Unit 4 - part 1 Vaccines and Hypersensitivity reactions

History of Vaccines

Started in 1500s with asian physicians using smallpox crusts as a form of immunization with mixed success (variolation)

Last case of smallpox

1979

Cowpox and smallpox viruses share what

some surface antigens, antibodies made against cowpox bind and neutralize the smallpx virus

Types of vaccines

Vaccination or Immunization

Killed microorganism or inactivated virus vaccines

• Salk inactivated polio vaccine (IPV)

• Rabies vaccine

• Influenza (Flu shot)

Live-attenuated vaccines

Mutant form of live pathogen that grows poorly in human cells or is no longer pathogenic.

Live-attenuated vaccines examples

• Sabin oral polio vaccine (OPV)

• MMR (Measles, mumps, and rubella)

• Chickenpox (varicella), Zoster/shingles vaccine

Subunit Vaccines

Purified single or mixed components, ex: proteins and polysaccharides, most immunogenic components of pathogens

Subunit vaccines examples

Toxoids (inactivated toxins): diphtheria and tetanus, Acellular pertussis (aP) (toxin+protein)

Conjugate vaccines

Protein-polysaccharide complex

Conjugate vaccine example

• Meningococcal

• Newer Hib vaccine

• Prevnar 13 - streptococcus pneumoniae, pneumococcal conjugate, vaccine (PCV)

Recombinant vaccines

Gene cloned into another microorganism in vitro

Recombinant vaccines Examples

• Herpes Zoster ( Shingrix)

• HPV (Gradasil-9)

• Hepatitis B (Recombivax HB)

DNA vaccines

Free DNA, e.g., plasmid, taken up. by host cell ( e.g., muscle) (IM or ID)

mRNA vaccines

Leads to production of target antigen by host cells

Vector vaccines

Adenovirus

Can too many vaccines at once produce a weakened immune response

No, Thimerosal, Anti-vax movement (pseudoscience)

Hypersensitivity

Heightened or unnecessary immune response to an innocuous environmental antigen that cause tissue damage in the host

Immediate/ Rapid

antibody-mediated (types I - III), within minutes to hours, or hours to days of second contact with an allergen

Delayed

cell-mediated (type IV, aka. DTH), >24 hours, maximum reaction time between 48-72 hours

Allergen

noninfectious environmental antigen that induces a hypersensitivity reaction

Sensitization

First exposure to an allergen (immunogen)

Type 1 hypersensitivity

ca be mild to life-threatening (anaphylaxis), fastest response (minutes)

Type 1 hypersensitivity mechanism

Allergen elicits an IgE antibody response upon sensitization, Signals for class switching to IGE, IL-4 & IL-13, CD40 on B cell binding to CD40L on T cell

Allergens airborne

pollen, fungal (mold) spores, cigarette smoke, animal dander, cockroaches & dust mites; others - insect venom, drugs, food, etc.

IgE historically known as reagin or reaginic antibody

Genetically predetermined tendency of some people to produce IgE to innocuous substances

Mast cells, circulating basophils and eosinophils

Found around blood vessels in connective tissue, lungs, liver, kidney, spleen, heart, etc.

Mast cells, circulating basophils and eosinophils bind to what

allergen specific IgE via the Fc portion to their surface using FcεRI receptors

Granules contain

heparin, histamine, proteases, prostaglandins, bradykinins, leukotrienes, platelet activating factor, and eosinophil & neutrophil chemotactic factors

Granules mechanism

Allergen cross-links two or more IgE antibodies fixed to the surface of mast cells or basophils

Early phase

mast cell degranulation occurs within seconds - smooth muscle contractions, increases capillary permeability, vasodilation, etc.

Late phase

Eosinophils, PMNs, macrophages arrive and degranulate - second release of mediators

Extent of allergic response

partly influenced by portal of entry, localized (atopic)

Allergic reactions in the skin

Can be due to foods, medications, contact, or insect bites/stings, Urticaria (hives). wheal, and flare reaction

Allergic reactions in the skin

• Angioedema

• Atopic eczema

Systemic anaphylaxis

Drugs, foods, and insect venom, risk of shock

Diagnosis

• Intradermal testing (skin prick testing)

• Radioallergosorbent test (RAST) - measures allergen specific IgE

• Radioimmunosorbent (RIST) - measures total serum IgE

• Food elimination diets

• Oral food challenges

Treatment

Avoid allergen(s), immunotherapy

Immunotherapy

• Allergy shots (desensitization) - repeated injections of the allergen (small doses)

  • Increasing doses

  • Build up: weekly shots for 3-6 months

  • Maintenance: monthly shots for 3-5 years

  • Patient may develop resistance to allergen (reacts less severly)

Anti-IgE monoclonal antibody (mAb)

Xolair

Treating symptoms

• Antihistamines, nasal corticosteroid sprays

• Albuterol

• Adrenaline (Epipen)

Type II hypersensitivity

Mechanism of cellular damage

Type II hypersensitivity mechanism

IgG or IgM produced and bind to cell surface molecules or extracellular material (e.g., basement membrane) it perceives as foreign, Self-reactive B and T cells (intrinsic antigens), Extrinsic antigens

Type II hypersensitivity reaction process

Antibody binds target cell receptors, blocks normal function (cellular dysfunction)

• Activation of complement (Opsonization, MAC cell lysis)

• Antibody-dependent cell mediated cytotoxicity (ADCC)

  • NK cells, macrophages, neutrophils, and eosinophils

Examples of Type II (cytotoxic) hypersensitivity reactions

Acute hemolytic transfusion reactions

Acute hemolytic transfusion reactions

Donor blood group antigens not compatible with recipient (ABO imcompatibility and Rh incompatibility)

Acute hemolytic transfusion reactions process

Anti-A and/or Anti-B IgM antibodies bind to and lead to destruction of donor RBCs

Acute hemolytic transfusion reactions can lead to

coagulopathy (DIC), kidney damage, fever, inflammation, low BP, chest pain, and N/V

Hemolytic disease of the newborn (HDN< erythroblastosis fetalis)

Rh- mother exposed to Rh+ fetal RBCs during birth

Hemolytic disease of the newborn

Mother’s B cells are activated by Rh antigen and produce anti-Rh Abs (IgG) (sensitization), Upon next Rh+ pregnancy IgG antibodies cross the placenta and attack fetal RBCs in utero

Hemolytic disease of the newborn prevention

RhoGAM (Rho(D) Immune Globulin, RhIG), Administered during pregnancy or shortly after delivery of an Rh+ baby

Drug-induced hemolytic anemia

>150 drugs, penicillin, NSAIDS, etc.

Myasthenia gravis (autoimmune disease)

Autoantibodies produced against acetylcholine receptors on muscle fibers, AutoAbs bind receptors and block acetylcholine binding, Muscle does not get stimulated to contract and becomes progressively weaker

Type III hypersensitivity (immune complex)

Deposition of circulating immune complexes (antigen-antibody complexes in tissues). Accumulation in the skin, joints, blood vessel walls, lung alveoli, and kidney glomeruli

Mechanism of Type III hypersensitivity

• Antigens infecting microorganism, medications, or self-antigens.

• Immune complexes usually cleared by monocyte-macrophage system

Immune complexes of Type III hypersensitivity

• IgG or IgM mediated

• Small complexes are not as attractive to monocytes/ macrophages and may continue to circulate then deposit in various tissues

Complement activation

Classical pathway, Lysis of bystander host cells by complement MAC

Anaphylatoxins (C4a, C3a, and C5a) cause:

• Vasodilation and vascular permeability

• Chemotaxis of neutrophils, monocytes, and macrophages

• Degranulation of mast cells

• Inflammation

Degranulation of PMNs

attempt ot phagocytize immune complexes, release toxic granules

Extent of reactions

Local antigen-antibody complexes - destructive inflammation of small blood vessels (vasculitis)

• Glomerulonephritis in kidneys

• Arthritis in joints (synovium)

Arthus reaction

localized areas of painful erythema and hard swelling (induration), lasts approximately 24hours

Insect bites

in addition to type I, with repeated exposure can develop type III (arthus reaction) over time

Farmer’s lung

hypersensitivity pneumonitis, inhaled allergens (hay dust or mold spores), appears 4-8 hours after exposure

Farmer’s lung symptoms

Flu-like symptoms: headache, cough, SOB, sometimes fever

Serum sickness

patients who receive foreign serum or some medications

• Snake bite - antivenom

• Abs made against antivenom

• If Ag remains in excess, immune complexes may not be easily cleared

• Classic Sxs: Rash, itching, joint pain, fever, malaise

Rheumatoid Arthritis

IgM, IgG, or IgA against IgG Fc reactions, anti-citrullinated protein antibodies (ACPAs, anti-CCP Abs)

Cell-mediated hypersensitivity

T cells (CD4 and CD8), reaction 1-3 days after exposure, peaks at 48-72 hours

Cell-mediated hypersensitivity mechanism

Response initiated by CD4+ T cells when they recognize and bind foreign antigen presented with MHC II by APCs - APC secretes IL-12 causing TH0 cell differentiation into TH1 cells

TH1 cells secrete IL-2 causing proliferation, and IFN-y

recruiting secondary cells like macrophages, neutrophils, and additional T cells

Phagocytes release proinflammatory cytokines

edema, redness, heat, degranulation causes cellular/ tissue damage

TH17 cells

Differentiate in response to IL-6 and TGF-B, IL-21 and IL-23 help promote/ maintain response

TH17 secretes

IL-17 - recruits neutrophils and promotes inflammation

CD8 + T cells

Intracellular antigen peptides are presented on MHCI to CTLs (from intracellular pathogens), CTLs kill target cells using perforins and granzymes

Tuberculin-type hypersensitivity

TST using purified protein derivative (PPD) derived from Mycobacterium tuberculosis (TB)

Contact Dermatitis

• Poison ivy, poison oak, nicklet, etc.

• Many allergens act as happens - require protein carrier binding to immunogenicity

• Langerhans cells or dendritic cells present processed Ags to T cells

Granulomatous hypersensitivity

Antigen (or allergen) persists - Chronic inflammation, cells in granulomatous lesion - Lymphocytes, macrophages, epithelioid cells, and multinucleated giant cells