SN 20- Types II, III, IV hypersensitivities
contributing factors to type 3 rxns
(1) the presence of antigens capable of generating particularly extensive antigen-antibody lattices (2) a high intrinsic affinity of antigens for particular tissues (3) the presence of highly charged antigens (which can affect immune complex engulfment) (4) a compromised phagocytic system
Type III Hypersensitivities - Example 2: Serum Sickness
(systemic type 3 reaction) May result from artificial passive immunization Horse serum has been used to treat snake bites, diphtheria, scarlet fever, tetanus, and other severe infections Serum sickness occurs 7-10 days after serum administration Occurs today in response to equine anti-venom, monoclonal antibodies, high-dose intravenous drugs (e.g. penicillin) Serum sickness symptoms occur as IgG is produced in response to the foreign antibody Symptoms abate as immune complexes are cleared Subsequent exposures result in responses within 1-2 days
3) Antibody-Dependent Cellular Cytotoxicity (ADCC)
-Autoantibodies binds to a cell surface antigen, and opsonize the cell -Natural Killer (NK) cells recognize Fc receptor on opsonizing antibodies -NK delivers perforin and granzymes killing the opsonized cell
1) Opsonization and phagocytosis
-Autoantibodies binds to a cell surface antigen, opsonizing the cell -Macrophages have cell surface receptor for antibody Fc regions -Macrophage phagocytoses and destroys the opsonized cell
type IV hypersensitivity process
A) Primary Exposure -CD4+ or CD8+ T Cell recognizesantigen presented on MHCClass I or MHC Class III -Effector cells and memory cells proliferate B) Re-exposure activates memory T Cells and causes proliferation of effector T Cells C) CD4+ T Cells trigger inflammation by macrophage and neutrophil activation, CD8+ T Cells kill cells presenting the antigen
type IV hypersensitivies: Responses occur more slowly (after 1-3 days) than Type I Hypersensitivity Reactions
Always require antigen processing & presentation and T Cell activation Other hypersensitivities occur at a faster pace due to the presence of pre-existing antibodies
autoantigen
An antigen of one's own cell or cell products
cause of rheumatic heart disease
Antibodies produced in the anti-Group A Strep response cross-react with certain self-antigens
hemolytic disease of the newborn: RhoGAM
Antibody coats the fetal red cells that cross the placenta and enter maternal circulation. All Rh antigen in the maternal circulation is complexed with human IgG -IgG bound to fetal RBCs binds to inhibitory Fc receptors on mother's naïve B Cells preventing immune activation
autoimmunity: Chronic, adaptive immune response to self-antigens
Antigen always present, effector and memory cells in constant production Immune reactions constantly occurring
antigen
Any molecule, macromolecule, virus particle, or cell that contains a structure that can be recognized and bound by an antibody, B-cell receptor or T-cell receptor Includes molecules from harmful things like pathogens AND molecules from harmless things found in the environment and the components that make up our bodies autoantigen
hemolytic disease of the newborn: during pregnancy
Around 28 weeks, some blood begins to be exchanged between mother and fetus -If mother is Rh- and fetus is Rh+, mother will recognize Rh+ RBCs as foreign antigen and mount a primary immune response
2) Activation of the classical complement cascade
Autoantibodies binds to a cell surface antigen, beginning the process of forming a C3 convertase Complement cascade activation results in: -Membrane attack complex formation and cell lysis -Opsonization and phagocytosis of the cell -Triggers inflammation and recruits leukocytes
4) Antibody-mediated cellular dysfunction
Autoantibodies binds to a cell surface receptor -This may block a receptor, preventing its activation by a ligand -This may inappropriately activate a cellular receptor even when the appropriate ligand is not present
result of type II hypersensitivity
B Cells produce IgG or IgM autoantibodies that are directed against antigens on the surface of cells or other tissues components
type 3: intrinsic soluble substance
DNA, histones, ribosomes, ribonucleoproteins
type IV
Delayed-Type Cell Mediated Cellular/T Cell-Mediated (only one mediated by T cells, types I-III are driven by some sort of antibody)
poison ivy: Urishol: Modified proteins generate modified peptides within the cytosol
Delivered to the cell surface by MHC class I molecules Recognized by CD8 T cells, which can cause damage either by killing the eliciting cell or by secreting cytokines such as IFN-γ.
type III: serum sickness: Horse serum has been used to treat snake bites, diphtheria, scarlet fever, tetanus, and other severe infections
Horse is injected with sub-lethal doses or the toxin, neutralizing antibodies develop, and serum or purified antibodies are collected Horse serum components (including antibody Fc regions) are recognized as foreign
Type III Hypersensitivities - Example 3: Infective Endocarditis
IE occurs when bacteria colonize heart valves Viridans streptococci may disseminate from periodontitis or periapical abscess or via bacteremia induced by dental procedures (including normal at-home hygiene) Patients with artificial or damaged valves, certain congenital heart defects, history of endocarditis, heart transplants with valve problems are at increased risk -Prophylactic antibiotics recommended for these patients
type 3 hypersensitivity result
IgG antibodies bind antigens in the blood and extracellular fluid, forming large networks called immune complexes which form deposits in blood vessels and lung alveoli
type I
Immediate hypersensitivity IgE-Mediated
type III
Immune Complex-Mediated Immune Complex, Neutrophil; and Complement-Mediated
type III reactions: farmers lung
Inhaled allergens may induce IgG instead of IgE, ---> Immune-complex mediated damage to alveolar epithelium Inhalation of biologic dusts coming from hay dust or mold spores or any other agricultural products Occurs in about 30/1,000 dairy famers
Type IV Reaction to toothpaste flavoring
Patient had a 7 month history of itching, painful dermatitis Symptoms were resolved by switching from mint to citrus flavored toothpaste
hemolytic disease of the newborn: -Immune reaction during the FIRST pregnancy
Predominant antibody is low-affinity IgM -Cannot cross the placenta Some IgG is made which cause minor destruction of fetal RBC Healthy newborn baby
hemolytic disease of the newborn: Rh- mother has a second pregnancy with a Rh+ fetus
Produced a SECONDARY immune response -Characterized by high affinity IgG -High affinity IgG crosses placenta -IgG transferred to the fetus opsonizes fetal RBCs -Fetal RBCs are destroyed by macrophages in the fetus's spleen -Anemic newborn baby
Type III Hypersensitivities: Examples:
Reaction to Diphtheria & Tetanus Vaccines (Arthus rxn) serum sickness infective endocarditis farmers lung chronic viral hepatitis
3. maintain tolerance
Self, Commensal Microbes, Food, Environment Loss of tolerance can lead to allergies and autoimmune disorders
Type IV Hypersensitivities - Example 1: Contact Hypersensitivity Phases
Sensitization Phase of Contact Hypersensitivity Phase 2 of Contact Hypersensitivity (Elicitation Phase)
haptens
Small, low molecular weight organic molecules that are antigenic but not immunogenic
mechanism of rheumatic heart disease
Some antibodies produced during the normal humoral adaptive immune response to streptococcus bacteria cross-react with self-antigens in the joints and hearts some individuals Cross-reactive antibodies bind to self-antigens in the heart (1) Neutrophils and macrophages recognize antibody Fc receptors and become activated (2) Leukocyte activation results in chronic inflammation damaging heart tissue (3)
Type IV Hypersensitivities - Example 2: Tb Test
Tuberculin placed under skin If sensitized: -APCs present antigen to memory CD4+ T Cells -Tuberculin-specific TH1 cells proliferate -IFNγ activates macrophages -Macrophages cause inflammation (Red bump appears)
type 3 hypersensitivities: immune complex
antigen-antibody association formed by antibody-antigen crosslinking Under normal circumstances, immune complexes are cleared via phagocytosis
RhoGAM
can neutralize Rh+ fetal RBC -RhoGAM = IgG antibody -Given to Rh- mothers at 28 weeks (The typical point when the mother begins mounting a response to transferred RBCs) -Second dose given within 3 days of birth if the baby is Rh+ (Blood exposure occurs during delivery labor and delivery, At least 1ml is exchanged between baby and mother, even in uncomplicated deliveries) -given in subsequent pregnancies as well
examples of type IV hypersensitivities:
contact hypersensitivity -poison ivy -nickel -acrylic resin -tooth paste flavoring Tb test
autoimmune disease
disease in which the pathology is caused by an adaptive immune response to normal components of healthy tissue
hypersensitivity reactions
haptens carrier proteins On their own, neither the hapten nor the carrier protein stimulate an immune response Haptens may covalently bond to carrier proteins (haptenization)
symptoms and pathologies of hypersensitivities are due to
misplaced/inappropriate adaptive immune responses -type 1, II, III, IV
type III: infective endocarditis: bacterial vegetation stimulates...
persistent antibody production Antibodies fail to clear infection on valves -Immune complexes cause widespread damage in capillaries -May present with oral petechiae, Osler's nodes -Often results in damage to skin and kidneys -Treatment: Antibiotics
examples of allergens
plant pollen dust mite feces insect venom drugs peanuts shellfish plant oil metal
rheumatic fever and heart disease are ____ but most commonly occur in ___
rare children ages 5-15
autoantibody
an antibody produced by the host that binds a self-antigen
type 3: Immune complexes then move through the capillary walls and into the tissues, where they are deposited
-Deposited complexes and set up a localized inflammatory response. -Complement activation results in the production of the anaphylatoxin chemokines C3a and C5a -Anaphylatoxins attract more neutrophils and macrophages -Neutrophils and macrophages are further activated by immune complexes binding to their Fc receptors to secrete pro-inflammatory chemokines and cytokines, prostaglandins, and proteases. -Proteases attack the basement membrane proteins collagen and elastin, as well as cartilage. -Tissue damage is further mediated by oxygen free radicals released by the activated neutrophils. -Immune complexes interact with platelets and induce the formation of tiny clots.
Sensitization Phase of Contact Hypersensitivity
-Hapten molecules like oils from poison ivy or nickel are able to penetrate the skin -Hapten binds carrier protein in the skin -Langerhans Cells (skin DCs) take up antigen and present to T Cells -Clonal expansion and formation of memory T Cells occurs
hemolytic disease of the newborn continued
-Immune reaction during the FIRST pregnancy -Rh- mother has a second pregnancy with a Rh+ fetus -RhoGAM
type 3 hypersensitivities
-Mediated by IgG-associated immune complex formation -occur when an excess of soluble immunogenic antigen is present
penicillin-type 2 hypersensitivity reaction process
-Penicillin binds to molecules on the surface of erythrocytes forming a unique antigenic structure -During normal turnover of erythrocytes, cells are broken down and digested -Modified antigen is presented on MHC and is seen as a foreign antigen by the immune system -Adaptive immune response occurs, IgG specific for the new antigen are produced -IgG autoantibodies coat the erythrocyte -Induces further complement deposition on the cell -Cellular destruction (cytotoxicity) occurs by MAC formation or opsonization
Phase 2 of Contact Hypersensitivity
-Re-exposure to the hapten occurs -Hapten-carrier complex presented to T Cells by Langerhans cells -Activation of Memory T cells occur, cells proliferate and produce effector cells -Inflammation damages tissue leading to rash
Type II Hypersensitivity - Example 3: Hemolytic Disease of the Newborn
-Rh antigen - on red blood cells (RBCs) in a portion of the population (85% Caucasians, 92% Blacks, 99% Asians -Rh- individual will recognize Rh+ RBCs as foreign antigens -during pregnancy
type III: pathogenesis of infective endocarditis
-Streptococci reach bloodstream -Damaged endothelium is coated by platelets -Platelets are colonized by oral streptococci (Platelet aggregation-associated proteins encourage adherence) -Fibrin deposition results in microbial/fibrin/platelet vegetation - protects bacteria -Can result in acute septic embolism (occlusion of capillaries) -also results in type III reaction
localized type 3 rxn: arthus reaction
1) IgG responds to injected antigen 2) Immune complex forms, complement activated 3) C5a and immune complexes trigger mast cell degranulation 4) Local inflammation and swelling 5) Blood vessel occlusion
type II hypersensitivity: autoantibodies binding cells leads to:
1) Opsonization and phagocytosis 2) Activation of the classical complement cascade 3) Antibody-Dependent Cellular Cytotoxicity (ADCC) 4) Antibody-mediated cellular dysfunction
3 major roles of the immune system
1. defense against infection 2. avoid collateral damge 3. maintain tolerance
type IV reaction to acrylic resin
60yoF reports burning sensation, bitter taste, hypersalivation, difficulty swallowing Symptoms improve following removal, treatment with corticosteroids
Immunogen
A molecule or substance that can activate B or T cells All immunogens are antigens - an antigen is not necessarily an immunogen
hemolytic disease of the newborn can also be caused by
ABO blood-group incompatibility between mom and fetus -Less severe -Type A or B fetuses carried by type O mothers most commonly develop these reactions. -Type O mother can develop IgG antibodies to the A or B blood-group antigens through exposure to fetal blood-group A or B antigens in successive pregnancies. -Major clinical manifestation: light elevation of bilirubin, with jaundice. -Exposure of the infant to low levels of UV light is often enough to break down the bilirubin and avoid cerebral damage
autoimmunity: May results in tissue damage, dysfunction and organ failure
Accumulation of damage due to chronic inflammation May take years (decades?) for symptoms to appear
autoimmune diseases: key point
All autoimmune diseases resemble a Type II, Type III or Type IV hypersensitivity Autoimmune diseases never resemble a Type I hypersensitivity -There are no autoimmune diseases caused by IgE responses
Type II Hypersensitivity - Example 1: Penicillin
Certain antibiotics (e.g., penicillin, cephalosporins, and streptomycin), as well as other drugs (ibuprofen and naproxen), can adsorb nonspecifically to proteins on red blood cell membranes -Forms a new forming a drug-protein complex -This is a new antigen which induces antibody formation in some patients
autoimmunity
Chronic, adaptive immune response to self-antigens May results in tissue damage, dysfunction and organ failure
type III: serum sickness: Serum sickness occurs 7-10 days after serum administration
Coincides with production of high affinity IgG Fever, chills, rash, arthritis, vasculitis, glomerulonephritis (on occasion) Induced by immune complexes against foreign equine serum proteins
type II
Cytotoxic IgG (or IgM) and Complement-Mediated
type 3: Reaction to Diphtheria & Tetanus Vaccines
Diphtheria and tetanus vaccines consist of inactivated bacterial toxins -Vaccine produces neutralizing antibodies towards to toxin A localized Type III reaction may occur in rare cases when receiving a diphtheria or tetanus booster shot localized type 3 rxn: Arthus reaction
Cellular destruction (cytotoxicity) occurs by MAC formation or opsonization
Drug-induced hemolytic anemia (Erythrocytes) Drug-induced thrombocytopenia (Platelets)
Allergens
Environmental antigens that cause hypersensitivity reactions Typically Type I or Type IV reactions May be inhaled, injected, ingested or contacted Allergy = Greek derivation of "altered reactivity"
T/F: all antigens activate the adaptive immune system
FALSE
type III reactions: chronic viral hepatitis
Failure to clear infection results in persistent antibody production --> Damage to liver
symptoms of type 3 reactions
Fever, urticaria (rashes/hives), joint pain, lymph node enlargement, protein in the urine Inflammatory lesions in blood vessels result in vasculitis Inflammatory lesions in the kidneys result in glomerulonephritis Inflammatory lesion in the joints results in arthritis
type III: Serum sickness symptoms occur as IgG is produced in response to the foreign antibody
Foreign antibodies are widespread throughout the circulation Immune complexes disperse throughout the body deposit in capillaries Numerous areas of inflammation contribute to widespread damage
type 3: exogenous soluble substance
Foreign serum, iv drugs, bacterial or viral antigens
exogenous molecules
Foreign substance such as a drug metabolite, Antigen that mimics a self-antigen
carrier protein
May be found in the body or externally Antigenic but not immunogenic
type IV: contact hypersensitivity: poison ivy
Mediated by CD4 & CD8 T cells 1st exposure results in sensitization Urishol = pentadecacatechol and other catechols -Lipid-soluble (Crosses the cell membrane and modify intracellular proteins) -Modified proteins generate modified peptides within the cytosol
symptoms of rheumatic heart disease
Mirrors symptoms of congestive heart failure (including chest pain, shortness of breath, fast heartbeat) New heart murmur Enlarged heart Fluid around the heart
blood transfusion reaction in hemolytic disease of the newborn
Mismatched ABO blood group transfusions result in Type II Hypersensitivity reactions.
intrinic molecules
Naturally occurring self-antigens, Autoimmune reaction
Haptens may covalently bond to carrier proteins (haptenization)
New conformation/complex is antigenic AND immunogenic Hapten-carrier complex can trigger hypersensitivity reactions
type IV hypersensitivities: nickel
Nickel binds to histidine-containing proteins to form novel antigen Alter the conformation or the peptide binding of MHC class II molecules, provoke a T Cell responses
symptoms of rheumatic fever
Painful, tender joints (most commonly in the knees, ankles, elbows, and wrists) Fatigue Rash (rare)
immunogenicity
The ability of an antigen to stimulate an immune response -Proteins are usually more immunogenic than lipids and nucleic acids -Large molecules are usually more immunogenic than small molecules
2. avoid collateral damage
The immune response is powerful - if it is not appropriately limited tissues will be damaged
Type II hypersensitivity ex 2- Rheumatic heart disease
The immune response to the infection causing strep throat (Group A Streptococcus) can lead to rheumatic fever and rheumatic heart disease
progression of a type 3 hypersensitivity reaction
Uncleared immune complexes bind to mast cells, neutrophils, and macrophages via Fc receptors These cells produce of vasoactive mediators and inflammatory cytokines (incr permeability of the blood vessel walls) Immune complexes then move through the capillary walls and into the tissues, where they are deposited
hypersensitivity/allergic reactions
Unnecessary overreaction of the immune system to innocuous environmental or self antigens
1. defense against infection
Viruses, Bacteria, Fungi, Protozoa, Worms, Cancer Weak or ineffective immune responses - chronic and persistent infections -Illness, death
type IV hypersensitivity
aka Delayed-Type Hypersensitivity, T Cell-Mediated Hypersensitivity Triggering antigens - T Cell Activating Antigens Result: Contact, tuberculin or granuloma response T Cell-Mediated (May be CD4+ or CD8+) Responses occur more slowly (after 1-3 days) than Type I Hypersensitivity Reactions
autoimmune response
adaptive immune response directed at an antigenic component of the responder's own body (autoantigen) can cause autoimmune disease
type II hypersensitivity
aka Cytotoxic Hypersensitivity Triggering antigens may be an intrinsic or an exogenous molecule
type III hypersensitivity
aka Immune Complex Hypersensitivity Triggering antigens may be intrinsic or an exogenous SOLUBLE substance