Exam 1- Autoimmune

Explain the process of hematopoiesis

Formation of blood cellular components

All cells are derived from HSCs which reside in the medulla of bones

Self-renewing & Pluripotent

What does Self-renewing and Pluripotent mean

Primary lymphoid organ goal

development of immune cells

What are the cells/organs in primary lymphoid

Bone marrow (B cells)

Thymus (T-cells)

What organ gets smaller the more you age?

Thymus

So less T cells

What is the goal for secondary lymphoid organs

Imitates immunological response

What are the organs involved in secondary lymphoid organs

Spleen, MALT, SALT

What is the first line of defense against blood bone pathogens?

Spleen (filters blood)

What two organs of the secondary lymphoid organs are the most highly organized

spleen & lymph nodes

MALT

• lines the gut

• M cell (microfold cells) lines the gut

• Antigen presenting cells → dendritic cell

SALT

Stratum corneum →keratin

Stratum granulosa → have lamellar granules (ceramides) and keratin that form filaments

Langerhans cells

will be presenting antigens

NK cells

• innate immune response

• causes cell destruction by perforins & granzymes

• produces cytokines that activate adaptive immune response

monocytes

• involved in tissue repair and remodeling

• destroy pathogens; produces cytokines

• leave circulation & mature in either macrophages or dendritic cells

  • Macrophages: phagocytes in tissues

  • Dendric cells: present antigens to other immune cells to help destroy Dendritic

In neutrophils, are there more segmented or bands

there are more segmented. Remember bands are the babies!

Absolute neutrophil count

WBC x (%segs + %Bands) divided all by 100

Neutrophils

• First responders

• ●       Contains granules with lysosomal enzymes for bacterial degradation

  ●       After infections, degradation of neutrophils leads to pus

What immune cell is most abundant (from lowest to highest )

Basophils → neutrophils (bands) → lymphocytes → neutrophils (segmented)

Are mast cells & basophils the same?

NO! They are two different cells

What is the function of basophils/mast cells

inflammation & allergies

What does heparin do

prevent clotsW

What causes inflammation

Histamine, Serotonin, Leukotrines

Eosinophiles

antiviral & anti-parasite

Eosinophil derived neurotoxin damages nerve cells

Major basic protein and peroxidases destroy parasistes

T cell major adaptive immune defense

against intracullar infections

Humoral immunity (antibodies) major adaptive immune defense

against extracullar infection

involves the transprotation of b lymphocytes into plasma cells that produce & secrete antigens

T/F

The complement system is produced in an inactive form

True

They are sequentially activated in three different ways: classical pathway, alternative pathway, lectin pathway

What are the main functions of the complement system?

1. Cytolysis → C3b

   1. Membrane attack complex (MAC) breaks down & destroys cells

2. Inflammation → C3a & C5a → bind to mast cells, basophils, platelets to release histamine & chemotactic

3. opsonization (C3b)

   1. Pathogens coat the surface

What are interferons?

Family of cytokines secreted by host cells to modulate immune respones

Type 1 vs Type 2 interferons

Type 1: INF-a & INF-b which is released by host cells in the presence of pathogens, alerting the other cells via antiviral protiens (AVPs)

Type 2: y-IFN (inflammation, stimulates other immune cells)

What interferon is used to treat multiple sclerosis

INF-b

What interferon is used to treat hairy cell leukemia

INF-a

What cells produce INF-y

Produced by activated T and NK cells

When released, it calls leukocytes to the site of infection, creating inflammation

Autoimmune diseases have been correlated with the upregulation of y-INF

CD4 T helper 1 cell

• activates cell mediated immunity pathway

• delayed hypersensitivity

CD4 T helper cell 2

• drives B cell proliferation

• secretes IL4.5.13

CD4 T helper 17 cell

• promotes inflammation

• secretes IL-17

CD4 regulatory T cells

• prevents autoimmunity

  • controls specific immune response

CD8 Cytotoxic T cells

• delayed hypersensitivity

• graft (organ) rejection

What are APCs

■       Antigen presenting cells are immune cells that help activate T cells by giving them pathogens. These include B cells, macrophages, and dendritic cells.

■       For a T cell to become fully activated, it needs TWO signals from the APCs

■       If there is only one signal but not two, this leads to anergy. This is a state where T cells become unresponsive even if it sees that antigen again. This is important to prevent autoimmunity.

What two signals are needed from APCs

●       Antigen-specific: this is when the T cell receptor on the T cell recognizes and binds to a specific antigen presented by MHC on the APC.

●       Co-stimulatory signal

○       This is a safety check. The APC gives an additional singal though other modules, like CD80 binding on the T cell (CD28) to confirm that this is really a threat!

What cytokine does Treg release

IL-10

Predict the outcome of having a drug that inhibits CD28

T cells will experience hypo response when APC cells present antigens

Predict the outcome of a drug that inhibits CD28

CD40 L of T cell could still interact with CD40 of B cells

What cells are involved in the complement activation

IgM & IgG

igE

allergy & asthma responses mediated by mast cells and basophils.

What is isotope switching

IgM to other Igs.

antibodies recognizing the same antigen but different types.

What must happen for antigen switching

B cell must receive costimulatory signals from CD40 to engage in isotype switching

Different cytokine signals determine the isotype

Activation-induced deaminase (AID) enyzme requires for isotype switching and affinity maturation

Explain isotype switching

○       Occurs in B cells

○       When B cells are first activated by an antigen, they typically produce igM antibodies.

○       Isotype switching is the process of changing the type of isotype of antibody they produce, from IgM to igG or igA, or igE.

Characteristics of an antigen to trigger the immune response

1. size

2. chemical composition & heterogeneity

3. foreignness

4. uptake & degradability

What are the two self antigens

HLA

MHC

(RBC do not have HLA, instead they have ABO/rh —> determines blood type)

what cells are the antigen presenting cells

dendritic

b cells

macrophages

Self antigen: HLA class 1

●       A, B, C, E, F, G

●       All nucleated cells & platelets

●       Present to CD8+ T cells

Self antigens:

HLA class 2

■       HLA class 2:

●       DR, DP, DQ

●       Antigen presenting cells: Dendritic, macrophages, and B-cells

●       Presented to CD4+ T cells

self- antigen

HLA class 3

●       Encodes for TNF, complement, soluble factors

What is tolerance

state of unresponsiveness in which the lymphocytes remain alive, but inactive against a particular antigen

i.e mom doesn’t fight fetus

central tolerance

• ■       Central tolerance is the immune system quality control check that happens early in the development in B cells (occurs in the bone marrow) and T cell (in the thymus). This makes sures our immune cells do not attack our own body.

  ■       The B & T cells are engaged in negative selection. This process occurs by putting self-proteins before the cells, and seeing how they react to it. If they react & try to kill it, they are apoptosis.

  ■       Sometimes, a few T cells react to it just a little bit, jut not enough to be dangerous. These cells become natural T regulatory cells, aka Tregs. They leave the thymus and express FoxP3, a transcription factor that suppress the immune response.

What is peripheral tolerance

■       Peripheral tolerance occurs after the T cells have already left the thymus and are circulating in the body. Their job is to catch & control any self-reactive T cells that escaped that prior screening in the thymus.

■       Occurs though three mechanisms: Anergy (T cells gets turned off) ; Apoptosis (programmed Cell death); become Tregs

How do Tregs work

■       Tregs use inhibitory cytokines like IL-10 & TFG-B & checkpoint molecules like CTLA-4 & PD-1 to send stop signals to immune cells trying to activate

what do tregs need to function

■       Tregs need IL-2  & FoxP3 to function

what triggers the apoptosis pathway

●       FasL binding to FasR which triggers apoptosis (this pathway is also used by CD8+ cells)

FasL is also expressed in what cell

NK

what cell is protected against induction of apoptosis

a cell expressing FasL

if FasR is activated, the cell will apoptosis

what happens if a cell does not express PDL-1

co activation of the T cell is predominantly causing immune response

patients will have a higher prevalence of autoimmune disease if they have mutations in

CTL4 & FoxP3

Tumor cells silence the immune system by expressing

PDL1 (anergy)

To treat this: PD-1 & PDL-1 inhibitors activate the immune system

PDL1 is also expressed in

the placenta

it maintains the fetus during pregnancy

testis, retina, and some cancers express _ so they are always protected aginst imune response

FasL

B cells express

CD20

Small molecules vs biologics

Small molecules

• targets protein kinases, nucleic acids

• JAK inhibitors (tofacinib & methotrexate)

• chemically synthesized, low weight, less immunogenic

Biologics

• large, compelx molecules from living organisms

• IV, SC, costly immunogenic

• Monoclonal antibodies like infliximab & fusion proteins (etenercept)

autoantigen

Self antigen on body cells ( HLA & CD markers)

In autoimmune, they are idenitfied as threats

What do we do Pharmacologically for autoimmune diseases

1. enhance tolerance by boosting inhibitory cytokines (IL-10 & TGF-b)

2. enhance treg cells by boosting FoxP3, IL-2, PD-1

3. inhibit immune activation by blocking proinflammatory cytokines (TNR-a, IL-17)

4. supress T/B cell activation

5. target protein kinases, cell surface ligand/receptors, nulecic acid pathway

Monoclonal antibodies

●       One clone of a B cell that has high specificity and reproducibility. It only recognizes one epitope.

●       Produced by hybridoma method  

●       Used for targeted therapy and precision tests

Polyclonal antibodies

●       Many clones of B cells that recognize multiple types of epitopes. They have lower specificity, and their reproducibility varies by batch.

●       They are produced by animal immunization

●       Used for general detection & broad screening

what do biologics target

○       Receptors: TNF  & IL receptor

○       Ligands: TNF-a, IL-17

○       Cells: B cells, T cells

○       Signaling pathways: JAK-STAT, NF-B

Biologics vs biosimilars

Biologics = original and fully tested complex drug made from living cells.

Biosimilars = close copies; not generic drugs but similar versions requiring comparability studies. Only some biosimilar drugs achieve interchangeability

what biologics are a higher risk for hypersensitivity

monoclonal antibodies, especially chimeric and murine derived

Compare the PK of small molecules with biologics

○       Small molecules

■       Oral, rapid absorption

■       Disturbed widely, often though passive diffusion

■       Eliminated via renal or hepatic metabolism (CYP450)

■       Low immunogenicity

■       Short half life

○       Biologics

■       Absorption through SC/IV, slow( lymphatic uptake)

■       Distribution is limited by size, receptor mediated

■       Eliminated via proteolysis by hepatocytes, antigens

■       Long half life (up to 3 weeks due to FcRN recycling)

■       High immunogenicity

what are the accreditation organizations for specialty pharmacy

URAC, ACHC, JCAHO, CPPA, NABP, and NCQA

Autoimmune conditions

• often caused by a dysregulation of inflammatory cytokines (cytokines are proteins that communicate between other cells)

• Proinflammatory cytokines activate immune cells & release more cytokines, starting the inflammatory cascade

Centralized vs decentralized specialty pharmacist

Centralized works from a call center

Decentralized works in a clinic

What is insurance formularies Tiers 1-4

Insurance formularies are a list of drugs covered by a drug plan

■       Tier 1 = typical, generic drugs that are automatically approved

■       Tier 2 = brand name drugs or more expensive generics

■       Tier 3 = more expensive brand name drugs or non preferred

■       Tier 4 = specialty drugs, new approved pharmaceutical drugs that payer want to discourage because of cost

What is step therapy

Trying less expensive drugs before stepping up to pricy drugs

what two things ensure that medications are prescribed appropriately

prior authorization & step therpay

T/F

Biologics are large weight

True

How are biologics adminstrered

parenterally

Can biologics have biosimilar products?

■       if considered to have no clinical different in safety, purity, and potency to the reference product

Can small molecules have generic products?

■       products if considered bioequivalent to the innovator product

Why would you use monoclonal antibodies (mAbs)

■       Type of biologic that can be used for more specific targeting and more tolerable safety profile

●       End in mab (i.e: dupilumab)

■       The MOA can be direct cell toxicity, immune-mediated cell toxicity, vascular disruption, and the modulation of the immune system

How are biosimilars, which differ from batch to batch, show their slight variants?

they show variations in protein mixes by adding 4 random letter suffixes to the name

denosumab-bbs

why would biosimilars go though additional testing?

■       testing to be considered interchangeable to the reference product (allows for pharmacist substitution pending specific state laws)

What determines the categorization or workflow for a specific medication

Medication risk assessment (MRA) or proactive risk assessment (PRA

What percent of drugs are specialty drugs

75% of 7000 new drugs

They take up 50% of the drug spending

What are the leading areas of drugs

Immunology & oncology

Type 1: hypersensitivity reaction

• Immediate

• IgE mediated

• (triggered by an allergen binding to IgE on mast cells

• Mast cell degradation releases histamine

Type 2: hypersensitivity reaction

• Antibodies IgM or IgG bind to antigens, activating the complement system & NK & macrophages to destroy cells

Type 3: hypersensitivity reaction

Immune complexes (antigens + IgG & IgM deposit in tissues, triggering inflammation & tissue damage

Type 4: hypersensitivity reaction

Antigen is processed & presented to T cells

CD8+ T cells & Th1 cells release cytokines

Pseduoallergy hypersensitivity reaction

Not antibody mediated; no IgE involved

direct activation of complement & mast cells

How do WBC and immune system get affected by glucorticoids

○       Glucocorticoids decrease circulating lymphocytes, monocytes, eosinophils, basophils, and macrophages, but they increase neutrophils (via bone marrow release and inhi ition of diapedesis)

What are the pro-inflammatory cytokines

IL-1,2,3,4,5,6,8,TNF

What is the MOA for antihistamines

blocks H1 histamine receptors, but do NOT block histamine release