TNF-y (NK/γδ)

IL-12 (APC)

IL-2

TNF-y

IL23 (APC

IL6

IL17

IL6

TNF-α

IL10

IL4 (mast)

IL4

IL5

IL13

CD 56

CD16 (binds Fc for IgG)

IL-2

IFN-y

IFN-y

TNF-a

TNF-α

N2

O2

preventing allograft rejection

Corticosteroids

Corticosteroids: inhibit T cell cytokine & HLA

preventing allograft rejection

Blocking agents

• platelet
• lymphocyte
• Monocyte
• Eosinophil

• compete with histamine for H1 H2 site
• prevent immediate symptoms
• given prophylactically

• stabilize mast cell membrane
• prevent degranulation
• given before exposure

prevent arachidonic acid pathway

prevent late phase reactants

• treat anaphylaxis
• reverse effect of histamine so relax smooth muscle in GI and respiratory, constrict vasculature

humanized anti IgE

prevents binding IgE to FecR1

Exogenous

Constitutive expression:

Dendritic cells at spleen and lymph nodes

Thymic epithelial cells

B cells

Inducible expression:

Macrophage

Fibroblasts

endothelial cells

they process and present intercelular AG to CD4+ T helper cells.

MHC I/MHC II

Which is a monomer?

Which is a Dimer?

MHC 1 is monomer

MHC 2 is dimer

MHC I/MHC II

which HLA?

MHC I:

HLA-A B and C on chromosome 6

MHC II:

HLA-DP DQ and DR on chromosome 6

MHC I/MHC II

which is exogenous?

WHich is endogenous?

MHC I:

Endogenous

MHC II:

Exogenous

MHC I/MHC II

who uses CD4+

who uses CD8+?

MHCI:

CD8+ cytotoxic T

MHCII:

CD4+ T helper

HLA class 1 molecule

structure

α1: makes deep groove cleft

α2: makes deep groove cleft

α3: binds to CD8 co receptor on T cells

β2-m: closely associated, but not covalently linked.

HLA Class II

structure

α1: forms groove/cleft

β1: forms groove/cleft

α2:

β2: binds CD4 co-receptor on T helper cells

Exogenous antigen processing pathway

(endosomal pathway)

1. phagocytosis

2. in ER, HLA2 with invariant chain (Ii) made.

3. HLA2 + Ii in vesicle transfered to endosome where it binds to processed forign AG.  Ii degraded leaving small pice called CLIP

4. peptide exchange: clip removed, now HLA2 can bind forign AG peptide fragments.

5. new HLA2 bound with peptide transfered to cell surface to interact with CD4+ T helper cells.

chaperons formation of HLA2

1.) stabilizes HLA2 during formation

2.) prevents binding of self Ag to HLA-D while being transferred to endosome.

endogenous antigen processing pathway

(cytosolic pathway)

1. endogenously made proteins have a ubiquitin attached, so degraded by proteasome

2. degraded fragment transferred to ER, by TAP-1 and TAP-2.  in the ER binds to HLA1

3. binding of protein fragments cause conformational change in HLA1. pops out chaperons. 

4. HLA1 transferred from Golgi to cell surface where recognized by CD8 cytotoxic T. 

5. cytotoxic T is induced, and kills infected cell

has chemokine receptors

in bone marrow

migrates via blood to thymus

Thymic cortex

TCR expression

CD3 formed

zeta chain added

• thymic cortex to cortico-medullary junction

• gains CD3+ CD4+ and CD8+ at thymic epithelial cells and at the interdigitating thymic dendritic cells.

Thymic medulla

posative selection and negative selection

CD4+ = mature helper T cells

CD8+ = cytotoxic T lymphocytes (CTL)

CD4 and CD8 must bind HLA2 and HLA1 with right affinity, if not, apoptosis.

learns self HLA restriction

survivors are "HLA restricted"

occurs after positive selection

happens at transition of thymic cortex to medulla

if T cell binds self, then apoptosis.  (tolerance)

survivors are self-tolderant

T cell antigen receptor complex

(TCR)

TCR

• part of IG supergene family

• made of α and β chains

• has conserved (c) and variable (v) domains

• recognizes AG + MHC on APC

T cell antigen receptor complex

(TCR)

CD3

• made of α β and γ chains
• on all mature T cells (T cell specific)
• chaperone for TCR.  transfers new TCR to cell surface
• signaling molecule

T cell antigen receptor complex

(TCR)

zeta chain

not T cell specific

signaling molecule

• triggered by TNF-y (from NK or yδ), and IL-12 (from APC)
• releases IL-2 and TNF-y
• activates NK/CTL/Th1/MØ/B cells to make IgG2
• cure TB,leprosy, STD, intracellular
• cause hypsersensitivity & silicosis

• From IL-6 and IL-23 (APC)
• Produce IL-17, IL-6 & TNF-α
• make Neutraphils
• Cause AIDS,

• From IL-4 (from mast) and IL-10
• Releases IL-4, IL-5 & IL-13
• IgG1-> 3 4 A E, plasma vs memory B cells, eosinophil & basophil
• Cure Pneumonia, Meningitis, worms
• Cause Allergy, Asthma, Lupus.

T regulatory cells

(Tregs)

• self specific TCR
• regulates T cell activation and autoimmune
• produces TGFβ, IL-10, & IL-4
• charicterized by CD25+ and FOXP3

type of AG

cytokine environment

location of activation

T killer cell

recognizes endogenously produced HLA1

endogenous AG from tumor/virus.

Granule mediate killing

(primary method for CTL)

1.) cytoplasmic granules from T cell releases perforins to infected cell.  perforin activated by Ca.

2.) granzymes from T cells go through perforins into infected cell

3.) T cell releases TNFα β & γ also cause apoptosis.

Fas Ligand killing machine

(FASL)

(secondary for CTL)

FASL binds to FAS on target cell

intracellular caspase activates, cell apoptosis.

NK cells

Large Granular Lymphocytes

(LGL)

• CD56 & (CD16 binds Fc of IgG) no T cell markers
• recognize lack of self due to low level HLA expression.
• has KIR, if bound to HLA1, doesn't kill.
• killing can be up regulated by IL-2 and IFN-γ

• activated by IFN-γ
• kills by TNF-α release or by producing O2 and N2 radicals.

Antibody-Dependent Cell-mediated Cytotoxic

(ADCC)

• Killer cells (Monocyte/macrophage/eosinophil/neutrophil/NK cells)
• CD16 binds Fc receptor of IgG

1. AB binds to AG, conformational change happens to Fc

2. K cell with Fc receptor binds to Fc

3. apoptosis

transplant to a syngenetic recipient

(histocompatable)

transplant to another person

(histocompatable or non histocompatable)

transplant to a pig

(Histocompatable, rejected)

Hyperacute rejection

what:

example:

therapy:

within hours of transplant

result of preformed AB

(eg) ABO

therapy: none, remove organ

Acute

what:

therapy:

• starts in 1 day, over in 14-21 days
• Usually PT that had a previous immune response
• T cell respond to HLA
• Therapy: Immunosupresion

Chronic

What:

Therapy:

• Months or years after transplant organ lose function
• cause by CD4 T helper
• Lymphoid follicles form, fibrosis happens.
• Therapy immune suppression, once started hard to stop

graft rejects host tissue

Leukocytes on donor tissue piggyback

1. CD4+ releases IL-2
2. CD8, B cells

Most graft rejection due to Th1

Graft Testing

Lymphocytotoxicity

1. Known AB against specified HLA + cells
2. add compliment
3. add dye, color = dead

preventing allograft rejection

Corticosteroids

Corticosteroids: inhibit T cell cytokine & HLA

preventing allograft rejection

Blocking agents

IgG IgM Complement

phagocitized if tagged by IgG

ADCC

harmful to host

alteration of response by pathogen

• decrease membrane fluidity
• makes enzymes to destroy viran RNA
• Inhibit pathogen protein synthesis
• HLA1 expression -> cell lysis

• LPS
• TNF-α
• γIFN

Immunity to Helmethins

(worms)

which leukocytes?

which Th?

• IGE
• Eosinophil
• Histamine
• Th2 response

Endotoxin

Gram?

Which cytokines?

Acquired immunity?

Toxoid?

• Gram -
• septic shock through IL-1 TNF-α IL-6
• No acquired immunity
• no toxoid available

Exotoxin

Gram?

Toxoid?

• Gram - and gram +
• Always present in low lvls
• highly specific
• Toxoid available

Type 1

Immediate hypersensitivity

Pathological Immune mechanism

Mechanism of tissue injury

• IgE
• Mast cell degranulation

Asthma/hay fever/Allergies/Anaphylaxis

Type 2

Antibody mediated hypersensitivity

• Immune mechanism
• Tissue damage
• Example

• IgG or IgM bound to host cell
• complement, phagocyte, abnormalities in membrane/receptor function

AIDS, HDN, transfusion reactions

Type 3

Immune complex mediated Hypersensitivity

• Immune mechanism
• Tissue damage
• Example

• Deposition of IgG or IgM IC
• Compliment activation, phagocyte activity

Arthus reaction, serum sickness

Type 4

delayed Hypersensitivity

• Immune mechanism
• tissue damage
• example

• activation of CD4 and CD8 T cells
• macrophage activation, CTL lysis of cell
• PPD, contact dermatitis

Type 1 hypersensitivity sequence of events

sensitization phase (1)

1. Exposure to allergen
2. Th2 activation, IgE production
3. IgE binds to mast cell Fc receptor (FceR1 for mast and basophils, FceR2 on platelets, lymphocytes, monocytes, eosinophils)

Type 1 hypersensitivity sequence of events

Activation phase (2)

1. Second exposure to allergen (more IgE made by memory B cells)
2. Allergen binds to mast cell-associated IgE (IgE-IgE). 
3. Signal transduction: degranulation

Type 1 hypersensitivity sequence of events

Effector phase (3)

1. mediator release (eg) histamine,serotonin, ECF-A, Heparin
2. End organ effects of mediators

"wheel and flare"

edema & vessel dilation.

mosquito bite

• initial response and release of preformed mediators in minutes
• late response in hours

• compete with histamine for H1 H2 site
• prevent immediate symptoms
• given prophylactically

• stabilize mast cell membrane
• prevent degranulation
• given before exposure

prevent arachidonic acid pathway

prevent late phase reactants

• treat anaphylaxis
• reverse effect of histamine so relax smooth muscle in GI and respiratory, constrict vasculature

humanized anti IgE

prevents binding IgE to FecR1

Hyposensitization technique

to allergen immunity

give small does of antibiotic, so mast cells use up granulocites

then can give high does since mast cell out of granules.