11/11 Other Hypersensitivities + 11/13 Tolerance & Transplatn

What is skin testing

Inject small quantities of known allergens under skin → look for swelling/redness

What do ELISA and Western Blot quantify? (in relation to allergies)

Quantifies total or allergen specific IgE serum levels 

What is the mechanism of antihistamines

Bind and block H1 receptors on target cells

What is the side effect of antihistamines

First generation antihistamines can cross into the CNS and cause side-effects

Name the first gen and second gen histamine brands

First gen = benadryl

Second gen = claritin

What is the mechanism of leukotriene antagonists 

Oppose inflammatory mediators

Side effect of leukotriene antagonists

Cause changes in mental health

What is the mechanism of corticosteroids

Inhibit innate immune cell activity and inflammation in airways when inhaled

What is the mechanism of immunotherapeutic treatments

Anti-IgE antibodies that inhibit binding to FCεR1 receptors on mast cells

What is the mechanism of epinephrine/norepinephrine agonist treatments (include what it prevents)

Keep cAMP levels high, which lowers permeability and calcium influx → prevents mast cell degranulation 

What is the mechanism of allergy shots (hyposensitization)

Repeated low dose exposure → increase in T regulatory cells and may induce competitive IgG subtypes that bind to FcyRII receptor that inhibits proinflammatory receptor 

What is the mechanism for clustering with inhibitory receptors

Mast cells express both FCεR1 (activating) and FcyRIID (inhibiting) Ig receptors → if a cell binds to IgE and IgG, the inhibting signal induced by IgG binding wins out → quiets response (no degranulation) 

Why does Type II hypersensitivities occur 

When antibodies, IgG and IgM, are directed against cell antigens → Ab mediated cytotoxicity

What is the timeframe for type II hypersensitivities

5-8 hours

What is Phase I (sensitization) for type II hypersensitivities 

Cell-surface Ag causes production of IgG or IgM via normal mechanisms

What is phase II (pathology) for type II hypersensitivities

Subsequent exposure results in IgG or IgM binding resulting in cell lysis via complement dependent cytotoxicity, antibody dependent cell cytotoxicity, and opsonization

What is complement dependent cytotoxicity

Activation of classical complement pathway

What is antibody dependent cell cytotoxicity

binds to Fc receptors on NK cells

Name 3 specific types of type II reactions

Transfusion reactions, drug-induced hemolytic anemia, hemolytic disease of the newborn 

What are transfusion reactions

Humans have antibodies to blood type antigens (carbohydrates) they don’t have

What is the 3 step process for transfusion reactions

1. Incorrect blood type transfusion

2. Recipient Abs bind to donor blood cells 

3. Activation of complement results in RBC lysis → anemia 

What is drug-induced hemolytic anemia

Some drugs non-specifically absorb proteins on RBC membranes

What is the 3 step process for drug-induced hemolytic anemia

1. Drug absorption of proteins stimulate Ab production following primary exposure 

2. Secondary exposure to drug causes Abs to bind to RBCs 

3. Complement-mediated destruction of RBCs → anemia 

How does hemolytic disease of the newborn occur (just 1 sentence)

Occurs when the baby is Rh+ and the mother is Rh-

What is the 3 step process for hemolytic disease of the newborn

1. If the fetus is Rh+, maternal plasma cells produce anti-Rh Abs (IgG)

2. Upon secondary exposure to Rh (via second pregnancy), these Abs can cross the placenta and attack the fetus 

3. Fetus experiences anemia 

What is the direct coombs test used for

Used to detect presence of anti-Rh IgG in mother

What are the 2 steps for the direct coombs test

1. Mix maternal blood with anti-human IgG 

2. Agglutination via cross-linking of RBCs by anti-human IgG = positive reaction 

What is agglutination

Clumping of particles such as RBCs

What is rhogam (treatment for hemolytic disease of the newborn)

Synthetic Ab that binds to fetal Rh, preventing Ab-mediated lysis

What is intrauterine fetal transfusion (treatment for hemolytic disease of the newborn) 

Matching donor blood is transfused directly into fetus while in the womb → counteracts anemi

How do Type III hypersensitivities occur

Occur when the accumulation of immune complexes gives rise to an inflammatory response + attraction of leukocytes 

What is the timeframe for type III hypersensitivities 

4-6 hours 

What is Phase 1 (sensitization) for type III hypersensitivities

Self (autoimmunity) or foreign Ag causes formation of Ab via normal mechanisms 

What is Phase II (pathology) for type III hypersensitivities 

Subsequent exposure to Ag → Ab binding → formation of immune complexes that aggregate into large numbers as a result of inefficient clearing → tissue damage 

What 3 things happen when immune complexes deposit in tissue (1 also has subbullet)

1. Triggers inflammatory or vasoactive mediators 

   1. leukocyte trafficking 

2. protease-mediated connective tissue damage is induced 

3. clot formation (via platelet activation) 

What is the arthus reaction

Injecting Ag into individual with high levels of anti-Ag Abs will result in formation of immune complexes → exacerbated inflammatory response

How was the arthus reaction discovered

Arthus repeatedly injected horse serum into rabbits and observed symptoms of edema and gangrene 

What are the symptoms of the arthus reaction (2)

Swelling and localized bleeding at injection site

What 3 situations can the arthus reaction develop after

1. Type I hypersensitivity to insect bite 

2. DPT vaccine 

3. Inhalation of Ag (ex: mold)

Vasculitis route and site of immunecomplex deposition

Intravenous and blood vessel walls

Nephritis route and site of immunecomplex deposition

Intravenous and renal glomeruli

Arthritis route and site of immunecomplex deposition

Intravenous and joint spaces

Arthus reaction route and site of immunecomplex deposition

Subcutaneous (under the skin) and perivascular area (fluid filled structures that surround blood vessels in the brain)

Farmer’s lung reaction route and site of immunecomplex deposition 

Inhalation and alveolar/capillary interface 

What are Type IV hypersensitivities

A cell mediated reaction (specifically by T cells and macrophages) that take several days to develop 

What is Phase I of Type IV hypersensitivities (Sensitization)

Exposure to Ag activates T cells (often CD4+ TH1) following macrophage antigen-presentation 

What is Phase II of Type IV hypersensitivities (pathology)

Subsequent exposure to Ag causes TH1 cells activation causing cytokine release and activation of macrophages 

What type are Type IV hypersensitivities and why?

Delayed-type because it takes time for the TH1 cell to recognize the Ag and begin proliferating

What is tuberculosis caused by

Intracellular mycobacterium that targets macrophages in the lung

What 2 steps are involved in tuberculosis

1. Prolonged inability to clear bacteria causes formation of granuloma (aka tubercle) = fusion of macrophages to cut off Tb 

2. T cells have formed a barrier or cuff around the outside to contain the macrophages and prevent spread 

Describe the TB/PPD Test

Inject Ag under the skin → if inflammation is present → sensitized Th1 cells present but not indicative of current, active infection

What is contact dermatitis caused by

Modified proteins that are presented to and activate T cells

What is the 3 step process of poison ivy

1. Urushiol (lipid) conjugates with self molecules → sensitize Th1 cells 

2. Th1 cells activated at second exposure → macrophage infiltrate causes inflammation and tissue damage 

3. Positive feedback causes lingering symptoms 

What are the two infectious causes of chronic inflammation

Continued microbial invasion and ineffective microbial clearance 

What are examples of continued microbial invasion

Gum disease, unhealed wounds, ineffective tolerance

What are examples of ineffective microbial clearance (3)

Tb, hepatitis B/C, STIs that induce pelvic inflammatory disease

What is a non-infectious cause of chronic inflammation

DAMPs = self Ag released under certain conditions associated with damage (e.g. tumors, autoimmune diseases) 

What are examples of diseases related to non-infectious causes of chronic inflammation (5)

Obesity, tumors, autoimmune diseases, atherosclerosis, injury 

Related effect of obesity with chronic inflammation

Visceral adipocytes (fat cells in abdominal cavity) are secretors of potent pro-inflammatory cytokines (TNF-alpha and IL-6) 

How is insulin resistance related to chronic inflammation

Adipose tissue (body fat) production of TNF-alpha and IL-6 induces signaling cascades that inhibit insulin receptors → insulin resistance results in production of pro-inflammatory cytokines

How is blood vessel production (angiogenesis) related to chronic inflammation 

Pro-inflammatory cytokines and VEGF promote the development of blood vessels but leads to damage to endothelial cells, inflammatory repair → plaque, promotes tumor formation and enhance production of blood vessels that provide nutrients to tumors 

How is atherosclerosis related to chronic inflammation

Microtears in endothelial cells lining blood vessels results in inflammation and recruitment of macrophages → macrophages ingest a lot of LDLs (cholesterol) from bloodstream leading to accumulation of LDLs = plaques 

What are immunogens (also name where they’re injected, dosage, structure, and presence)

An antigen that the immune system responds to

Injected: subcutaneous / intramuscular

Dosage: specific

Structure: large, complex, processed

Presence: transient (impermanent)

What are tolerogens (also name where they’re injected, dosage, structure, and presence)

An antigen that the immune system doesn’t respond to

Injected: oral / intravenous 

Dosage: non-specific 

Structure: small, simple, “raw”

Presence: long-term 

What is central tolerance

Deleting lymphocytes with receptors that recognize self-ags before they mature 

Where does central tolerance occur and what does binding to self Ag (3) lead to

primary lymphoid organs and clonal deletion, anergy, and receptor editing

What is peripheral tolerance

Renders self-reactive lymphocytes non-responsive or actively generates inhibiting lymphocytes like Tregs

Where does peripheral tolerance occur and what does binding in part I and partII lead to (3 bullets)

• Occurs in the peripheral lymphoid organs 

• Part I binding to self Ag leads to clonal deletion, anergy, and turning into a T reg cell

• Part II binding to self Ag leads to pro survival signal 

What is a leaky system

Weakly reactive cells may not be eliminated during peripheral tolerance

What are the 5 ways for how Treg cells suppress the immune system

1. Produce inhibitory cytokines (IL-10 and TGF-beta)

2. Sequester IL-2 through high affinity IL-2R 

3. Direct killing of T cells through Perforin, granzyme, FasL 

4. Induce metabolism changes → decrease T cell function 

5. “Decommission” APCs by blocking APCs that bind to same antigen

What is bystander suppression

Tregs interacting with an APC can downregulate APC costimulatory signals, suppressing other T cells being activated by the APC

What are the defining molecules

CD25+, CTLA-4 (co inhibitory molecule), high levels of IL-2R, and FOXP3 master transcription facotr 

What does FoxP3 mutation cause?

Multi-organ autoimmunity due to the absence of Tregs

What are B regulatory cells (B10) and what do they do

Newly characterized cells that secrete immunosuppressive cytokines (Il-10, IL-35, Tgf-beta) 

What can B10 cells induce and how 

Treg formation by presenting antigen with low costimulatory molecule expression 

What does expression of co-inhibitory molecules (PD-L1 and FasL) do? 

Suppress T cell activation induced apoptosis 

What are myeloid derived suppressor cells

Immature heterogeneous group of myeloid cells (granulocytes and monocytes)

What do MDSCs do

Use inhibitory cytokines, chemicals, and immunosuppressive cell receptors to reduce immune response 

Where are MDSCs found and what do they do there 

Found at tumor sites and quiet the immune response leading to a poor prognosis 

What are immune privileged sites and name 4 examples

Tissues that are protected from an immune attack (brain, reproductive organs, eye, placenta) 

Describe lack of lymphatic drainage and where does it occur

No lymphatic vessels are present, preventing Ags from interacting with immune cells (ex: lens of eye)

Describe restricted immune entry and where does it occur

Cells restrict any movement of immune cells from blood vessels into endothelial cells of tissues (ex: placenta)

Where is there a limited presence of immune cells

Brain, cornea, testes

What does histocompatibility determine and describe

Determines rejection → “histocompatible” grafts share sufficient antigen similarity, decreasing change of rejection

Who is the donor for an autograft?

Self

Who is the donor for an isograft?

Genetically identical individual (ex: identical twin)

Who is the donor for an allograft?

Genetically different member of same species (ex: parent)

Who is the donor for a xenograft?

Different species