Lecture 11: Hypersensitivity and Vaccines

(Hypersensitivity and Vaccines) Lecture 11 4 Types of Hypersensitivity: · Type 1: "Allergy": immediate IgE mediated (anaphylactic) ↳ localized (hives, hay fever, asthma) ↳ general anaphylaxis (shock) · Type 2: "Cytotoxic" (cellbound antigens) ↳ transfusion reactions, Hemolytic Disease of the Newborn (HDN) · Type 3: "Immune Complex-mediated" (soluble antigens) ↳ serum sickness, Arthus reaction, SLE · Type 4: "Delayed cell-mediated" (no antibodies involved) ↳ Tuberculin test, contact hypersensitivity Hypersensitivity · When the immune system goes haywire · immune reactions that can cause tissue damage · all "Hypersensitivity" reactions require previous exposure to the antigen/allergen Type I hypersensitivity Type 1 reactions · either localized or systemic ↳ localized includes hives, "urticaria", allergic rhinitis, hay fever ↳ systemic reactions result in anaphylactic shock, and a need for an epi-pen ① Sensitization: result of classical antigen presentation with T helper cell involvement and B cell activation → IgE antibodies ② Activation: cross linking of at least two IgE molecules bound to FC receptors on mast cell → triggers mast cell/basophil degramulation (more IgE produced) ③ Effector: 2 phases ↳ primary mediators released: histamine, eosinophil chemotactic factor, neutrofil chemotactic factor, proteases ↳ secondary mediators released: leukotrienes and prostaglandins Cross linking Type I Systemic Reactions · immediate reaction (minutes) · life-threatening impaired breathing due to swelling of the airways · uterine cramps, involuntary urination + defecation = due to smooth muscle contraction · edema from fluid leaking into tissue spaces · blood pressure drops dramatically, leading to life threatening anaphylactic shock Mediators Released by Mast Cells and Basophils Histamine, lipid molecules, and cytokines collectively act to: ↳ increase permeability and dilate blood vessels (wider) -leading to edema and erythema (redness) ↳ increase mucous secretion, contract smooth muscle Treatment of Anaphylaxis · Antihistamines ↳ blocks action of histamine ↳ prevents symptoms of allergy · Epinephrine (Epi-pen) ↳ constricts blood vessels, raises blood pressure ↳ dilates air passages in lungs (more air) ↳ effects smooth muscle ↳ used for systemic allergies Type II hypersensitivity Type 2 Reactions Transfusion Reaction · Type A blood cells have "A" antigen on the surface · Recipient has anti-B antibodies · Donor blood has anti-A antibodies which attach to A blood cells in recipient and leads to hemolysis ↳ hemolysis: complement is activated leading to lysis of blood cell HDN (hemolytic disease of the newborn) · mother is RhD- and baby is RhD+ · first pregnancy: baby develops separate from mother, but blood merges after birth and the mother produces an immune response to the RH+ antigen from the babies blood · second pregnancy: RH+ antibody is now present in the mother, which will attack the baby (memory cells) ↳ will lead to blue babies unless treated with special shot Type II · involves complement, cell bound antigen & IgG or IgM antibodies · prevention of Rh sensitization: ↳ administering Rhogam (anti-Rh antibodies) ↳ given before and after birth to the mother to remove fetal red blood cells from circulation before B cell activation can occur · Other transfusion reactions: ↳ ABO incompatibilities ↳ A doesnt like B ↳ O doesn’t like B and A Type III hypersensitivity Type 3 Reactions autoimmune damage · immune complex antibodies bound to antigens circulate in blood ↳ this is called soluble · immune complex sticky deposition is in skin, joints; and kidney (glomerular basement membrane) · generalized type: systemic dissemination of antigen antibody floating in the blood circulation eg. poststreptococcal glomerulonephritis or SLE · Bottom line: immune complex in circulation binds to endothelium then activates complement which generates chemoattractants for neutrophils (C5a is chemoattractant) ↳ these arrive and release their granules and enzymes to damage tissue · due to haywire immune system (bad) · When it circulates in blood its called soluble · sticks to cell wall (usually blood vessels) · complement proteins in blood activate classical pathway and C5a is released, which is a chemoattractant. C5a calls in neutrofils which releases all its granules because theres Type 4 Reactions Type IV hypersensitivity no actual bacteria ↳ leads to damage of blood vessels · slow response (2-3 days), had previous exposure and has memory cells · activated macrophages are the principal effector cell · lytic enzymes that leak from activated macrophages cause local tissue destruction. CTL induced by Th1 cells may also participate in tissue destruction · DTH responses can cause allergic responses such as contact dermatitus (eg. skin reaction to poison oak and poison ivy where an oil from the plant complexes with skin proteins (haptens) that are then presented by skin dendritic cells to Th1 cells) · other type IV reactions: tuberculin test, transplant rejection · Treatment: Corticosteroids for contact dermatitus, immunosuppressive drugs including cortisone for transplant rejection DTH: delayed hypersensitivity CTL: cytotoxic T Lymphocyte Comparison of Hypersensitivity Reactions Vaccines Types of Vaccines: were immune to the more severe smallpox disease ② Inactivated whole-agent and sub-unit pox (Vaccinia Virus) to protect them against small pox ④ Conjugated · Jenner observed that milkmaids who contracted cow pox ① Attenuated whole-agent · in 1776 Jenner successfully inoculated people with cow ③ Toxoids (Variola Virus) ⑤ Nucleic Acid ↳ attempt to deliberately induce immunity ① Attenuated Whole-agent Vaccines a. DNA b. RNA · living but changed (weakened) microbes → does not cause disease! ↳ antigens intact but virulence diminished · closely mimics real infection (get a CTL response) ↳ vaccine strain replicates in host cells · 95% effectiveness, often life-long immunity ↳ stimulates both humoral and cell-mediated immunity, memory cells created eg. Sabin (polio), MMRV (measles, mumps, rubella, varicella) · Disadvantage: ↳ if the microbes mutate back to the virulent form it may cause disease ↳ cannot use for people with compromised immunity or pregnant women ② Inactivated and Subunit Vaccines · use whole microbes that have been killed, usually by formalin or phenol, or use parts of the organism (ie. glycoproteins) eg. rabies, salk (polio), one of the many influenza vaccines, Gardasil, Hep B · no replication in host cells; safe for immunocompromised ↳ b/c there is no replication theres less antigens to stimulate the immune response. In viruses there will be no presentation of proteins on MHC I and no CD8+ (cell-mediated) response · cannot revert to wildtype · pregnant women can be vaccinated · immunity does not last as long as attenuated vaccine, boosters must be given to ensure adequate exposure to the antigen, some memory can be made but only B cell memory ③ Toxoids · toxin isolated and chemically treated to preserve the antigenicity but to make the toxin non-functional · toxoid then used as vaccine to produce antibodies to toxin, not the microbe (only humoral immunity) · Requires boosters for full immunity eg. diphtheria, tetanus (clostridium tetanus) ④ Conjugated Vaccines Short lived response and no memory · used for organisms that have polysaccharide capsules (poor antigens) ↳ the best antigens are proteins (peptides) · children under 2 years can't respond well to polysaccharides as antigens (only respond to protein antigens) · Conjugate vaccine: polysaccharides from capsules are combined with a protein which is highly immunogenic (eg. diphtheria toxoid) ↳ fooling immune system to react to protein, and at the same time get immunity to the carbohydrate eg. Haemophilus influenza type B, Neisseria meningitidis, Streptococcus pneumoniae (3 causes of meningitis) ⑤ Nucleic Acid Vaccines a. DNA Vaccines · introduce a gene for an organism into human host cells, hope that it will persist there and get transcribed (and produce proteins) · induce cells to produce organism specific proteins that linger and keep the immune system activated to the organisms · Covid-19 vaccines like Astra-Zeneca and Johnson & Johnson vaccines · Adenovirus from a chimpanzee that does not infect humans is engineered so that it carries the genetic information from covid-19, specifically the glycoprotein spikes. The virus in the vaccine enters human cells and the DNA from the virus is transcribed to RNA and the mRNA then directs the production of proteins (glycoproteins), giving a sustained immune stimulation b. mRNA Vaccines · developed during the covid pandemic although many years of research had preceded the final product (most well known are Pfizer and Moderna) · based on mRNA from covid-19 which has one uridine base changed, so when it is injected it does not get identified as an invading virus and ejected from the host cell · Changed mRNA is put into a lipid nanoparticle which will be taken up by our cells, then the mRNA can go to the ribosomes and produce protein that stimulates our usual adaptive immune system ↳ mRNA leaves cells in ~3 weeks · 95% effectivity, requires boosters Tuberculin Skin Test · test to determine previous exposure to tuberculosis antigens (indicated by detection of memory cells) · small amount of PPD (purified protein derivative) proteins from M. tuberculosis are injected into skin of the forearm. Positive test is indicated by reddening and thickening of skin 48-72 hours after inoculation ↳ this is caused by the infiltration of lymphocytes and macrophages after they have been mobilized by pre-existing memory cells · cell-mediated reaction (type IV) Restrictions of Tuberculin Tests · cannot be used in people who are anergic (unresponsive to antigens) or patients that are immunosuppressed as they do not react predictably to an immune stimulus eg. AIDS patients · tuberculin test is not specific for M. tuberculosis, other mycobacterium also give a positive test · people with BCG vaccine will also test positive ↳ increased costs to determine if it is vaccine effect or real exposure positive test: red and swollen circle at injection site ↳ the diameter determines exposure to TB QuantiFERON-TB Gold Test · new blood test for TB that tests for memory cells and activated T lymphocytes ↳ looks for production of interferon · can confirm latent or active tuberculosis, or BCG vaccination · processed in lab within 12 hours which complicates clinical utility and availability ↳ patients don't have to come back to get results · Advantage: different antigens used than BCG vaccine Naturally Acquired Active Immunity · individual exposed to antigens in course of daily life ↳ produces immune response from disease antigen eg. un-immunized child gets chickenpox and develops immunity after the infection Naturally Acquired Passive Immunity · the natural transfer of antibodies · transferring IgG antibodies from mother to fetus through placenta · IgA antibodies in mothers breast milk Artificially Acquired Active Immunity · result of vaccination where specifically prepared antigens (vaccines) are introduced into the body · vaccines are altered so they cannot cause disease, but stimulates immune response Artificially Acquired Passive Immunity · introduction of antibodies from an animal or person who is already immune to the disease eg. varicella immunoglobulin given after exposure of un-immunized person to varicella