OUTLINE
Introduction Antibody Mediated Neutralization Cytolytic/Cytotoxic Immune Complex Anaphylactic
Cell Mediated T-cell Cytotoxic (Killer T-cells) Delayed Hypersensitivity
Antibody or Cell Mediated Granulomatous Reactions IMMUNE EFFECTOR MECHANISMS LEVELS OF REACTIONS OF ANTIGEN WITH ANTIBODY OR CELLS
PRIMARY SECONDARY TERTIARY REACTION REACTION REACTION in vitro in vivo ANTIBODY MEDIATED INACTIVATION NEUTRALIZATION
AGGLUTINATION, LYSIS CYTOLYTIC REACTIONS OPSONIZATION Ag+Ab AgAb IMMUNE COMPLEX PRECIPITATION REACTIONS
MAST CELL ANAPHYLACTIC DEGRANULATION REACTIONS
CELL MEDIATED DELAYED T-DTH HYPERSENSITIVITY LYMPHOKINES REACTIONS +Ag-> MACROPHAGE ACTIVATION
BLAST CELL TRANSFORMATION T-CTL TARGET-CELL LYSIS DESTRUCTION
Ab or + INSOLUBLE ANTIGEN GRANULOMA NEUTRALIZATION/INACTIVATION REACTIONS
PROTECTIVE REACTIONS
TOXIN NEUTRALIZATION DIPHTHERIA,, TETANUS, ANTHRAX, CHOLERA
RECEPTOR BLOCKADE PERTUSSIS VIRUSES MEASLES. FLU, POLIO, HEPATITIS, PAPILLOMA, ETC.
PASSIVE ANTIBODY TREATMENT – CHOLERA, EBOLA VIRUS
DESTRUCTIVE REACTIONS
DIABETES, HEMOPHILIA, APLASTIC ANEMIA, MYASTHENIA GRAVIS, GRAVE’S DISEASE, BULLOUS SKIN DISEASES EVIDENCE FOR NEUTRILIZING ANTIBODIES
DICK AND SCHICK TESTS
PEOPLE WHO RECOVER FROM STREPTOCOCCAL OR DIPHTHERIA INFECTION HAVE NO REACTION TO SKIN INJECTION OF TOXIN
DUE TO PRODUCTION OF NEUTRALIZING ANTIBODY SCARLET FEVER GROUP A STREPTOCOCCUS TOXIN
Sequella: Glomerulonephritis; Rheumatic heart disease (IMMUNE COMPLEX REACTION)
VACCINE UNDER DEVELOPMENT TREATED WITH ANTIBOTICS PENICILLIN OR AMOXICILLIN Dale JB, et al, Current approaches to Group A streptoccal Vaccine development. In Streptoccus pyogenes ED. Ferretti, Steverns, Fichetti. U. Oklahoma Press, 2016. DICK TEST FOR SUSCEPTIBILITY TO SCARLET FEVER 1924 GEORGE AND GLADYS DICK
INJECTION OF 0.1 CC OF SCARLET FEVER TOXIN INTO THE SKIN:
INFLAMMATORY REACTION OF 10MM WITHIN 24 HOURS INDICATES LACK OF IMMUNITY.
STAPH STREP TOXIN
NO REACTION -- INDICATES IMMUNITY ANTIBODY NEUTRALIZES TOXIN Schick Test Diphtheria Toxin Bela Schick New York 1925 0.1 ml of diphtheria toxin injected into skin of one arm 0.1 ml of heat inactivated toxin into the other
Individuals with toxin neutralizing antibodies will have no reaction at either site;
Those without will have reaction at toxin site, but not inactivated site. VACCINES INACTIVATION / NEUTRALIZATION
TOXIN NEUTRALIZATION BACTERIA TOXINS TETANUS DIPHTHERIA PERTUSSIS CHOLERA ANTHRAX
RECEPTOR BLOCKADE VIRUSES MEASLES FLU EBOLA HEPATITIS HERPES POLIO PAPILLOMA ETC.
DPT DIPHTHERIA - LARYNGEAL MEMBRANE PNEUMONIA TOXIN – Enters cell through receptors (EGF) and blocks protein synthesis
VACCINE – HEAT INACTIVATED TOXIN PERTUSSIS WHOOPING COUGH - TOXIN AND RECEPTOR
PERTUSSIS VACCINE Acellular pertussis antigens [10 µg detoxified pertussis toxin (PT), 5 µg filamentous hemagglutinin (FHA), 3 µg pertactin, and 5 µg fimbriae types 2 and 3 (FIM)]. TETANUS
LOCKJAW
NEONATALTETANUS OPISTHOTONOS OPISTHO – BACKWARD; TONO - TENSION PROPHYLACTIC IMMUNIZATION USING TETANUS TOXOID
BACTERIA LIVE IN DEAD TISSUE
TOXIN BLOCKS INHIBITORY NEURONS WHICH MODULATE ACTIVITY OF STIMULATORY NEURONS AND PREVENT THE CONTINUOUS MUSCLE CONTRACTION OF TETANUS
ANTIBODY TO TETANUS TOXIN PREVENTS UPTAKE FROM DEAD TISSUES TO LIVING NEURONS CHOLERA
JOHN SNOW LONDON 1854
FIRST APPLICATION OF PUBLIC HEALTH TO PREVENT DISEASE
GIVEN ORALLY RECEPTOR AND TOXIN STIMULATES IgA ANTIBODY ANTHRAX VACCINE 1881 LOUIS PASTEUR
Mab TREATMENT VACCINATE COWS “HERD IMMUNITY” PREVENTS HUMAN INFECTION
ANTIBODY BLOCKS AT MULTIPLE STAGES OF PROCESS
BINDING OF TOXIN TO RECEPTOR
ASSEMBLY OF TOXIN COMPONENTS
PORE FORMATION
ENDOCYTOSIS
TOXIN TRANSLOCATION
Froude JS, Thullier P, Pelat T. Antibodies against anthrax: mechanism of action and clinical applications. Toxins 3:1433-1452, 2011 HUANIZED MONOCLONAL ANTIBODY VIRUS VACCINATION PREVENTION MOSTLY BY RECEPTOR BLOCKADE*
Measles Rabies Mumps Hepatitis Rubella Chaga disease Varicella Yellow Fever Influenza Japanese Encephalitis Coronavirus Dengue Polio West Nile Zika HIV Rotavirus Ebola Etc.
* ALSO T-CELL CYTOXICITY TO BE PRESENTED LATER Virus
Receptor Blockade MMRV VACCINE MEASLES, MUMPS, RUBELLA, VARICELLA ATTENUATED LIVE VIRUS VARICELLA TARGET MUCOSA OF RESPIRATORY TRACT MEASLES, MUMPS , REBULLA VIRUS INFECTS MUCOSA Vaccine induced IgA antibody blocks protein receptor
IgAantibody
However, with direct contact with skin some skin infections ( ie. Smallpox) are not blocked by antibody and require T-CTL (more later)
DISEASE RETURNS WHEN FAMLIES REFUSE VACINE
POLIO VACCINES POLIO BOTH IgG and IgA ANTIBODY
INCLUDES INFLUENZA, CORONAVIRUS PATHOGENESIS OF ACUTE INFLUENZA PNEUMONIA H&E-stained section of the lung from a 1918 influenza victim showing necrotizing bronchiolitis. There is necrosis of the bronchiolar wall, with submucosal edema and vascular congestion. The epithelial layer is desquamating, and necrotic epithelial cells are present in the lumen. A mixed inflammatory cell infiltrate is present throughout (original magnification400×). Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu. Rev. Pathol. Mech. Dis. 3:499-522, 2008. INFLUENZA VACCINES THREE LEVELS OF PROTECTIVE IMMUNITY
1. ANTI-VIRUS 2. ANTI-CELL MEMBRANE 3. T-CTL
T-CTL TO BE PRESENTED IN DETAIL IN NEXT LECTURE INFLUENZA VACCINE
Why is a “new” vaccine required every year?
Antigenic drift
Mutation produces “new” surface HA (hemaglutinin) INFLUENZA VACCINE KILLED OR WEAKENED VIRUS
HEMAGGLUTININ ANTIGENIC COMPONENTS OF HEMGGLUTININ CHANGE EVERY FLU SEASON, NEW VARIENTS ARE SELECTED FOR EACH YEAR,
•egg-based flu vaccine, •cell-based flu vaccine, and •recombinant flu vaccine.
Most common
Egg-based vaccine manufacturing is used to make both inactivated (killed) vaccine (usually called the “flu shot”) and live attenuated (weakened) vaccine (usually called the “nasal spray” flu vaccine MUTIPLE IMMUNE MECHANISMS IN RESPONSE TO FLU VIRUS
IgA BLOCKING AB IgG NEUTRALIZING AB
CYTOTOXIC T-CELLS DTH T-CELL More later
SARS CoV-2 POTENTIAL IMMUNOGENS CORNAVIRUS VACCINE MODERNA ASTRZENKA mRNA-1273 Spike protein
DA approved for Phase 3 clinical trials HUMAN PAPPILOMA VIRUS AND HUMAN PAPILLOMA VIRUS ANTIBODY AND T-CTL
HIV NO VACCINE - INFECTS CD 4 HELPER T-CELLS
AZT AZIDOTHYMIDINE THYMIDINE ANALOG BLOCKS REVERSE TRANSCRIPTASE VACCINATION PREVENTION BY RECEPTOR BLOCKADE
H. Influenza HIV Meningococcus Rabies Pneumococcus Hepatitis Viral Exanthems Polio Smallpox Chagas disease Measles Yellow Fever Rubella Japanese Encephalitis Varicella Dengue Influenza West Nile Mumps Zika Ebola Typhoid Rotavirus MONOCLONAL ANTIBODIES
TREATMENT WITH INACTIVATING ANTIBODIES PASSIVE TRANSFER OF MONOCLONAL ANTIBODIES FOR
ANTHRAX
EBOLA SNAKE VENOM EBOLA VIRUS
Rial P, Elias SC. et al. (28 Co-authors) Alan R. Townsend. Therapeutic monoclonal antibodies for Ebola virus infection derived from vaccinated humans. Cell Reports 27:172-`86, 2019 NY times August 13, 2019
2018/19 Epidemic
%died
Untreated 70
Anti-viral 33 (Giliad)
Z-Mapp 24 (Mapp Biopharm.
REGN-EB3 6 (Regeneron) mAb-114 (Ridgeback Biother.) 11 ANTI-VENOM TREATMENT
Kills 100,000 annually and permanently disfigures >300,000
• May 16, 2019 AVI (International AIDS Vaccine Initative)and the Liverpool School of Tropical Medicine (LSTM) have formed a research consortium to apply antibody discovery technologies to develop affordable, accessible, and effective monoclonal antibodies (mAbs) for snakebite treatment. The consortium, the Scientific Research Partnership for Neglected Tropical Snakebite (SRPNTS), also includes • The Nigeria Snakebite Research & Intervention Centre (Bayero University, Kano), • The Kenya Snakebite Research & Intervention Centre (Institute of Primate Research, Nairobi), • The Indian Institute of Science (Bangalore), • The Scripps Research (La Jolla).
• The consortium is funded with UK aid from the UK government through the Department for International Development (DFID). NEUTRALIZATION DISEASES
ANTIBODIES BLOCK NORMAL BIOLOGICALLY ACTIVE MOLECULES OR RECEPTORS
DIABETES INSULIN, INSULIN RECEPTOR ISLET CELLS
HEMOPHILIA BLOOD CLOTTING FACTORS
PERNICIOUS ANEMIA PARIETAL CELLS
APLASTIC ANEMIA ERYTHROID TANSCRIPTION FACTOR
MYASTHENIA GRAVIS ACTEYLCHOLINE RECEPTOR
GRAVE’S DISEASE HYPERTHYROIDISM THYROID HORMONE RECEPTOR LATS
BULLOUS SKIN DISEASES EPIDERMAL CELLS/BASEMENT MEMB. IMMUNE FACTORS IN DIABETES
. NORMAL ISLET LYMPHOCYTIC INFILTRATE
HYLINIZED ISLET IMMUNOLABELING TISSUE TEST FOR ISLET CELL AUTOANTIBODIES 1. MICROSCOPIC SLIDE OF PANCREAS 2. ADD PATIENT’S SERUM, INCUBATE AND WASH 3. ADD PEROXIDASE LABELED ANTI-HUMAN IgG
ROLE OF ANTI-ISLET CELL ANTIBODIES NOT CLEAR
INFILTRATING LYMPHOCYTES ARE CD 8 (AUTO-REACTIVE CYTOTOXIC T-CELLS)
La Torre D, Lenmark A. Immunology of beta-cell destruction. Adv. Exp. Med. Biold2010:654:537-583 doi: 10.1007/978-90-481-3271-3_24. Veld, PI. Insulinitis inhuman type 1 diabetes. Islets 3:131-138, 2011 soi: 10.4616/isl.3.4.15728 INSULIN ANTIBODIES
INSULIN- NOBLE PRIZE FOR DISCOVERY – 1923 Frederick Banting and John Macleod
ANTIBODIES TO EXOGENOUS ADMINISTERED INSULIN ARE COMMON WITH TREATMENT
USUALLY IgG – SEVERE INSULIN RESISTENCE (AUTOIMMUNE HYPOGLYCEMIA) ALSO IgE – INSULIN ALLERGY
HIGHER FREQUENCY WITH BEEF OR PORK INSULIN, MUCH LESS WITH RECOMBINANT HUMAN INSULIN
MEASURED BY RIA (NOBLE PRIZE IN 1977; Rosalyn Yalow)
TREATMENT – SWITCH INSULIN SOURCES GLUCOCORTICOIDS PERNICIOUS ANEMIA – Megaloblastic Anemia
Failure to absorb Vitamin B12 (poor diet, gastrectomy, H. pylori infection, congenital deficiency of intrinsic factor)
Immune Atrophic gastritis Auto antibodies to parietal cells
NORMAL STOMACH AUTOIMMUNE ATROPHIC GASTRITIS ANTIBODIES TO PARIENTAL CELLS HEMOPHILIA HEREDITARY Congenital lack of a blood clotting factor, most often Factor VIII Bleed into joints (hemarthrosis) ACQUIRED AUTOANTI-FACTOR 8 (Post-partum, cancer, infections, etc.)
FACTOR VIII EPITOPES
Oh, J, Lim, Y, Jang MJ, Huh JY, Shima M, Oh D. Characterization of anti-factor VIII antibody in a patient with acquired hemophilia A. Blood Res 48:58-62, 2013 MYASTHENIA GRAVIS - SEVERE MUSCLE WEAKNESS
EXOPTHALMOS – HYPERTHYROIDISM (GRAVE’S DISEASE) AUTOANTIBODY MIMICS EFFECT OF THYROID STIMULATING HORMONE (TSH) ACTIVATIOIN LATS – LONG ACTING THYROID STIMULATOR NORMAL THYROID GRAVE’S DISEASE
BLISTERING SKIN DISEASES Normal skin Epidermolysis bulosa acqusita
EPIDERMOLYIS BULLOSA AQUISITA
AQUIRED SKIN BLISTERS
SEPARATION OF EPIDERMIS SERUM FROM PATIENT FROM DERMIS AT BASEMENT BINDS TO BASEMENT MEMBRANE MEMBRANE OF NORMAL SKIN PEMPHIGUS ANTIBODY TO SKIN EPITHELIAL CELLS
NEUTRALIZATION/INACTIVATION REACTIONS
PROTECTIVE REACTIONS
TOXIN NEUTRALIZATION TETANUS, DICK TEST, DIPHTHERIA, PERTUSSIS, ANTHRAX, CHOLERA
RECEPTOR BLOCKADE VIRUSES MEASLES. FLU, POLIO, HEPATITIS, PAPILLOMA, ETC.
PASSIVE ANTIBODY TREATMENT – CHOLERA, EBOLA VIRUS
DESTRUCTIVE REACTIONS
DIABETES, POMPE’S DISEASE, HEMOPHILIA, APLASTIC ANEMIA, MYASTHENIA GRAVIS, GRAVE’S DISEASE, BULLOUS SKIN DISEASES CYTOLYTIC REACTIONS
PROTECTIVE REACTIONS
LYSIS AND PHAGOCYTOSIS OF VIRUSES AND BACTERIA
DESTRUCTIVE REACTIONS
LYSIS AND PHAGOCYTOSIS OF BLOOD CELLS
) ANTIBODY DIRECTED COMPLEMEMT MEDIATD LYSIS OF BACTERIA PNEUMOVAX STREPTOCCUS PNEUMONIA COMPLEMENT SYSTEM - CLEAVAGES AND AGGREGATIONS
Immune complex reactions CYTOLYTIC REACTIONS BLOOD CELLS
RED CELLS HEMOLYTIC ANEMIA HEMOLYTIC DISEASE OF NEWBORN TRANSFUSION REACTIONS
PLATELETS IDIOPATHIC THROMBO-CYTOPENIC PURPURA
WHITE BLOOD CELLS (PMNS) AGRANULOCYTOSIS - INFECTIONS NORMAL RBC + ANTIBODY TO RBC +C
AGGLUTINATION LYSIS
HEMAGGLUTINATION AND LYSIS TRANSFUSION REACTION
+ COMPLEMENT
ERYTHROBLASTOSIS FETALIS
ERYTHRO- BLASTOSIS FETALIS
BLOOD FORMING CELLS IN LIVER COOMB’S TEST
TEST FOR ANTIBODY COATED CELLS
TEST FOR ANTIBODIES
NEUTROPENIA NEXT LECTURE PURPURA IN INDIOPATHIC THRMBOCYTOPENIC PURPURA
CYTOLYTIC REACTIONS BLOOD CELLS
RED CELLS HEMOLYTIC ANEMIA HEMOLYTIC DISEASE OF NEWBORN TRANSFUSION REACTIONS
PLATELETS IDIOPATHIC THROMBO-CYTOPENIC PURPURA
WHITE BLOOD CELLS (PMNS) AGRANULOCYTOSIS - INFECTIONS
) IMMUNE COMPLEX REACTIONS
ARTHUS REACTION
SERUM SICKNESS
LEUKOCLASTIC VASCULITIS
POLYARTERITIS NODOSA
GLOMERULONEPHRITIS
RHEUMATOID ARTHRITIS
SCLERODERMA (PREGRESSIVE SYSTEMIC SCLEROSIS)
COLLAGEN DISEASES