Objectives:1. understand how the appropriate lymphocytes are selected and activated and

amplified2. understand how immune cells “talk” with each other via cytokines3. compare and contrast activation and response of T and B lymphocytes 4. compare and contrast the activation and response of Th1, Th2, and TC

5. understand the interactions between nonspecific and specific host defenses6. understand how the specific immune response focuses the nonspecific response7. understand the power of the secondary (anamnestic) immune response

B. Specific Defenses = adaptive = acquired 3rd line of defense – only one with antigenic memory feedback into the nonspecific defenses – enhance the effectiveness of the non-

specific defenses

Specific immune system has to:1. recognize2. activate3. respond

1. Overview

a. RecognitionA specific interaction between an antigen and a receptor

Anti gen

Antigens incl:***proteins (incl. proteins + carbos or lipids) (T and B)***complex polysaccharides (B only)***nucleic acids (B only)

Full activation of the specific defenses involves several different types of immune cells working in concert:

non-specific cells (antigen-presenting cells) specific cells (lymphocytes)

Antigen-Presenting Cell (APC)Specialized cells that present antigenic determinants in a way that can be more easily recognized by lymphocyte RMost significant: dendritic cells (tissues) > macrophages > B cells

2 main types of Lymphocytes T lymphocytes (T cells) B lymphocytes (B cells

Lymphocyte receptors (R) constant region – transmembrane variable region – interacts with antigenic determinant

Antigenic determinant (= epitope) - small region of the antigen linear or conformational small in size

General Overview of Antigen Presentation - Diagram

Presentation of antigenic determinant by an APC to a lymphocyte occurs in draining lymph nodes (surfaces, tissues) or spleen (blood)

Initiates a chain of events that transforms a small, resting, naïve lymphocyte into a highly active, functional lymphocyte.

b. Activation - of lymphocytes with complementary receptor1. receive and secrete cytokines

2. undergo proliferation = clonal expansion1à104 – 105 - occurs in lymphoid organs

3. differentiate into functional sub-typeseffector – fight this timememory – reserves, to be deployed in the future

c. Response – of activated effector sub-types

activated (= primed) effector T lymphocytes either:1. kill2. coordinate and regulate

activated effector B lymphocytes (called plasma cells)secrete antibodies

2. Add in specifics

T Lymphocytes

2 categories of T cells by surface marker called Cluster Determinant

1. CD4 - 2 functional types1) T helper cells = TH - regulate the immune system by activating other immune

cellsa) Subset Th1 – secrete -IFN – respond to intracellular pathogens - boost

macrophages, NK, mature TC; inhibit Th2b) Subset Th2 – secrete IL-4 – respond to extracellular pathogens - stimulate B cells to proliferate and differentiate; inhibit Th1

2) T regulatory cells (=Tregs) - regulate the immune system by ¯the response

2. CD8 =T cytotoxic cells =TC - attack & kill cells infected w/ intracellular pathogens

a. Antigen Recognition by Naïve Resting T lymphocytes

*T cell receptor interacts with microbial (foreign) antigen + self antigen

Self antigens – Major Histocompatibility Complex (MHC) proteins

2 classes of MHC Class I - on the surface of all nucleated host cellsClass II – on the surface of APC

THR - recog. foreign antigen complexed w/ Class II MHC + co-stimulatory interactions (depend on who the APC is)TCR - recog. foreign antigen complexed w/ Class I MHC + co-stimulatory interactions

b. Activation of T lymphocytes

1. Activation signal - cytokines, esp. IL from APC ex. IL-1 from macrophage

2. ↑ IL-2R and secrete/receive IL-2 à proliferation

3. Differentiation into effector and memory cells

c. Response of Effector T Lymphocytes

Each category of effector T cell has a unique response:

regulating the immune response = immunoregulation enhance response - TH

Subset Th1 - secretes -IFN - activates macrophages to kill their intracellular pathogens; activates NK, TC (down regulates Th2)

Subset Th2 – secretes IL-4 – stimulates B cell proliferation (down regulates Th1)

suppress response - Tregs direct cell killing = cytotoxicity – TC

Integration via Lymphocyte Recognition, Activation, and Response - Diagram

B Lymphocytes

a. Antigen Recognition by B Lymphocytes

Receptor interacts with foreign antigen alone – does not need to see an MHC marker.

b. Activation of B Lymphocytes1. IL-4 from subset Th2 (also IL-2)2. Clonal expansion (= proliferation)3. Differentiation into effector (= plasma) and memory cells

c. Response of Effector B lymphocytes (=Plasma Cells)

Secrete Antibody (Ab) at the rate of 1,000 molecules/min.

Antibody Structure - Diagram

Actions of Antibody Molecules – focus the non-specific

1. direct – binding to antigen – interfere with receptor interaction – any microbe that uses specific attachment sites = neutralizing

***2. indirect – linking a bacterium to a phagocyte = opsonization (followed by phagocytosis)

Opsonin Rate of PhagocytosisMicrobe+phagocyte

none -/+C3b +CRP +AbC3b + Ab

3. indirect - link many small antigens together = agglutination (followed by phagocytosis)

4. indirect - complement activation - classical pathway (followed by either opsonization and phagocytosis or lysis)

5. indirect - ADCC - antibody dependent cellular cytotoxicity

Activation of Classical Complement Cascade - Diagram

C1

C2 C4

C2b C2a C4b C4a

C2a4b

C3 C3

C3a C3b C3a C3b

C5

C5a C5b

C5b678 multiple C9 (MAC)

Fill in:Triggers –Important molecules – Consequences - Timing –

Complement activation enhances phagocytosis and inflammation and leads to cell lysis.

Classes of Antibody Molecules

Antibody = Immunoglobulin (Ig) – proteins found in fluids in the body

5 Classes:Class Structure % Location RolesIgG monomer 75-80 serum, extra vascular

spaces, crosses placenta

fix complementopsonin

IgA monomerdimer

15-21 serum, tears, saliva, mucus, colostrum

neutralizing

IgM pentamer 6-7 serum, 1st made by virgin B cells, 1st made by fetus

fix complementagglutinating

IgD monomer <1 low levels in serumB cell surface

? regulate clonal expansion?

IgE monomer 0.01 skinRT fluid

bind to mast cells & basophils

Feedback into the non-specific defenses; esp. complement, phagocytosis

Function of Memory Lymphocytes – the reserves - stronger response on secondary exposure to antigen1. are more memory cells then there were naive cells at the beginning of the

primary response2. were primed to antigen during primary response so are able to bind more

strongly to APC3. memory is usually long-lasting, years

Primary versus Secondary (= anamnestic) Response - Diagram

Misc.

Killer (K) cells

Rely on antigen specific antibodies BUT interact with antibody in a nonspecific way, participate in the non-specific interior defenses:

K cells include:NKmacrophageeosinophil

All K cells have receptors for Fc of antibody molecules

K cells bring about lysis of the antibody-coated cell in a process called antibody-dependent cellular cytotoxicity (ADCC); for pathogens that are too big to phagocytize.

SUMMARIZE – Specific Defenses

Fill in tableCytokine or pro-inflammatory mediator

Secreted by: Acts on: Functions to:

IL-1IL-2IL-4IL-23IFN IFN IFN TNF

Complete:TH

function – recognition – activation – response – Th1 -

-- Th2 –

TC

function – recognition - activation – response –

Treg

function – recognition - activation – response –

B Lymphocyterecognition – activation – response –

SUMMARIZE – Specific Defenses

List the Specific Interior Defenses important against Bacteria

List the Specific Interior Defenses important against Viruses

CONCEPT CHECK – Specific defenses

Concept Map

Draw a concept map that illustrates the connections between the specific and nonspecific immune responses

CONCEPT CHECK – Specific Defenses

Continuation of the Case of SteveWhen Steve. awoke on the second morning, his condition was clearly deteriorating. The first thing he noticed was that the small area of redness and swelling had extended to include his entire hand, with the margin of redness now visible just above his wrist. Faint red streaks had appeared along the inner part of his arm and tender lumps were noticeable below his elbow and under his arm. His fever seemed higher than the night before, and he felt too weak to walk.

Steve was too sick to travel, and his friends figured that it would take several days to return with medical help. They decided to stay in camp and let Steve rest. Over the next couple of days Steve and his friends were relieved to find him gradually improving. The red area did not advance past his forearm. Although the hand remained painful and swollen, he felt less tired and the fever was gone. Four days after the first presentation of inflammation, when he was a little better, they headed back and took Steve to the nearest emergency room.

The doctor diagnosed a presumed bacterial infection and prescribed a broad-spectrum antibiotic that was likely to be effective against the unknown infecting bacterium. The medication was taken orally, and Steve was sent home. The redness and swelling of the hand subsided gradually over the next two weeks.

1. What were the tender swellings that Steve noticed behind his elbow and under his arm and why were they swollen?

2. Steve began to improve within 4-5 days of initial infection. How could antibody have played a role in resolving Steve’s symptoms within this time frame?

3. What functions did these antibodies play in the immune response to Steve’s bacterial infection?