Immunology II- Hypersensitivity reactions Flashcards
Hypersensitivity reactions- definition
exaggerated, inappropriate immunologic reaction that is harmful to the host
Sensitization
First exposure to antigen with immune response (antibody) Subsequent exposures= hypersensitivity rxn
4 types of hypersensitivity rxns
A- Type I: Allergy or Anaphylaxis
C- Type II: antibody dependent or Cytotoxic
I- Type III: Immune complex
D- Type IV: Cell-mediated or Delayed type
“ACID”
Which type of hypersensitivity reaction involves Immune complex?
Type III
Which type of hypersensitivity reaction involves Cell-mediated or delayed type
Type IV
Which type of hypersensitivity reaction involves allergy or anaphylaxis
Type I This is immediate hypersensitivity
Which type of hypersensitivity reaction involves Antibody dependent or cytotoxic
Type II
Which types of reactions are antibody mediated
I= IgE II and III= IgG
Mechanism of Type I Hypersensitivity rxn
- First exposure to antigen causes IgE formation
- IgE binds to mast cells
- Subsequent exposure- antigen binds to IgE bound-mast cell
- Degranulation of mast cells
- Release of mediators
*1st exposure is “priming”
What is the typical time of onset of type I
minutes
Antigens involved in Type I
substances that most people dont react to- pollen, animal dander, foods, drugs (things in environment)
Result of Type I hypersensitivity rxn
increased vascular permeability
edema
smooth muscle contraction
What are the clinical manifestations of Type I hypersensitivity rxn?
edema
erythema
itching
urticaria
eczema
rhinitis
conjunctivitis
asthma
most severe: systemic anaphylaxis (severe bronchoconstriction and hypotension)
What happens during an allergic response during sensitization
- During sensitization, an antigen presenting cell (APC) picks up the allergen and presents part of it to a Th2 cell, which helps a B cell become a plasma cell 2. Plasma cells produce allergen-specific antibodies called IgE, which binds to mast cells
What happens during an allergic response with re-exposure
When allergen returns, mast cells release histamine and other chemicals
Th2 cells release chemicals that attract inflammatory cells (i.e. eosinophils)
This results in allergy sxs (sneezing, mucus production, swelling, itching, runny nose, coughing and wheezing)
What is the mediator of a Type I hypersensitivity rxn and what is its effect?
Histamine
Effect- vasodilation, increased capillary permeability, smooth muscle contraction
What is the immunologic rxn involved in Type I hypersensitivity rxn?
Antigen (allergen) induces IgE antibody that binds to mast cells and basophils. When exposed to the allergen again, the allergen cross links the bound IgE on those cells. This causes degranulation and release of mediators (ex: histamine)
What is the emergency concern regarding anaphylaxis (Type I) nand what is the treatment?
low BP, bronchoconstriction treatment- Epi (bronchodilates and vasoconstricts–> increases BP)
What is the preventative medicaiton option for anaphylaxis (Type I)?
antihistimines, steroids
What infections can exacerbate a patients asthma (type I hypersensitivity rxn)
Bronchitis, influenza, pneumonia **can prevent with vaccines
What is the plan for a pt that presents with Type I Hypersensitivity rxn (anaphylaxis)?
- IM/SQ Epinephrine x1 now 2. IV corticosteroids 3. IV fluids for hydration and to increase BP 4. IV diphenhydramine (Benadryl)–> antihistamine 5. IV promethazine (Phenergan)–> antiemetic 6. observation
What foods cause 90% of food allergies
milk
egg
fish (bass, flounder, cod)
shellfish (crab, lobster, shrimp)
Tree nuts (almonds, pecans, walnuts
wheat
peanuts
soybeans
**also a consideration: fruits, preservatives, dyes
What results when there is systemic histamine release in anaphylaxis (type I hypersensitivity)
Hypotension
nausea
hives
swollen hands/feet
What is the other name for Type II: cytotoxic hypersensitivity
antibody dependent
antibody= IgG
Antigens involved in Type II hypersensitivity rxn
on cells or in extracellular matrix
can be endogenous or exogenous antigens
Antibody involved in Type II hypersensitivity rxn
IgG
Immunologic rxn of Type II hypersensitivity rxn
Antigens on a cell surface combine with IgG antibody this leads to complement-mediated lysis of the cells (ex: transfusion or Rh reactions or autoimmune hemolytic anemia)
What is the typical time of onset of a Type II cytotoxic hypersensitivity rxn?
hours to days
What are the clinical manifestations of Type II hypersensitivity rxn
Hemolytic anemia
neutropenia
thrombocytopenia
ABO transfusion rxns
Rh incompatibility (erythroblastosis fetalis, hemolytic disease of the newborn)
rheumatic fever
Goodpasture syndrome
What is hemolytic anemia
Example of Type II cytotoxic hypersensitivity 1. antibody attaches to antigen on RBC 2. Complement mediated lysis via MAC 3. complement also attracts phagocytes
What is the antibody associated with Type III Immune complex hypersensitivity?
IgG
What is the immunologic rxn associated with Type III Immune complex hypersensitivity?
-antigen-antibody immune complexes are deposited in tissues, complement is activated, and polymorphonuclear cells are attracted to the side -They release lysosomal enzymes, causing tissue damage
What is the typical time of onset of Type III Immune complex hypersensitivity?
2-3 weeks
What is the clinical manifestations of Type III Immune complex hypersensitivity?
Systemic lupus erythematosus
rheumatoid arthritis
poststreptococcal glomerulonephritis
IgA nephropathy
serum sickness
hypersensitivity pneumonitis (Farmers lung)
What is the mechanism of Type III Immune complex hypersensitivity?
- Antigen-antibody immune complexes form and deposit in tissue
- Inflammatory response induced in tissue
- Complement activated, and PMNs attracted to the site -Lysosomal enzymes released -tissue damage
Systemic Lupus erythematosus
Example of Type III Immune complex hypersensitivity.
- Antibodies formed to DNA and cell nucleaus (ANA=antinuclear antibody)
- antibodies form immune complexes that activate complement
- Complement activation produces C5a, which attracts neutrophils that release enzymes, thereby damaging tissue
***butterfly rash on face
Rheumatoid Arthritis
Example of Type III Immune complex hypersensitivity
- Serum and synovial fluid of pt contain “rheumatoid factor” (i.e. IgM and IgG antibodies that bind to the Fc fragment of normal human IgG)
- Deposits of immune complexes (containing the normal IgG and rheumatoid factor) on synovial membranes in blood vessels
- Activate complement and attract polymorphonuclear cells, causing inflammation
What is seen on labs of patients with Rheumatoid arthritis?
-Pts have high titers of rheumatoid factor and low titers of complement in serum, especially during periods when their dz is most active.
**this is an example of Type III Immune complex hypersensitivity
Immunologic reaction of Type IV Delayed (cell mediated) hypersensitivity
T lymphocytes, activated/sensitized by an antigen, release lymphokines upon second contact with the same antigen
-The lymphokines induce inflammation and activate macrophages, which in turn, release various inflammatory mediators (and causes damage)
What is the typical time of onset of Type IV Delayed (cell mediated) hypersensitivity?
2-3 days
What are the clinical manifestations of Type IV Delayed (cell mediated) hypersensitivity
Contact dermatitis, poison oak/ivy, tuberculin skin test reaction, drug rash, stevens-johnson syndrome, toxic epidermal necrolysis, erythema multiforme
Mechanism of Type IV Delayed (cell mediated) hypersensitivity
- The macrophage ingests the antigen, processes it, and presents an epitope on its surface in association with class II major histocompatibility complex (MHC) protein
- the helper T (Th-1) cell is activated and produces gamma interferon, which activates macrophages
- these two types of cells mediate delayed hypersensitivity
Important clinical aspects of delayed hypersensitivities- What are the main immune cells involved?
CD4 (helper) T cells and macrophages
CD8 (cytotoxic) T cells
Important clinical aspects of delayed hypersensitivities- What are the important diseases/ skin tests having to do with CD4 (helper) T cells and macrophages?
- Tuberculosis, coccidioidomycosis
- Tuberculin or coccidioidin (or spherullin) skin tests
Important clinical aspects of delayed hypersensitivities- What are the important diseases/ skin tests having to do with CD8 (cytotoxic) T cells
- Contact dermatitis
- Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Overview of Important clinical aspects of delayed hypersensitivities (graph)
Type IV hypersensitivity- Repeat exposure
•T lymphocytes activated/sensitized by an antigen release of lymphokines upon second contact with the same antigen.
-The lymphokines induce inflammation and activate macrophages–>release various inflammatory mediators
What is Hereditary Angioedema
A congenital immunodeficiency of C1 protease inhibitor
Autosomal dominant
-Patient has excess C3a, C4a, C5a
What is the typical time of onset of Type IV hypersensitivity reaction
2-3 days
What is the result of Hereditary angioedema?
- capillary permeability and edema
- Episodic local subcutaneous and submucosal edema typically involving GI and upper respiratory tracts
**essentially an overdrive of the complement cascade (deficiency of C1 protease= increased complement)
How do you make a diagnose Hereditary Angioedema?
- Family history
- Lack of pruritis (NOT histamine dependent) and urticarial lesions
- Recurrent abdominal colic and/or laryngeal edema
- Labs: decreased C1 inhibitor levels (or decreased function, or mutation in C1 inhibitor gene altering synthesis/function)
What is the function of the immune system?
•Provide a protective response against infective organisms and foreign cells WHILE Avoiding damage to self
What are the targets of the immune system?
- Infectious organisms (bacteria, viruses, fungi, parasites)
- Foreign bodies
- Toxins
- Cancer
What are “markers of self”?
- Distinctive surface proteins that identify “self”
- Able to coexist with your immune system
- Unique markers on human cells–> the major histocompatibility complex (MHC) proteins
- MHC Class I proteins found on all cells
- MHC Class II proteins found only on certain specialized cells
What are markers of “non-self”?
- Non-self substance (antigen) can trigger the immune system
- Area on the antigen that triggers a response is the epitope
- Example: Transplanted tissues are recognized as foreign and attract antibodies
What is the purpose of Self-antigens?
Mechanisms for avoiding damage to self (preventing autoimmunity):
- Sequestration
- Tolerance
- Regulation
Mechanisms of preventing autoimmunity: Generation and maintenance of tolerance
- Central deletion of autoreactive lymphocytes
- peripheral anergy of autoreactive lymphocytes
- receptor replacement in autoreactive lymphocytes
Mechanisms of preventing Autoimmunity: Regulatory mechanisms
- Regulatory T cells
- Regulatory B cells
- Regulartory mesenchymal cells
- regulatory cytokines
- idotype work
What is an autoimmune disease?
a trigger interferes with normal mechanisms protecting auto-antigens against an immunologic response causing tissue injury
Types of triggers of autoimmune disease
Exogenous
endogenous
molecular mimicry (infection/pathogen gets into system and has very similar mechanism to self so antibodies released that also attack self)
Criteria of an autoimmune disease
Autoantibodies
self-reactive T lymphocytes
Imbalance b/w T and B cell pathogenic factors and regulatory factors that control immune response
What are examples of Exogenous triggers of autoimmunity?
molecular mimicry
superantigenic stimulation
microbial and tissue damage-associated adjuvanticity
What are examples of Endogenous triggers of autoimmunity?
- Altered antigen presentation
- Increased T cell help
- increased B cell function
- Apoptotic defects or defects in clearance of apoptotic material
- Cytokine imbalance
Endogenous triggers of autoimmunity- altered antigen presentation
- Loss of immunologic privelege
- Presentation of novel or cryptic epitopes (epitope spreading)
- Alteration of self-antigen
- Enhanced function of antigen-presenting cells (Costimulatory molecule expression and cytokine production)
example of Endogenous triggers of autoimmunity- Increased T cell help
- Cytokine production
- Costimulatroy molecules
Example of Endogenous triggers of autoimmunity- Increased B cell function
- B cell activating factor
- Costimulatroy molecules
Etiologies of autoimmune disease
- Genetic susceptibility
- Environmental immune stimulants
- Infectious agents
- Loss of T regulatory cells
- Decreased clearance of apoptotic material
- Antibodies that react with apoptotic material
Triggers of imbalance that leads to autoimmune disease
Bacteria-
- Streptococcus pyogenes (Strep throat)–> Rheumatic fever
- Borrelia burgdorferi–> Lyme Arthritis
Viruses-
- Hepatitis B virus–> Multiple Sclerosis
Graves disease
Autoimmune disease
Hyperactive thyroid disorder- Involves autoantibody stimulation of the TSH receptor–> Thyroid stimulating immunoglobulin (TSI)
(TSI is the antibody that reacts with TSH receptor and causes it to be hyperactive)
Environmental and genetic factors of autoimmune disease Grave’s Disease
- Stress
- Smoking (minor risk factor; but major risk factor for ophthalmopathy)–> dont have to have this risk factor
- Sudden increased iodine intake
- Post-partum
Myasthenia Gravis
Autoimmune disease
- Autoantibody blocking/inactivation of the alpha-chain of the nicotinic acetylcholine receptor at neuromuscular junctions
- Causes Abnormalities of the thymus
- Anti-AChR antibodies
This is an inhibitory reaction (As opposed to Graves Disease which is hyperactive)
What happens if you have Graves Disease and have Thyroid associated opthalmopathy?
T cells will activate cytokine infiltration of extraocular muscles
What is the role of Anti-AChR antibodies in Myasthenia gravis?
- Increases receptor turnover
- Damage to postsynaptic muscle membrane by antibody and complement
- Blockage of AChR active site that normally binds acetylcholine
What thyroid abnormalities are involved in Myasthenia gravis?
- Hyperplastic
- Tumors (thymoma)
- Muscle-like cells within the thymus – these cells have AChRs on their surface which may be a source of autoantigen triggering the autoimmune reaction within the thymus
Rheumatic fever
- Autoimmune reaction to infection with group A streptococcus —>Molecular mimicry – immune response against streptococcal antigens also recognizes human tissues causing cross-reactive antibodies
- Cardiac valve damage – rheumatic heart disease
Susceptibility of rheumatic fever
•Human leukocyte antigen class II alleles – some are associated with susceptibility and some are protective
Systemic lupus erythematosus (SLE)
Autoimmune disease
- Type III hypersensitivity reaction
- Immune complex formation targeting double-stranded DNA
- Genetic susceptibility and environmental factors result in abnormal immune responses
- Immune cell activation leads to sustained autoantibody and immune complex production, activation of complement, release of chemical mediators
- Chronic inflammation leads to irreversible tissue damage (fibrosis/sclerosis of glomeruli, arteries, lungs, and other tissue)
Which specific antibodies are involved in the autoimmune disease Systemic Lupus Erythematosus?
Anti-dsDNA
anti-Smith
Type I Diabetes mellitus
Autoimmune disease
- Genetic (genes that code for MHC II) and environmental factors (perinatal, viruses, dietary)
- Insulin and islet cell autoantibodies
- T cell cytokine production and cellular cytotoxicity (destruction of pancreatic beta cells)
Which autoantibodies are involved in Type I diabetes mellitus?
Insulin autoantibodies
Islet cell autoantibodies (likely target proinsulin/insulin)
Which type of Hypersensitvity reaction is Rheumatoid Arthritis
Type III hypersensitivity rxn
Autoimmune disease
Rheumatoid arthritis
- Type III hypersensitivity reaction
- Genetic and environmantal factors
- Environmental factors (ex: tobacco smoke exposure, Exposure to silicone dust and mineral oil)
-Involves autoantibodies and pro-inflammatory cytokines
What are the autoantibodies involved in Rheumatoid arthritis?
Rheumatoid factor
anti-CCP antibodies
**RA also has cytokine involvement
Multiple Sclerosis
- Genetic susceptibility
- Pro-inflammatory autoimmune response causing destruction of CNS myelin–> Both T and B cell involvement
**No specific antibody involvement
What is the effector of Graves Disease in addition to its mechanism and target?
Effector= autoantibody
mechanism= stimulation
target= TSH receptor (LATS)
What is the effector of Myasthenia Gravis in addition to its mechanism and target?
Effector= Autoantibody
Mechanism= Blocking or inactivation
Target= alpha chain of the nicotinic acetylcholine receptor
What is the effector of Systemic lupus erythematosus in addition to its mechanism and target?
effector- autoantibody
mechanism- immune complex formation
target- ds DNA
What is the effector of Rheumatoid arthritis in addition to its mechanism and target?
Effector- autoantibody
Mechanism= immune complex formation
Target- immunoglobulin
Effector #2= T cells
Mechanism- cytokine production
What is the effector of Type I DM, Multiple sclerosis and rheumatoid arthritis in addition to its mechanism and target?
Effector= T cells
Mechanism= cytokine production
target= ?
What is the effectors of DM type I in addition to its mechanism and target?
Effector: T cells
Mechanisms: Cytokine production and cellular cytotoxicity
Target: ?
What is the concept of immunizations in relation to the immune system?
Vaccinations exploit the adaptive immune response
- Uninfected individuals given controlled infection or exposed to antigen that elicits an immune response
- When exposed to pathogen in environment, memory T and B cells can quickly mount immune response before pathogen can spread
What are active immunity vaccinations?
-These are your traditional vaccines
- Artificial antigens administered to elicit controlled immune response
- Mediators: Antibody and T cells
- Advantage: Long duration (years)
- Disadvantage: slow onset
Passive immunity vaccinations
- Antibody transferred from immune individual to nonimmune individual
- Advantage: immediate protection
- Disadvantage: short duration (months)
**You would give immunoglobulin with known exposure
Active vs passive immunity- Specifcity vs memory
Active immunity provides memory and specificity
Passive immunity DOES have specificity but DOESNT have memory
Live attenuated vaccine
- Weakened form of virus
- Antigens stimulate immune response
- Must be refrigerated
- Possible to become virulent again if mutates in host (rare)
- Not for immune compromised or pregnancy
- Examples: measles, mumps, rubella, varicella, rotavirus, influenza (intranasal) yellow fever
Inactivated vaccines
- Pathogens killed to inactivate them – can isolate antigenic material
- Freeze-dried, don’t require refrigeration
- Induce weaker immune response
- Need multiple doses to sustain immunity
- Examples: poliovirus, hepatitis A, Japanese encephalitis
Subunit vaccines
- Use component of the pathogen as vaccine antigen to mimic exposure
- Weaker immune response than live attenuated
Types:
- recombinant subunit vaccine
- polysaccharide subunit vaccine
- Surface protein subunit
- Toxoids
Subunit vaccines–> Recombinant subunit vaccine
•antigens manufactured via recombinant DNA technology
Subunit vaccines- polysaccharide subunit vaccine
utilize polysaccharide antigens (meningococcal, pneumococcal PPSV)
Subunit vaccines- Surface protein subunit
utilize purified proteins from the pathogen
Subunit vaccines–> Toxoids
Inactivated or killed toxins used to elicit immune response resulting in antibodies that can neutralize toxins (Diptheria)
Conjugate subunit vaccine
- Technology binds polysaccharide from bacterial capsule to a carrier protein
- This antigen combination induces long-term protection in infants and adults
- Examples: Hib, Pneumococcal (PCV), meningococcal
