apoptosis and replace with new cells

Effector Cells
Lymphocytes and other leukocytes Effectors are in the innate and adaptive immune system
innate macrophages and some granulocytes directly recognize microbes and eliminate them adaptive B and T cells call in and activate other leukocytes to kill microbes

Most cells are eliminated when the infection is cleared but memory cells will live for very long periods of time
see antigen 2nd time - 2 immune response

Effector Cells
B-cells secrete Ab = plasma cell CD4+ T-cells secrete cytokines to activate B-cells and macrophages CD8+ T-cells kills infected cell Memory cells both B and T cells
long-lived but functionally inactive until sees Ag again

Tissues of the Immune System

Generative 1 or central lymphoid organs mature and become competent to respond to Ag; very few cells are specific for any one Ag
T cells in the thymus B cells in the bone marrow

Peripheral 2 lymphoid organs where the adaptive immune response to microbes initiates
lymph nodes, spleen, mucosal and cutaneous immune system concentrate Ag so that APC and lymphocytes work in a way that optimize interaction among cells and development of adaptive immunity

Ag in

Lymph Nodes
Nodular aggregates along lymphatic channels fluid (lymph) moves thru nodes, APCs in nodes able to sample Ag that may enter through epithelial and tissues Concentrate Ag in draining lymph Must know parts of LN

Lymph out

Cells in

Spleen
Responds similarly to lymph nodes except filters blood thru sinusoids Dendritic cells and macrophages trap Ag and abundant phagocytes to kill extracellular microbes

Cutaneous and Mucosal Lymphoid Tissue

Catch microbes that breach the epithelial barrier Pharyngeal tonsils Peyers patches in the gut > of lymphocytes are in mucosal tissue and many of these are memory cells

B/T Cell Distribution

Peripheral lymphoid tissue have B and T cell in different anatomic compartment s
LN have B cells in discrete follicles in the cortex around the periphery; germinal center forms when activated B cells are present, makes Ab (Chapter 7) T cells are concentrated outside in the paracortex, containing dendritic cells

Spleen
T cell are concentrated in periarteriolar lymphoid sheaths around small arterioles B cells in the follicles

Distribution is tightly regulated to allow immune responses to occur

Lymphocyte Distribution

Movement of Lymphocytes
Follicular dendritic cells (FDC) secrete chemokines chemoattractant cytokines that attracts B cells to follicle while T cells move to the edge of the follicle because contain CCR7 receptor that recognize chemokines B and T cells migrate to towards each other after activation by microbe antigens and function at edge of follicle
T cells help B cells make Ab

Activated B and T cells leave the lymph node by efferent lymphatic vessels or in spleen by veins

Recirculation
Refers to T cells in the LN Nave lymphocytes constantly recirculate between blood and lymph tissues where Ag are; activated lymph to sites of infection
have distinct life stages in different areas

Nave T cells enter lymph nodes through specialized post-capillary venules High Endothelial Venules (HEV) L-selectin on nave T cells bind carbohydrate ligands only on HEV cells loosely bound; chemokines cause tighter binding and T cell can move thru HEVs into the lymph node

Recirculation (continued)
Nave cells scan dendritic cells looking for Ag, binds and then activates which reduce the expression of adhesion molecules and chemokine receptors to keep lymphocytes in the LN
increase expression of receptor for phospholipid sphingosine-1-PO4 and draws activated lymphocytes out into circulation as effector T-cells (Chapter 6)

T cell can activate when encounter Ag specific for it but will usually will circulate through some lymph nodes once a day, can also have memory T cell

T-Cell Recirculation

Overview of Immune Response

Innate immune system is meant to protect the host from microbes If get past the innate system then the host can react rapidly
phagocytes ingest and destroy microbe and release cytokines that stimulate inflammation and lymphocyte responses natural killer cells remove viral infected cells using interferon use proteins of the complement systems stimulate adaptive system which is initiated by molecules and cells of innate system

3 Main Strategies of Adaptive System

Secrete Ab coat extracellular microbes
blocks ability to infect host promotes ingestion and destruction by phagocytes

Phagocytes ingest microbe, kill them and helper T cell will enhance microbiocidal ability of phagocyte Cytotoxic T cell destroy cells infected with microbes which are inaccessible to Ab

Adaptive Immune Response

Phases of Adaptive Immune Response

1. Ag recognition nave Ag-specific lymph recognizes Ag on microbe 2. Activation of lymphocyte requires 2 signal types
binding signal from microbe and innate system

3. Elimination of Ag or effector phase effector cells and innate immune system remove microbe 4. Decline of lymph response apoptosis to remove cells activated by Ag cleared by phagocytes 5. Memory long-term response to Ag

Signal Types

1. Ag binding to Ag receptor on the lymphocyte 2. Signal from the microbe and the innate system Causes the cell to undergo clonal expansion through rapid cell division creates many effector lymphocytes become cells that produce substances to eliminate Ag