PAMPs--> NOD1,2--> Activation of NFKB--> Macrophage activation--> IL-1, IL-6, TNF alpha, IL-8, IL-12

Injury/Pathogen--> Neutrophils go there first--> At the venules they cross the endothelial cells--> E-
Selectin in increased by endothelial cells--> Adhesins on the Neutrophil (No) slow them down and roll
along the endothelial layer--> No has a receptor for IL-8 (chemoattractant/signaling)--> Activation--> No
increases affininity to Integrin (Ig-CAM)--> Strong adhesion of Neutrophil--> Neutrophil stops moving-->
Mast cells release histamine-> increases vascuar permeability--> Neutrophil migration

LAD--> No CD18 ( B2 chain)-->Important for the Ig-CAM--> Neutrophils can not adhere to the endothelial
layer--> Can not migrate to teh site of inflammation--> No pus and or abcess formation

Neutrohil migration into the site of infection--> Secrete chemoattractants: IL-8, Leukotriene B4, Formyl
methionyl peptides ( from the pathogen)--> more Neutrophils/phagocytes go there to the site of
infection/inflammation

Phagocytosis--> Psudopodia (engulf material)--> Pseudopodia fuse together--> Phagosome-->

Phagosome + lysosome--> Phagolysosome--> Digestion--> exocytosis--> NETs--> Trap and kill pathogens--
> Tissue damage due to ROS into tissues.

Tissue damage--> 1. Activates Complement--> C5a--> Mast cell activation--> HIstamine (short lived), PGs,
Lukotrienes--> Go to blood 2. Bacteria releases Formyl methionyl peptides--> attracts Macrophage-->
Phagocytosis--> ingest and digest particulate debris

Neutrohil migration into the site of infection--> Secrete chemoattractants: IL-8, Leukotriene B4, Formyl
methionyl peptides ( from the pathogen)--> more Neutrophils/phagocytes go there to the site of
infection/inflammation

LAD--> No CD18 ( B2 chain)-->Important for the Ig-CAM--> Neutrophils can not adhere to the endothelial
layer--> Can not migrate to teh site of inflammation--> No pus and or abcess formation

Chediak Diseae--> Phagosome cannot fuse with the lysosome--> Pathogen can not be destoyed--> Due to
a Lyst ( Lysosomal transport) gene mutation--> Microtubules can not be reorganized--> fusion can not
occur. Due to the mutation, melanocytes can not migrate either leading to albinism.

Opsonins--> They make the pathogen look like a donut :)--> C3b (complement product) and IgG
(humoral)--> Macrophages have receptors for them.

O2 independent killing--> Enzymes that degradate the pathogen--> Lysozyme, Defensins, Lactorerrin,
DNAses, proteases--> H2O2 (hydrogen peroxide) is formed in small quantities.

O2 independent killing--> Enzymes that degradate the pathogen--> Lysozyme, Defensins, Lactorerrin,
DNAses, proteases--> H2O2 (hydrogen peroxide) is formed in small quantities.

O2 independent killing--> Enzymes that degradate the pathogen--> Lysozyme, Defensins, Lactorerrin,
DNAses, proteases--> H2O2 (hydrogen peroxide) is formed in small quantities.
Arginine--> Nitric Oxide + Citrulline--> Nitric Oxide kills bugs as well.

CGD--> NADPH oxidase is deficient ( X-linked recessive)--> O2- can not ne formed--> H2O2 can not be
formed--> Inections with Catalase positive organisms is increased (Staph, Pseudomona, Kleibsiella,
Serratia, E. coli, Candida, Aspergillus, Mucor) --> Bc they can convert H2O2 into H2 and water

Myeloperoxidase deficiency--> Oxident independent is intact, H2O2 is still made--> They are usually
asymptomatic

Glucose-6- Phosphate Dehydrogenase (G6PH) --> Generates NADPH--> Essential for the NADPH oxidase
to work. If G6PD is deficient--> Catalase positve infections + hemolytic anemia (bite cells on blood smear)

G6PD enzyme is part of the pentose monophosphate shunt--> Generates NADPH--> maintains
glutathione in its reduced form--> to keep the Reactive oxygen species (ROS) at check--> If G6PD is
deficient--> low NADPH--> low protection agains ROS--> Red Blood cells are suceptible because they can
only get NADPH from G6PD enzyme activity.

Th1--> INF gamma--> Activate Macrophages--> engulfing the bugs--> Granuloma formation. As we age,
Th1 cells count decrease--> no granuloma formation--> Increase reactivation of TB bc withouth
granuloma we can not erradicate the infection.

WBC from patient --> Incubate with NBT (yellow)--> NBT turns blue if the person has NADPH oxidase is
working. If NBT does not change color to blue--> No NADPH oxidase--> Granulomatous disease

INF---> Type I: INF alba and beta. Type II: Gamma

NK cells (CD16 positive)--> Lymphocytes part of the innate response--> Activated by IL-12 (macrophage),
INF alfa and Beta

NK cell with KIR + HLA-E--> NK cell DO NOT killif HLA-E is not there--> NK cell can kill

TA Dr. Alan Liu(privately): Granzymes are serine proteases released by cytoplasmic granules within
cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target
cell.

APCs (Mo, Dendritic cells, B cells)---> Activate CD4 potive T cells

Dendritic cells--> activates CD8 and CD4 T cells--> cross priming

he invariant chain (Abbreviated Ii) is a polypeptide involved in the formation and transport of MHC class
II protein

When MHC class II molecules are produced in an APC, the invariant chain (Ii) is synthesized also.

During assembly, a small segment of invariant chain termed CLIP (class II–associated invariant chain
peptide) facilitates correct class II folding. CLIP occupies the peptide-binding pocket of the class II
molecule. This prevents premature occupation of the peptide-binding pocket by self peptides, and it
ensures the conformation integrity.

class II trans-activator (CIITA) are transcription factors required for the coordinate transcriptional
regulation of MHC class II genes.SCID has a mutation in transciptin factor (CIITA)

The endogenous pathway is used to present cellular peptide fragments on the cell surface on MHC class I
molecules. Proteasomes break the protein up into peptides that are suitable for fitting within the
peptide binding cleft of MHC class I molecules

Transporter associated with antigen processing (TAP), a protein that spans the membrane of the rough
endoplasmic reticulum, transports the peptides into the lumen of the rough endoplasmic reticulum
(ER)Transporter associated with antigen processing (TAP), a protein that spans the membrane of the
rough endoplasmic reticulum, transports the peptides into the lumen of the rough endoplasmic
reticulum (ER)

Once antigen is processed and presented to a T cell, the adaptive immune response is initiated. CD4 T
cells: T helper cells.CD8 T cells: Cytotoxic T LymphB cells: Plasma CellsMemory cells

Helper T cell and Macrophage Adhesion:1) recognition of the MHC:peptide comples by the T cell
receptors (CD4 and CD8).2. Costimulatory signal with recognition of B7(marcophage) by CD28 (Helper T
cell).Thus secrete cytokines and incrase surface expression of cytokine receptors. Example: IL-2, INF-
gamma. Expression of CD40 ligand.

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system.
Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive
cytokine release.SAgs must bind to the major histocompatibility complex (MHC) class II molecules.

IL-12 -> Secreted by MacrophagesIFN-gamma -> secreted by NK cells* Will induce differentiation of TH0
to TH1

Remember -> IFN-gamma drives isotype to IgG

IL-4 -> Induces TH2 response and turns off TH1 response! Also drive Isotype switching to IgE

IL-4 -> Induces TH2 response and turns off TH1 response! Also drive Isotype switching to IgE

il-5 -> Eosinophil activation and Isotype switching to IgA!

M2 macrophages activated under the influence of IL-4 and IL-13 -> TH2 response

IL-23, IL-6 and TGF-Beta induces Th17 cells which will then secrete IL-17 and IL-22!

IL-17 -> induces local cells to increase Chemokine production to recruit neutrophils

Tuberculoid (TH1 response) -> Granulomas are formed (IC pathogens), cell-mediated responseLepromatous
(TH2 response) -> Foamy macrophages, acid fast bacilli, cell-mediated response is depressed!
B-lymphocytes activation can be:1) Thymus-independent 2) Thymus-dependent

Thymus independent:1) Weaker response compared to TD2) Antigen binding by surface IgM3) B-
lymphocytes activated by TI antigens are found in spleen and mucosa

Thymus Dependent:1) Will involve helper T-Cells and will influenced by cytokines (can induce isotype
switching!)2) Stronger response

B-cell ag presentation do CD4 via MHC II -> CD40 receptor (on B-cell) binds to CD40L (on helpter T-cell) will
provide 2nd signal!

B-cell paghocytes, breaks into peptides -> will present Ag to T cell (MHC II to TCR) = PRIMARY SIGNAL

B7 in will bind CD 28 -> Second signalCD40 -> CD40L -> Costimulatory signal

First wave -> Plama cell will secrete IgMSecond wave:-The longer the immune response goes on -> the higehr
the affinity- Cells allow Somatic Hypermutation - Affinity maturation- Isotype switching (IgG, IgA and IgE)

its when IgM made first later on replaces to plasma cells that produce igg, iga and ige

\IgE:- Binds to fcE receptors in mast cells, eosinophils and basophils- Protective against parasites and
allergen

IgA characteristics:- Defense of mucosal surfaces - Inhibit binding of toxins or pathogens to mucosa of
digestive, respiratory and urogenital systems.- Function = neutralize pathogens and toxins!!- Does not
activate complement- 2 isotypes: IgA1 and IgA2- Induced by IL-5 and TGF-B

Hyper IgM syndrome: deficiency of igG, igA, igE and elevated levels of IgM! Fail to make germinal centers -
recurrent bacterial, viral and fungal infections in the respiratory tract (no IgA because no switching)!

vIgM: first isotyoe / activate complement / found in naive B cells (with IgD)IgG: Opsonin / classical
pathway / neutralizer / cross placenta / activates adccIgA: mucosas / neutralizing antibody / passive
immunization through breastfeedingIgD: serve as develeptomental marker - mature B cells / high levels:
anergic b cellIgE: mast cells, eosinophils and basophils*Found on memory cells: IgA, IgG, IgE

Avidity is depend on the number of Ag binding sites -> some antibodies are multivalent and bind
MULTIPLE antigens => overall strenght in avidity.

Hyper IgM syndrome: deficiency of igG, igA, igE and elevated levels of IgM! Fail to make germinal centers -
recurrent bacterial, viral and fungal infections in the respiratory tract (no IgA because no switching)!

IgA characteristics:- Defense of mucosal surfaces - Inhibit binding of toxins or pathogens to mucosa of
digestive, respiratory and urogenital systems.- Function = neutralize pathogens and toxins!!- Does not
activate complement- 2 isotypes: IgA1 and IgA2- Induced by IL-5 and TGF-B

IgG characteristics:- Activates complement- Acts like opsonin - phagocytosis- Neutralizes pathogens and
toxins- Mediates ADCC (antibody dependent cellular cytotoxicity)- ONLY isotype that CROSS the placenta!
2 types of pathogens in cell mediated immunity:- Facultative intracellular - Obligate intracellular

Th0 --> Th1 / T-bet --> IGN gamma (amplifies th1, inhibits th2, activates classic macrophage, isotype switch
to IgG)

Th0 --> Th1 / T-bet --> IGN gamma (amplifies th1, inhibits th2, activates classic macrophage, isotype switch
to IgG)

Primary signal for CD8+ T cell: MHC1 presenting specific peptide to that cell!

Cytotoxic T cell killing: 1- If a cell is expressing a specific peptide on MHC1 --> cell will die!! Degranulates
and release perforin and activate caspases OR 2- Independent of specificity --> express Fas on its surface
which bind to FasL (on CTL) --> apoptosis through caspase activation

CD16 = Fc gamma receptor - recognize IgG

CD16 is found on surface of NK cellsCD32 is found on macrophages, neutrophils and eosinophilsCD16

and cd32 both recognize Fc receptors --> activity is the same --> bind Fc region of IgG!Remember: 16X2
= 32

Target cell killing involves:- Lytic enzymes - Tumor necrosis factor- Perforin / granzymes

*Reminder: Know all diseases from chapter 11 and chapter 12 (go through the tables - high yield
clinical presentations)!

Immunizations:1- Active --> give antigenNatural: Infection. Eg: HepB (if you recover, you are
immunized!)Artificial: Vaccination2- Passive --> receive antibodyNatural: IgA through breastmilk and
IgG from crossing placentaArtificial: Anti-serum, Anti-venoms, Anti-toxins, IVIG** Tetanus toxoid is
artificial active!!

Passive Immunotherapy: potential of reactions!- Anaphylaxis --> type 1 hypersensitivity / IgE- Type 3
hypersensitivity = serum sickness*High Yield: When you give patient immunoglobulin, you have to
TEST for selective IgA deficiency! Why? Because if they have it, they dont make IgA and have Abs
against IgA --> anaphylaxis

Vaccines:- Know what ages, contraindications and what is inside the vaccine!- Age for live viral
vaccines: AFTER 12 months because until then they have immature immune response (can get disease
from vaccine)- Live vaccines also are not given for immunocompromised patients

Non-attenuated live vaccines:- Adenovirus against serotypes 4 and 7 - only in military!!

Killed vaccines: RIPA! - Rabies, Influenza (only killed in the USA), Polio (salk - only this in the USA),
HepA

Component vaccines:- HBV - HepB surface antigen- HPV - 9 valent --> serotypes 6 and 11 cause warts;
the remaining serotypes are oncogenic - cervical or penile cancer!
Bacterial vaccines:1- Toxoid - diphteria, tetanus, pertussis. - Remain the b subunit (binds to receptor),
so toxin is no longer active!- Pertussis: acellular, given to children 2- Conjugate: H. influenza, S.
pneumoniae, N. meningitis- All encapsulated - capsules made of polysacharides. To get memory cells,
polysacharide is ATTACHED to protein --> can present to T cells!- HI: serotyoe B / S. pneumo: 13
serotypes / N. meningiditis: A, C, W-135, Y - has no B which is the most common cause of meningitis
(new vaccine)!

Rotavirus --> live vaccine given at 2, 4 and 6 months old --> risk with vaccine is less than the disease