Immunology final new content

antibody dependent cell mediated cytotoxicity

1. antibodies bind to antigens on target cells
2. NK cells express CD16 Fc receptors and bind to the antigen bound antibody
3. Fc receptors become cross linked
4. crosslinkages promote degranulation of NK and release of perforin and granzymes
5. target cell dies via apoptosis

passive immunity

immunity that can be passed directly through antibodies rather than exposure (i.e. immunoglobulin injections, breast milk)

how is protective immunity provided via IgG to newborns

IgG passes through the placenta during gestation and provides protection against viruses and bacteria while humoral immunity functions are temporarily insufficient.

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at birth, the neonates IgG values equals its mothers and slowly declines as IgA increases and humoral immunity begins

IgA and newborns

IgA is passed via breast milk to perform gut mucosal defense until gut microbiota can form and proliferate

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IgA typically starts low and increases over time with consumption of breast milk

mucin

structural components of mucus

peyers patch

lymph nodes located in the GALT which house B and T cells

isolated lymphoid follicle

lymph nodes in the GALT that house B cells

lamina propria

basement membrane of the GALT

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surrounds all internal structures beneath the villus epithelium

M cells

located on top of Peyer’s patches

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assist in immune sensing of bacteria

distinct functions of mucosal immunity in comparison to systemic

1. IgA provides a protective immune response rather than reactive
2. effector function is to decrease invasive pathogenic bacteria by blocking uptake systemically
3. IgA can be increased **without** causing inflammation in response to food and commensal bacteria. systemic response is incapable of this

intestinal epithelial cell effector function (mucosal immunity)

1. Bacteria on cell surface or in intracellular vesicles is recognized by TLRs on the surface intestinal epithelial cells. Bacteria in cytosol is recognized by NODs inside the cell.
2. Bacteria is broken down into peptides
3. peptides are presented via TLR or NOD to NFkB
4. NFkB becomes activated binds LkB and transports it to the nucleus
5. inflammatory cytokines, chemokines, and other mediators are upregulated in response to NFkB
6. upregulation recruits neutrophils and monocytes for proliferation of immune response

M cells and lymphocytes in mucosal immunity

1. M cells capture bacteria from gut lumen and endocytose them to Peyer’s patch (can be whole antigen or peptides)
2. whole antigens bind and activate B cells
3. peptides bind with DCs and then T cells for activation
4. B and T cells travel into the mesenteric lymph node and through lymphatics until they reach the lamina propria
5. B and T cells exit the lymphatics by undergoing diapedesis and entering mucosal tissue
6. cells isotype switch and reenter the gut lumen prn

how is inflammation suppressed in mucosal response

intestinal macrophages are only capable of phagocytosis and killing

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intestinal macrophages cannot secrete inflammatory cytokines which means they are incapable of chemotaxis, co stimulation, or respiratory burst

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because they have limited function they are only capable of clearing debris which promotes tissue healing and healing is an innately anti inflammatory response

role of IgA in mucosal immunity

IgA blocks the attachment of bad bacteria and promotes the attachment of good bacteria in the gut microbiota at the mucosal surface by binding bad bacteria. It is then capable of transporting toxins and pathogens into the GI lumen where they will be eliminated.

FcyRIII

aka CD16.

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the Fc region expressed by NK cells that is capable of binding antigen bound antibodies on pathogens. Binding serves as an activation signal for ADCC.

NKG2D

An activating receptor located on NK cells that binds to MIC on target cells

NKG2A

An inhibiting receptor on NK cells capable of binding to HLA-E on target cells

KIR

a transcription factor which is responsible for initiating NK cell education

VAV

upregulates or downregulates NK activation signals based on its phosphorylation status

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dephosphorylated causes inhibition; phosphorylated causes activation

ITAM vs ITIM

activating regions on NK cells are ITAMs. Inhibitory regions on NK cells are ITIMs

NK activation via ADCC (IgG)

1. NK FcyRII (CD16) b/w antibody coating on pathogen
2. binding initiates release of perforin and granzymes
3. target cell apoptoses

NK activation using 2+ activating receptors

1. Target cell expresses MIC (stress signals) and binds NKG2D on NK
2. Target cell expresses CD48 which binds 2B4 on NK cell
3. NK becomes activated and preforms functions

Inhibition of NK

1. NK binds with activating receptor on target cell
2. Ag. is presented using MHCII (HLA-E, HLA-A) on target cell surface
3. Ag is recognized by NKG2A on NK cell
4. Inhibitory signals are sent to stimulate ITIMs
5. NK function is inhibited and target cells are protected by neutralization of charges

what happens when NK cells fail to recognize MHC

1. NKG2B receptors bind with activating ligands on target cell
2. NKG2D receptor is expressed on NK cell but fails to bind MHC
3. cell becomes inappropriately activated and apoptoses target cell

Increased activating ligand on target cells

even though the activating and inhibitory receptors become appropriately bound, increased activating ligand proliferates activating response and apoptosis

NK cell education

1. immature NK cells in BM express DAP12
2. DAP12 b/w HLA-C
3. KIR is expressed
4. KIR recognizes self Ag. and activates SHP-1
5. SHP-1 dephosphorylates VAV to cause inhibition
6. simultaneously, NKG2D and 2B4 phosphorylate VAV to cause activation
7. once an appropriate balance of activation and inhibition has been achieved cell is considered educated and enters circulation

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SHP creates inhibitory signals and dephosphorylated VAV to promote self tolerance in circulation

Activation signals phosphorylate VAV faster than SHP-1 can dephosphorylate VAV which upregulates activation signals

why do most inhibitory receptors recognize MHC-1

Healthy cells express MHCI to avoid recognition and destruction by CD8+ cells and NK cells. It is important that inhibitory receptors specifically recognize MHC1 on target cells because it ensures self tolerance by downregulating cytotoxic responses.

inactivated vaccine

entire virus or bacteria that has been inactivated

subunit vaccine

entire virus or bacteria that has been activated and purified

live attenuated vaccine

an altered less virulent live virus or bacteria

toxoid vaccine

purified modified toxins

protective immunity

when antibodies against a pathogen remain temporarily high for a period of time after infection to prevent subsequent secondary infections

central memory T cells

a form of CD8+ t cells that circulate in lymphoid organs and are capable of preforming diapedesis. can further differentiate prn.

effector memory T cells

a form of fully differentiated CD8+ t cells that circulate in non lymphoid tissues and cannot preform diapedesis

adjuvant

a therapy that upregulates immune responses to an antigen by inducing inflammation

primary immune response

the body’s first response to a pathogen

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slower activation time, less B cells and T cells produced as a whole

secondary immune response

the body’s subsequent immune responses to pathogens it has already been exposed to.

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has a quicker activation period and a greater amount of B and T cells produced as a whole in comparison to previous immune responses

long lived plasma cells

plasma cells that linger after infection to create protective immunity

memory B cells

circulating B cells that create secondary robust immune response and maintain a certain level of protective immunity after initial infection

vaccine hesitancy

delayed refusal or acceptance of a vaccine despite its availability and effectiveness etc

why are adjuvants important in vaccination

adjuvants create a stronger inflammatory response which helps vaccines to produce a stronger immune response. this creates additional memory which promotes vaccine effectivity

why is secondary immune responses only produced in response to memory cells

during the primary response some naive b cells differentiate into memory b cells. One of the advantages of memory B cells is quicker response times to subsequent exposures. Therefore, secondary immune responses can only be produced in response to memory cells because naive cells must become further differentiated in order to produce the same response.

Explain how RhoGAM shots prevent hemolytic disease of the newborn

First pregnancy: in Rh- mother carrying Rh+ baby primary immune response releases IgM and low affinity IgG. This causes some fetal erythrocyte destruction but pregnancy is relatively normal.

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Subsequent pregancies: IgM and high affinity IgG is transcytosed in response to memory formed during first pregnancy. This initiates anti-RhD IgG response which causes massive destruction of fetal erythrocytes

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RhoGAM shots prevent this by introducing a small amount of RhD specific IgG which inhibits presence of Rh+ specific IgG from forming

Primary vs secondary immune response

primary response starts slowly with low to medium affinity IgM. It has a high threshold and relies on a small response from innate immunity

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secondary response is a quick robust action with high affinity isotype switched cells. It has a low threshold and relies on both adaptive and innate responses.

Memory T cells vs naive

location: memory can be in circulation or tissues, naive can only be in circulation

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threshold: memory is low, naive is high

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lifespan: memory can survive for extended periods of time, naive cannot

memory B cells vs naive

Receptor function: memory cells express BCRs and can be isotype switched. Naive b cells do not express BCRs and cannot isotype switch as effectively

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affinity: memory B cells express high Ag. affinity and naive B cells express low affinity

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plasma cells: Memory B cells can rapidly become plasma cells, naive cells become plasma cells much slower

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MHC2: memory T cells can express MHC2 faster than B cells

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somatic hypermutation and affinity maturation: only expressed by memory B cells

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B cells lifespan: memory B cells have longer lifespans than naive

mast cells

mediates inflammation via histamine release

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plays a role in innate immune response and assists with tissue repair

eosinophils

circulating cells that cause inflammation against allergens and parasites by degranulating

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recruit mast cells

basophils

releases granules and enzymes in response to allergies

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recruits mast cells

IgE

an antibody isotype that is formed in response to allergens and parasites

Granule

components bound within granulocytes that when released promote inflammation and cellular attack

histamine

a substance released by granulocytes in response to allergic and inflammatory responses that promotes contraction of smooth muscles and dilation of capillaries

sensitization

the development of IgE antibodies in response to allergens

degranulation

the process by which granules are released from granulocytes

atopy

the genetic predisposition to developing allergies

allergic asthma

1. mucosal cells capture allergen in lower airway
2. degranulation in response to allergen occurs
3. inflammation, smooth muscle contraction, increased mucus, and increased permeability occurs

chronic asthma

occurs when mucosal cells hold on to allergens for extended periods of time which causes increased Th2, cytokine release, and eosinophil degradation

sensitization to antigens via IgE

1. allergens stimulate B cells in airway
2. IL4 proliferates release of Th2
3. Th2 promotes isotype switching to IgE
4. IgE b/w FcERI on mast cells


1. sensitization has occured
5. secondary exposure promotes Ag. binding to IgE/FcERI complex on mast cell
6. degranulation of mast cell begins and allergic response is initiated

Sensitization in airways

1. peptides are diapedesed or inhaled into airway
2. Ag. is engulfed and presented by APCs
3. Ag. specific T cells become activated
4. Allergy complex becomes formed (IgE b/w FcERI on mast cell)
5. Secondary exposure causes Ag. binding to allergen complex in lungs
6. binding promotes degranulation of mast cells and eosinophils are recruited
7. increased mucus, histamine, permeability, and vasodilation cause asthma

developmental stages of IgE

1. DC
2. CD4
3. Th2
4. B cells, mast cells, eosinophils, and mucus production
5. B cells isotype switch to IgE
6. degranulation
7. ejection of parasite

which cytokines promote development of IgE

IL4 and Th2

Neutral proteases

remodel connective tissue matrices to increase permeability

histamine and heprin

increase vascular permeability and smooth muscle contraction

TNFa

promote inflammation, upregulate cytokine production, and activates endothelial responses

IL4

upregulates Th2 response and eosinophil production/activation

chemokines in allergic response

attract monocytes, macrophages, and neutrophils

lipid mediators in allergic response

upregulate redundant allergic responses

outcomes of mast cell degranulation

increased permeability, swelling, loss of pressure, contraction of smooth muscle, constriction of airways, and GI symptoms

why does atopy occur

Variations in MHC2 genes or T cell receptors can cause increased presentation and recognition of allergens.

Increased levels of IL4 or IL4R promotes increased expression and signaling of allergic cytokines.

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These polymorphisms have been shown to have genetic linkages.

hygiene hypothesis

The hygiene hypothesis states that in areas with lower pathogenic burden, immune systems are “underdeveloped” which results in exaggerated responses to foreign antigens that should be essentially ignored. In countries that are more hygienic leading to lower pathogenic burden, there is an increased expression of conditions such as allergies. This potential linkage is considered the hygiene hypothesis.

How are allergies prevented/treated?

1. prevention (exposure)
2. drugs: antihistamines, corticosteroids, epinephrine
3. desensitization using IgG shots (prevents switching directly from IgM to IgE)

Molecular mimicry

Primary response to antigen causes plasma cells to create antibodies. Antibodies proliferate and cross react with self-peptides damaging healthy tissues.

Self-tolerance

the ability of antibodies to ignore self-tissues and act on foreign tissues

Graves disease mechanism

anti TSH receptor antibody causes constant stimulation of TSH receptor. stimulation promotes cleavage of iodinated thyroglobulin within the thyroid follicle which massively upregulates the release of T3 and T4

treatment of graves disease

iodine uptake inhibitors

thyroid inhibitors

removal of thyroid

Myasthenia gravis mechanism

antibodies bind to Ach receptors and degrade Ach molecules via receptor mediated endocytosis

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by preventing binding of Ach. to its receptor, Na+ influx is prevented causing progressive weakness of muscles

Myasthenia gravis treatment

immunosuppressants

anti-CD20 antibodies

Rheumatic fever mechanism

body generates antibodies in response to streptococcal bacteria

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some antibodies migrate and cross react with heart tissue (molecular mimicry). This activates complement and eventual destruction of heart tissues.

autoimmune hemolytic anemia mechanism

erythrocytes bind anti-erythrocyte antibodies in circulation and undergo three outcomes:


1. erythrocyte binds FcR in spleen → phagocytosis and destruction
2. erythrocyte binds CR1 in spleen and activates complement fixation → phagocytosis and destruction
3. antibody coated erythrocyte activates complement and intravascular hemolysis → erythrocyte lysis and destruction

treatment of rheumatic fever

rheumatic fever is irreversible when it develops so prompt identification of strep and treatment is important

autoimmune hemolytic anemia treatment

corticosteroids

immunosuppressants

splenectomy

systemic lupus erythematosis mechanism

small auto reactive antibodies bind IgG. Widespread occurrence causes Ag. bound IgG to aggregate and form deposits. Deposits sit in tissue causing eventual damage which leads to development of more Ag. and the process continues (epitope spreading).

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eventually leads to vasculitis, arthritis, kidney inflammation, and organ failure

systemic lupus erythematosis treatment

nothing effective → eventual death

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immunosuppressants and steroids for symptoms

MS mechanism

Th1 upregulates INFy which upregulates macrophage activation

CD8+ infiltration occurs

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results in eventual destruction of myelin sheaths → impairs neuromuscular functions

MS treatments

nothing effective → eventual death

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immunosuppressants and steroids for symptoms and slowing of disease progression

Celiac disease mechanism

1. resistant gluten fragments in gut lumen enter GALT
2. gluten fragment is deaminated by transglutaminase
3. deaminated peptides are presented by HLA-DQ
4. Th1 → naive CD4+ → response to presented peptide
5. release of inflammatory effector T cells (CD8+)
6. villous atrophy

Celiac disease treatment

avoid gluten

rheumatoid arthritis mechanism

leukocytes infiltrate joints (increased T cells, B cells, macrophages, neutrophils) and anti IgG antibodies are produced. This results in massive inflammation which causes tissue damage

rheumatoid arthritis treatment

anti inflammatories

steroids

anti-TNFa (humira)

anti-CD20

T1D mechanism

APCs present anti-self antigens to CD4+ which causes 2 outcomes:


1. CD4+ activate CD8+ cells
2. CD4+ activates CD19+ (b cell)

Both B and T cells then travel to the capillary of pancreatic islets and cause mass destruction of beta cells

T1D treatment and diagnosis

diagnosed by anti self antibodies in blood

treated with immunosuppressants and insulin

How do T cells cause autoimmunity

CD8+ cells can become self reactive and exhibit cytotoxic effector functions against healthy tissues causing autoimmunity

CD4+ can recruit and activate cytotoxic cells to stimulate response against

how to B cells cause autoimmunity

B cells are capable of isotype switching into self reactive antibodies

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they can also bind to Fc regions on APCs to upregulate T cell functions against cell tissues

what is meant by a breakdown in self tolerance? how does this contribute to autoimmunity

Self-tolerance is when immune cells can ignore self-antigens and attacking foreign antigens appropriately. When self-tolerance breaks down and begins to attack healthy self-antigens and tissues, autoimmunity begins to form where the body attacks itself which is a result of the breakdown of self tolerance.

Genetic components in autoimmunity

certain MHC/HLA genes (specifically MHC-II)

reduced immune regulations


1. AIRE defects
2. FoxP3 mutations (effects Treg functions)

Environmental components in autoimmunity

reduced immune regulations

viral infection

molecular mimicry

Reactivation of disease

occurs when the initial infection allows for infiltration of a body structure (like a nerve) where the pathogen is capable of remaining dormant from some time. Eventually the pathogen will reactivate and travel back towards the initial site of infection causing reactivation.

Latency

ability of the pathogen to remain dormant in the body for a period of time before causing infection

superantigens

Ag. that can bind to MHCII outside of the peptide binding groove → aggressive T cell response

AIDs forms when

the CD4 t cell count is below 200 cells/mcL