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

OUTLINE

PRIMARYREACTION

SECONDARY REACTION

TERTIARY REACTION

ANTIBODY MEDIATED

CELL MEDIATED

Ag+Ab AgAb

in vitro in vivo

INACTIVATION

AGGLUTINATION, LYSIS

OPSONIZATION

PRECIPITATION

MAST CELLDEGRANULATION

NEUTRALIZATION

CYTOLYTIC REACTIONS

IMMUNE COMPLEX

REACTIONS

ANAPHYLACTIC

REACTIONS

+Ag->

T-DTH

T-CTL

LYMPHOKINES

MACROPHAGE ACTIVATION

TARGET-CELL LYSIS

DELAYED

HYPERSENSITIVITYREACTIONS

CELL

DESTRUCTION

BLASTTRANSFORMATION

LEVELS OF REACTIONS OF ANTIGEN WITH ANTIBODY OR CELLS

IMMUNE EFFECTOR MECHANISMS

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

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

EVIDENCE FOR NEUTRILIZING ANTIBODIES

VACCINE UNDER DEVELOPMENT TREATED WITH ANTIBOTICS

PENICILLIN OR AMOXICILLINDale JB, et al, Current approaches to Group A streptoccal

Vaccine development. In Streptoccus pyogenes ED. Ferretti,

Steverns, Fichetti. U. Oklahoma Press, 2016.

SCARLET FEVER GROUP A STREPTOCOCCUS TOXIN

Sequella: Glomerulonephritis; Rheumatic heart disease

(IMMUNE COMPLEX REACTION)

DICK TEST FOR SUSCEPTIBILITY TO SCARLET FEVER1924 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.

NO REACTION -- INDICATES IMMUNITY

ANTIBODY NEUTRALIZES TOXIN

STAPH STREP TOXIN

Schick Test Diphtheria Toxin

Bela Schick New York 19250.1 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 TOXINSTETANUS

DIPHTHERIA

PERTUSSIS

CHOLERA

ANTHRAX

RECEPTOR BLOCKADE

VIRUSESMEASLES

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 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)].

PERTUSSIS WHOOPING COUGH - TOXIN AND RECEPTOR

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

JOHN SNOW LONDON 1854

CHOLERA

FIRST APPLICATION OF PUBLICHEALTH TO PREVENT DISEASE

GIVEN ORALLYRECEPTOR AND TOXINSTIMULATES IgA ANTIBODY

Mab

TREATMENT

ANTHRAX VACCINE 1881 LOUIS PASTEUR

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

Measles

Mumps

Rubella

Varicella

Influenza

Coronavirus

Polio

HIV

Rabies

Hepatitis

Chaga disease

Yellow Fever

Japanese Encephalitis

Dengue

West Nile Zika

Rotavirus

Ebola

Etc.

VIRUS VACCINATIONPREVENTION MOSTLY BY RECEPTOR BLOCKADE*

* ALSO T-CELL CYTOXICITY TO BE PRESENTED LATER

Virus

Receptor

Blockade

MMRV VACCINEMEASLES, MUMPS, RUBELLA, VARICELLAATTENUATED LIVE VIRUS

VARICELLA TARGET MUCOSA OF RESPIRATORY TRACT

MEASLES, MUMPS , REBULLA VIRUS INFECTS MUCOSA

Vaccine induced IgA antibody blocks protein receptor

However, with direct contact with skin some skin infections ( ie.

Smallpox) are not blocked by antibody and require T-CTL (more later)

IgAantibody

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 VACCINESTHREE 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)

•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

ANTIGENIC COMPONENTS OF HEMGGLUTININ CHANGE EVERY FLU SEASON, NEW VARIENTS ARE SELECTED FOR EACH YEAR,

INFLUENZA VACCINE KILLED OR WEAKENED VIRUS

HEMAGGLUTININ

https://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.htmlhttps://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.html

MUTIPLE IMMUNEMECHANISMS IN RESPONSE TO FLU VIRUS

IgA BLOCKING ABIgG NEUTRALIZING AB

CYTOTOXIC T-CELLSDTH T-CELL

More later

SARS CoV-2 POTENTIAL IMMUNOGENS

MODERNAmRNA-1273Spike protein

DA approved forPhase 3 clinical trials

CORNAVIRUS VACCINE

ASTRZENKA

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

H. Influenza

Meningococcus

Pneumococcus

Viral Exanthems

Smallpox

Measles

Rubella

Varicella

Influenza

Mumps

Ebola

Rotavirus

HIV

Rabies

Hepatitis

Polio

Chagas disease

Yellow Fever

Japanese Encephalitis

Dengue

West Nile

Zika

Typhoid

VACCINATION PREVENTION BY RECEPTOR BLOCKADE

TREATMENT WITH INACTIVATING ANTIBODIES

PASSIVE TRANSFER OF MONOCLONAL ANTIBODIES FOR

ANTHRAX

EBOLA

SNAKE VENOM

MONOCLONAL ANTIBODIES

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

EBOLA VIRUS

NY times August 13, 2019

2018/19 Epidemic

%died

Untreated 70

Anti-viral

(Giliad)

33

Z-Mapp

(Mapp Biopharm.

24

REGN-EB3

(Regeneron)

6

mAb-114(Ridgeback Biother.) 11

Kills 100,000 annually and permanently disfigures >300,000

ANTI-VENOM TREATMENT

• 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

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

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

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)

ImmuneAtrophic gastritis

Auto antibodies to parietal cells

NORMAL STOMACH AUTOIMMUNE ATROPHIC GASTRITIS

ANTIBODIES TO PARIENTAL CELLS

HEMOPHILIA

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

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

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

Epidermolysis bulosa acqusitaNormal skin

EPIDERMOLYIS

BULLOSA

AQUISITA

AQUIRED SKIN

BLISTERS

SERUM FROM PATIENT

BINDS TO BASEMENT

MEMBRANE OF NORMAL SKIN

SEPARATION OF EPIDERMIS

FROM DERMIS AT BASEMENT

MEMBRANE

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

PROTECTIVE REACTIONS

LYSIS AND PHAGOCYTOSIS OF VIRUSES AND

BACTERIA

DESTRUCTIVE REACTIONS

LYSIS AND PHAGOCYTOSIS OF BLOOD CELLS

)

CYTOLYTIC REACTIONS

ANTIBODY DIRECTED COMPLEMEMT MEDIATD LYSIS OF BACTERIA

PNEUMOVAX STREPTOCCUS PNEUMONIA

COMPLEMENT SYSTEM - CLEAVAGES AND AGGREGATIONS

Immune complex reactions

RED CELLS

HEMOLYTIC ANEMIA

HEMOLYTIC DISEASE OF NEWBORN

TRANSFUSION REACTIONS

PLATELETS

IDIOPATHIC THROMBO-CYTOPENIC PURPURA

WHITE BLOOD CELLS (PMNS)

AGRANULOCYTOSIS - INFECTIONS

CYTOLYTIC REACTIONSBLOOD CELLS

NORMAL RBC + ANTIBODY TO RBC +C

AGGLUTINATION LYSIS

+ COMPLEMENT

HEMAGGLUTINATION AND LYSISTRANSFUSION REACTION

BLOOD

FORMING

CELLS

IN LIVER

ERYTHRO-

BLASTOSIS

FETALIS

ERYTHROBLASTOSIS FETALIS

COOMB’S TEST

TEST FOR ANTIBODY COATED CELLS

TEST FOR ANTIBODIES

NEUTROPENIA

NEXT LECTURE

PURPURA IN INDIOPATHIC THRMBOCYTOPENIC PURPURA

RED CELLS

HEMOLYTIC ANEMIA

HEMOLYTIC DISEASE OF NEWBORN

TRANSFUSION REACTIONS

PLATELETS

IDIOPATHIC THROMBO-CYTOPENIC PURPURA

WHITE BLOOD CELLS (PMNS)

AGRANULOCYTOSIS - INFECTIONS

)

CYTOLYTIC REACTIONSBLOOD CELLS

IMMUNE COMPLEX REACTIONS

ARTHUS REACTION

SERUM SICKNESS

LEUKOCLASTIC VASCULITIS

POLYARTERITIS NODOSA

GLOMERULONEPHRITIS

RHEUMATOID ARTHRITIS

SCLERODERMA (PREGRESSIVE SYSTEMIC SCLEROSIS)

COLLAGEN DISEASES