Hypersensitivity reactions: Antibody-mediated (type II) cytotoxic reactions
Antibody Mediated Neutralization Cytolytic/Cytotoxic ......Granulomatous Reactions OUTLINE. PRIMARY...
Transcript of Antibody Mediated Neutralization Cytolytic/Cytotoxic ......Granulomatous Reactions OUTLINE. PRIMARY...
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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
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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
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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
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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
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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)
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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
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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.
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VACCINES INACTIVATION / NEUTRALIZATION
TOXIN NEUTRALIZATION
BACTERIA TOXINSTETANUS
DIPHTHERIA
PERTUSSIS
CHOLERA
ANTHRAX
RECEPTOR BLOCKADE
VIRUSESMEASLES
FLU
EBOLA
HEPATITIS
HERPES
POLIO
PAPILLOMA ETC.
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DPT
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DIPHTHERIA - LARYNGEAL MEMBRANE PNEUMONIA
TOXIN – Enters cell through receptors (EGF) and
blocks protein synthesis
VACCINE –
HEAT INACTIVATED TOXIN
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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
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TETANUS
LOCKJAW
NEONATALTETANUS
OPISTHOTONOS OPISTHO – BACKWARD;
TONO - TENSION
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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
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JOHN SNOW LONDON 1854
CHOLERA
FIRST APPLICATION OF PUBLICHEALTH TO PREVENT DISEASE
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GIVEN ORALLYRECEPTOR AND TOXINSTIMULATES IgA ANTIBODY
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Mab
TREATMENT
ANTHRAX VACCINE 1881 LOUIS PASTEUR
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VACCINATE COWS “HERD IMMUNITY” PREVENTS HUMAN INFECTION
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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
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HUANIZED MONOCLONAL ANTIBODY
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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
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Virus
Receptor
Blockade
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MMRV VACCINEMEASLES, MUMPS, RUBELLA, VARICELLAATTENUATED LIVE VIRUS
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VARICELLA TARGET MUCOSA OF RESPIRATORY TRACT
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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
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DISEASE RETURNS WHEN FAMLIES REFUSE VACINE
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POLIO VACCINES
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POLIO
BOTH IgG and
IgA ANTIBODY
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INCLUDES INFLUENZA, CORONAVIRUS
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PATHOGENESIS OF ACUTE INFLUENZA PNEUMONIA
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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.
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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
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INFLUENZA VACCINE
Why is a “new”
vaccine required
every year?
Antigenic drift
Mutation produces
“new” surface HA
(hemaglutinin)
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•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
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MUTIPLE IMMUNEMECHANISMS IN RESPONSE TO FLU VIRUS
IgA BLOCKING ABIgG NEUTRALIZING AB
CYTOTOXIC T-CELLSDTH T-CELL
More later
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SARS CoV-2 POTENTIAL IMMUNOGENS
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MODERNAmRNA-1273Spike protein
DA approved forPhase 3 clinical trials
CORNAVIRUS VACCINE
ASTRZENKA
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HUMAN PAPPILOMA VIRUS AND
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HUMAN PAPILLOMA VIRUS ANTIBODY AND T-CTL
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HIV NO VACCINE - INFECTS CD 4 HELPER T-CELLS
AZT AZIDOTHYMIDINE THYMIDINE ANALOG BLOCKS REVERSE TRANSCRIPTASE
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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
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TREATMENT WITH INACTIVATING ANTIBODIES
PASSIVE TRANSFER OF MONOCLONAL ANTIBODIES FOR
ANTHRAX
EBOLA
SNAKE VENOM
MONOCLONAL ANTIBODIES
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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
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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
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Kills 100,000 annually and permanently disfigures >300,000
ANTI-VENOM TREATMENT
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• 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).
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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.
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IMMUNE
FACTORS IN
DIABETES
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NORMAL ISLET LYMPHOCYTIC INFILTRATE
HYLINIZED ISLET
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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
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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
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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
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ANTIBODIES TO PARIENTAL CELLS
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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
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MYASTHENIA GRAVIS - SEVERE MUSCLE WEAKNESS
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EXOPTHALMOS – HYPERTHYROIDISM (GRAVE’S DISEASE)
AUTOANTIBODY MIMICS EFFECT OF THYROID
STIMULATING HORMONE (TSH) ACTIVATIOIN
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LATS – LONG ACTING THYROID STIMULATOR
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NORMAL THYROID GRAVE’S DISEASE
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BLISTERING SKIN DISEASES
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Epidermolysis bulosa acqusitaNormal skin
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EPIDERMOLYIS
BULLOSA
AQUISITA
AQUIRED SKIN
BLISTERS
SERUM FROM PATIENT
BINDS TO BASEMENT
MEMBRANE OF NORMAL SKIN
SEPARATION OF EPIDERMIS
FROM DERMIS AT BASEMENT
MEMBRANE
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PEMPHIGUS ANTIBODY TO SKIN EPITHELIAL CELLS
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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
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PROTECTIVE REACTIONS
LYSIS AND PHAGOCYTOSIS OF VIRUSES AND
BACTERIA
DESTRUCTIVE REACTIONS
LYSIS AND PHAGOCYTOSIS OF BLOOD CELLS
)
CYTOLYTIC REACTIONS
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ANTIBODY DIRECTED COMPLEMEMT MEDIATD LYSIS OF BACTERIA
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PNEUMOVAX STREPTOCCUS PNEUMONIA
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COMPLEMENT SYSTEM - CLEAVAGES AND AGGREGATIONS
Immune complex reactions
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RED CELLS
HEMOLYTIC ANEMIA
HEMOLYTIC DISEASE OF NEWBORN
TRANSFUSION REACTIONS
PLATELETS
IDIOPATHIC THROMBO-CYTOPENIC PURPURA
WHITE BLOOD CELLS (PMNS)
AGRANULOCYTOSIS - INFECTIONS
CYTOLYTIC REACTIONSBLOOD CELLS
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NORMAL RBC + ANTIBODY TO RBC +C
AGGLUTINATION LYSIS
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+ COMPLEMENT
HEMAGGLUTINATION AND LYSISTRANSFUSION REACTION
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BLOOD
FORMING
CELLS
IN LIVER
ERYTHRO-
BLASTOSIS
FETALIS
ERYTHROBLASTOSIS FETALIS
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COOMB’S TEST
TEST FOR ANTIBODY COATED CELLS
TEST FOR ANTIBODIES
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NEUTROPENIA
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NEXT LECTURE
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PURPURA IN INDIOPATHIC THRMBOCYTOPENIC PURPURA
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RED CELLS
HEMOLYTIC ANEMIA
HEMOLYTIC DISEASE OF NEWBORN
TRANSFUSION REACTIONS
PLATELETS
IDIOPATHIC THROMBO-CYTOPENIC PURPURA
WHITE BLOOD CELLS (PMNS)
AGRANULOCYTOSIS - INFECTIONS
)
CYTOLYTIC REACTIONSBLOOD CELLS
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IMMUNE COMPLEX REACTIONS
ARTHUS REACTION
SERUM SICKNESS
LEUKOCLASTIC VASCULITIS
POLYARTERITIS NODOSA
GLOMERULONEPHRITIS
RHEUMATOID ARTHRITIS
SCLERODERMA (PREGRESSIVE SYSTEMIC SCLEROSIS)
COLLAGEN DISEASES