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1. INTRODUCTION
INFLAMMATIONINNATE (NATURAL) IMMUNITYADAPTIVE IMMUNITYIMMUNE EFFECTOR MECHANISMS
2. ANTIBODY-MEDIATED MECHANISMS
INATIVATION/NEUTRALIZATIONCYTOLYTICIMMUNE COMPLEXATOPIC/ANAPHYLACTIC
3. CELL-MEDIATED MECHANISMS
T-CELL CYTOTOXICDELAYED HYPERSENSITIVITY
GRANULOMATOUS REACTIONS
DEMYSTIFYING HUMAN IMMUNOLOGY
What is the alternative to understanding the complexity of the
world? Atul Gawande
1. COMPLEXITY
2. LACK OF KNOWLEDGEIf we knew a lot more, it would be a lot easier
3. NEW VOCABULARYImmunology jargon confusing
THIS WON’T BE EASY PROBLEMS WE FACE
5. THE TIMES THEY ARE A-CHANGINGWhat I tell you today may be different tomorrow
4. TOO MANY NOTESSo much to cover, so little time
https://www.azquotes.com/quote/705338?ref=complexityhttps://www.azquotes.com/author/5398-Atul_Gawande
IMMUNITY1. RESISTENCE TO INFECTION2. EXEMPTION FROM OBLIGATION (DRAFT, LEGAL ACTION)3. LACK OF SUSCEPTIBILITY TO SOMETHING HARMFUL
ALLERGY (HYPERSENSITIVITY)ALTERED (INCREASED OR PATHOLOGICAL)BODILY REACTIVITY DUE TO IMMUNE RESPONSE
ANERGYABSENCE OF IMMUNE RESPONSE
DEFINITIONS
NATURAL BARRIERS
FIRST LINE OF DEFENSE
SKIN AND MUCOUS MEMBANES
WHEN BREACHED NEED ACTIVE DEFENSE
INFLAMMATIONRESPONSE TO ATTACK
“a localized physical condition in which part of the body becomes reddened, swollen, hot, and often painful, especially as a reaction to injury or infection”
“a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue.”
GOOD GUYS VS BAD GUYS
GOOD GUYS BAD GUYSINFLAMMATION INFECTIONSSerum mediators Bacteria
Histamine, etc. Mycobacteria Interleukins, Cytokines VirusesComplement FungiEtc. Worms
Inflammatory cells Etc.Polymorphonuclear leukocytes CancerLymphocytesMacrophages
INNATE IMMUNITY: NK, NKT, γδT-Cells
ADAPTIVE IMMUNITY Antibody, Cells Some times the good guys become bad guys.
WE HAVE EVOLVED COMPLEX SPECIFIC MECHANISMS TODEFEND AGAINST OUTSIDE INVADERS; AT THE SAME TIMETHE OUTSIDE INVADERS HAVE EVOLVED MECHANISMS TO EVADE OUR DEFENSES
MILITARY COMPONENTSOF IMMUNE SYSTEM
PERSONNEL: WHITE BLOOD CELLS (HEAVILY ARMED)
INTELLENCE: RECEPTORS ANTIBODIES/LYMPHOCYTES
TRAINING: THE IMMUNE RESPONSE LYMPHOID ORGANS
SUPPLY: BLOOD CIRCULATION AND LYMPHATICS
Anti-coagulated blood allowed to settle or centrifuged in a capillary tube
Buffy Coat-White BloodCells – Leukocytes
Put a drop of blood toward one end of a slide.
While tilting the coverslip toward the drop, slowly move it toward the drop until it contacts the blood and "grabs" the drop.
Without changing the tilt of the coverslip, move it back over the slide, to draw the blood across the slide.
When dry, stain with Wright-Giemsa stain
BLOOD SMEAR – SIMPLE WAY TO COUNT CELLS(PERCENTAGE OF CELL TYPES) NOW DONE BY MACHINES
Making a blood smear
BLOOD SMEAR
WRIGHT GIEMSA STAINJames Homer Wright 1902Born in Pittsburgh, PA 1869Chief of PathologyMass General Hospital 1896-1926
Gustav Giemsa, 1904Hamburg, Germany
Eosin Y – ACIDICProteins are BASIC
Wright JH. A rapid method for the differential staining of blood films and malarial parasites. J. Med Res 7:138–144, 1902.Giemsa G. Eine Vereinfachung und Vervollkommnung meiner Methylenblau-Eosin-Färbemethode zur Erzielung der Romanowsky-Nocht’schen Chromatinfärbung. Centralblatt für Bakteriologie I Abteilung 32, 307–313, 1904
Methylene Blue – BASICNucleic acids are ACIDIC
40X 100X
200X 400X
BLOOD SMEAR
EOSINOPHIL
NEUTROPHIL
LYMPHOCYTES
MONOCYTES
BASOPHIL
ERYTHROCYTES
PLATELETS BLOOD CELLS
ON PATROL DUTY
LEUKOCYTES – WHITE BLOOD CELLS
MONONUCLEAR CELLS POLYMORPHONUCLEAR CELLS
LYMPHOCYTESNEUTROPHILS
EOSINOPHILS
BASOPHILSMONOCYTES
MAST CELLS
POLYMORPHONUCLEAR NEUTROPHIL - ACUTE INFLAMMATIONGRANULES CONTAIN OXYGEN RADICALS, PROTEASES, ETCRELEASED FROM GRANULES –ATTACK AND KILL MICROORGANISMS - PUS
POLYMORPHONUCLEAR EOSINOPHIL – ACUTE AND CHRONIC INF.GRANULES CONTAIN MAJOR BASIC PROTEIN – STAINS REDKILL PARASITES -INHIBIT ALLERGIC INFLAMMATION.
LYMPHOCYTE – CHRONIC INFLAMMATIONMAY BE IMMUNE REACTIVE T-CELL OR B-CELL
POLYMORPHONUCLEAR BASOPHIL – RELATED TO TISSUE MAST CELLS – GRANULES CONTAIN HEPARIN, HISTAMINE, ETC.CHANGE COLOR OF EOSIN (RED TO BLUE) – METACHROMASIA PRECURSORS TO PROSTAGLANDINS – CAUSE VASODILATION
MONOCYTE – CHRONIC INFLAMMATION – BECOMES MACRO-PHAGE IN TISSUE – PHAGOCYTOSIS AND DIGESTION OFTISSUE DEBRIS AND DEAD ORGANISMS – MAY BE ACTIVATED BY PRODUCTS OF ACTIVATED T-CELLS
WHITE BLOOD CELLS
NEUTROPHIL GRANULES
EOSINOPHILS
MAST CELLSSMOOTH MUSCLESASTHMA SHOCK
INFLAMMATION – DEFENSE AGAINST INFECTION, REPAIROF TISSUE INJURY
ACUTE INFLAMMATION – DELIVERY OF SERUM PROTEINS AND BLOOD CELLS TO TISSUES AT SITE OF INFECTION OR INJURY TO ATTACK INVADERS –POLYMORPHONUCLEAR CELLS
CHRONIC INFLAMMATION – DELIVERY OF INFLAMMATORYCELLS FROM BLOOD TO SITE OF INFECTION OR INJURY
TO CLEAR PRODUCTS OF ACUTE INFLAMMATION LEADINGTO HEALING (RESOLUTION) OR SCARRING -MONONUCLEAR CELLS
IMMUNE INFLAMMATION – VARIATION OF ACUTE OR CHRONIC INFLAMMATION INITIATED BY REACTION OF ANTIBODIES (ACUTE) OR SPECIFICALLY SENSITIZED LYMPHOCYTES (CHRONIC) TO A SPECIFIC TARGET
ACUTE INFLAMATION CHRONIC INFLAMATION
POLYMORPHONUCLEARWHITE CELLS MONONUCLER WHITE CELLS
From: Sell S. Immunology, Immunopathology and Immunity. 6th Edition; ASM press, 2001
MYOCARDIAL INFARCT
POLYMORPHONUCLEAR CELLS
LYMPHOCYTES AND MOMNOCYTES
DEAD MUSCLE
FIBROSIS
MYOCARDIAL INFARCT - HISTOLOGIC STAGES
From: Sell S. Immunology, Immunopathology and Immunity. 6th Edition; ASM press, 2001
THE CARDINAL SIGNS OF ACUTEINFLAMMATION(GALEN)
RUBORTUMORCALORDOLOR
FUNCTIO LAESA(VIRCHOW)
SKIN ABCESS
NORMAL ABCESS
DEGRANULATED PMN’SDERMIS COLLAGEN FIBERS
ACUTE INFLAMMATION STREPTOCOCCAL INFECTION
CELLULITIS
CELLULITIS ACUTE INFLAMMATION
NORMAL LUNG NORMAL LIVERSPONGY SOLID – FIRMCREPITANT RUBBERY
PNEUMONIA
HEPATIZATION
PNEUMONIA LUNG FILLS WITH INFLAMMATION
OR SCARRING
NORMAL LUNG HEMMORAGIC PNEUMONIA
BLOOD LEAKS FROM DAMAGED ALVEOLAR WALLS
NORMAL LUNG SCAR
From: Sell S. Immunology, Immunopathology and Immunity. 6th Edition; ASM press, 2001
MAJOR PLAYERS IN INFLAMMATION AND IMMUNE RESPONSE
DENDRITIC MACROPHAGEProcesses antigen during immune response
M1 MACROPHAGE - PROINFLAMMATORYA macrophage subtype that produces pro-inflammatory cytokines and acts as an effector of cell killing as well as scar formation.M2 MACROPHAGE – ANTI-INFLAMMATORYA macrophage subtype that acts to dampen inflammatory responses and scavenge debris, as well as promote angiogenesis and tissue remodeling.
DURING INFLAMMATORY PROCESS REPLACE M1 WITH M2
MONOCYTES/MACROPHAGES“BIG EATER”
INNATE OR NATURAL IMMUNITY
FURTHER EXTENSION OF THE PROCESS OF INFLAMMATION
DOES NOT RQUIRE SPECIFIC IMMUNE RESPONSE
TWO KINDS OF IMMUNE REACTION
INNATE IMMUNITY (INFLAMMATION NOT INDUCED BY ADAPTIVE IMMUNE EFFECTOR MECHANISM – DOES NOT REQUIRE IMMUNIZATION)
MAST CELLSPMNs (Neutrophil, Basophils and Eosinophils)MACROPHAGES
T-CELLSNKTγδT
ADAPTIVE IMMUNITYB-CELLS - ANTIBODIESCD4+ HELPER TCD4+ EFFECTOR TCD8+ T KILLER
Streptoccocus pyogenes
F-met peptidesNecrotic tissue
Attract andActivatePMNs/MAST CELLS
DEGRANULATION
Microbiocidal enzymes(cathepsins, peroxidase, protease, etc)Oxygen radicalsCollagenase, Gelatinase, Elastase
INTERLEUKINSAttract and Activate Macrophages CYTOKINES
Attract and ActivateLymphocytes and Macrophages
MACROPHAGES
NATURAL IMMUNITY
NK CELLSγδT CELLS
COLONY INHIBITION ASSAYFINDING: LYMPHOCYTES FROM PATIENTS WITH TUMORS WOULD INHIBIT GROWTH OF TUMOR CELLS IN VITRO IF TUMORS WERE CLOSELY RELATED AS COMPARED TO LYMPHOCYTES FROM PATIENTS WITH UNRELATED TUMORS OR NORMALCONTROLS
BUT! CONTROL LYMPHOCYTES HAD BE SELECTED FROM A RESTRICTED GROUP OF CONTROLS WITH LOW ACTIVITY
IF UNRESTRICTED SELECTION OF CONTROLS, LYMPHOCYTES FROM MANY NORMAL INDIVIDUALS COULD INHIBIT COLONY GROWTH AS WELL AS LYMPHOCYTES FROM PATIENTS
NATURAL KILLER CELLS
KARL ERIC AND INGREGARD HELLSTROM
DANGER SIGNALS - STRESS
INFLAMMATION – inflammatory mediatorsINNATE IMMUNE REACTION - INFγ and IL-12 CANCER – disruption of microenvironment/tissue necrosisActivate antigen processing (dendritic) cells Enhances induction of adaptive immunity. NO DANGER SIGNALS – NO IMMUNE RESPONSENO IMMUNE RESPONSE – CANCER GROWS
THE DANGER HYPOTHESIS AND IMMUNITY(DANGER, DANGER, DANGER)
POLLY MATZINGER - NIH
George Bernard Shaw – The Doctor’s Dilemma“STIMULATE THE PHAGOCYTES” –ACTIVATED MACROPHAGES – ALSO EFFECTOR ARM,ENHANCED PHAGOCYTOSIS OF TARGET CELLS
IMMUNE ADJUVANTS
PRODUCE DANGER SIGNALS
INDUCE INFAMMATION
ACTIVATE INNATE IMMUNITY
GREATLY ENHANCE ADAPTIVE IMMUNE RESPONSE
ADJUVANT EFFECT
PRR-Pattern recognition Receptors
Recognize bacterial products
LippopolysaccrhardePeptidoglycansBacterial DNALipoproteins
ADAPTIVE/ACQUIRED IMMUNITY
INFLAMMATION MODIFIED BY IMMUNE MECHANISMS
USUALLY DIRECTED TO A SPECIFIC TARGET
B-Cells and T-Cells
Immune response
Immunoglobulin antibodies
Antigen-Antibody reactions
Monoclonal antibodies
CDs – Clusters of differentiation Cell markers
T-Cell activation
Interleukins and Cytokines
Autoimmunity and Tolerance
Immune effector mechanisms
OUTLINE
ACQUIRED IMMUNITYDIRECTED BY B-CELLS AND T-CELLS
B-CELLS
BURSA (BONE MARROW) DERIVED
T-CELLS
THYMUS DERIVED
HUMAN B-CELL ORGANS
TONSILS, PEYER’S PATCHES, APPENDIX
THYMUSPRECURSORCELL FROMBONE MARROW
T-CELLS THYMUS DERIVED
WEIGHT GAIN AFTER NEONATAL THYMECTOMY
CONVENTIONAL GERMFREE ALLOGENEIC SKIN GRAFT (BALB/C) SURVIVAL IN NEONATALLY THYMECTOMIZED (C57BL) GERMFREE MICE
GvH REACTION IN GERMFREE BALB/c MICE INJECTED WITH C57BL SPLEEN CELLS AT BIRTH
McIntire KR, Sell S, and Miller, JFAP. Pathogenesis of the postneonatal-thymectomy wasting syndrome. Nature 204:151-155, 1964.
NEONATAL THYMECTOMY WASTING SYNDROMENEONATALLY THYMECTOMIZED GERMFREE MICE DO NOT WASTE, ACCEPT ALLOGRAFTS; BUT UNDERGO GvH REACTIONS TO ALLOGENEIC CELLS
JACQUES MILLER
LYMPHATICS
DRAIN FLUID THAT LEAKS FROM CAPILLARIES BACK TO CIRCULATION (THORACIC DUCT TO SUBCLAVIAN VEIN)
PICK UP ANY SMALL OBJECTSTHAT ENTER INTERSITIAL TISSUE
CANCER CELLS FREQUENTLY GROW INTO LYMPHATICS
LYMPHATICS DRAIN TO LYMPHNODES
PRESENCE OF METASTATIC CANCER IN LYMPH NODES INDICATES LYMPHATIC SPREAD
Subclavian Vein
LYMPH NODE SITE OF IMMUNE RESPONSE
LYMPH NODE – HYPERPLASTIC
CORTEX
FOLLICULARB-CELLSGERMINAL CENTERS
DIFFUSE T-CELLS
MEDULLASINUSOIDSDRAIN FLUID AND CELLS FROM CONTEX
THE ADAPTIVE IMMUNE RESPONSE
BT
AFFERENT CENTRAL EFFERENT
ANTIBODY
SENSITIZED CELLS
ANTIGEN
DENDRITICMACROPHAGE
LYMPH NODE
AFFERENTLYMPHATICS
EFFERENTLYMPHATICS
T CD4
CD8
Mρ+
TCTL
DTH
THEORIES OF ANTIBODY FORMATION
SELECTIVE OR INDUCTIVE
SIDE CHAIN THEORY
ONE REACTIVE CELLHAS MANY RECEPTORS
ANTIGEN SELECTS ONE CELL THEN PRODUCESAND SECRETS MANYMORE
INSTRUCTIVE
ANTIGEN INDUCES CHANGE IN STRUCTUREAND STIMULATESPRODUCTION
CLONAL SELECTION
MANY CELLS, EACHWITH SINGLE RECEPTORANTIGEN SELECTSCELL AND STIMULATESPROLIFERATION
B-CELL
alpha beta gamma gamma
SERUM ELECTROPHORESIS
Complementary Determining RegionParatope
IgG MAJOR ANTIBODY IN CIRCULATION
IMMUNOGLOBULIN CLASSES
IgA MUCOSAL SURFACES
IgE MAST CELL – ALLERGIC REACTIONS
B-CELL PLASMA CELL
ENDOPLASMICRETICULUMGOLGI APPARATUS
PROTEIN SYMTHESISAND SECRETION
PRIMARYRESPONSE
SECONDARYMEMORY ORANAMNESTICRESPONSE
ANTIBODY RESPONSE TO COVID-19 INFECTION
SARS –CoV-2 RNA AND ANTIGEN
Paratope
ANTIBODY – ANTIGEN REACTIONS
ANTIGENICDETERMINANTANTIBODY
BINDING SITE
Epitopes
DIPHENYL HYDRIZINE
BINDS TO PROTEIN (CARRIER)
CHEMICALLY ACTIVE SMALL MOLECULE THAT IS NOT IMMUNOGENIC BY ITSELFNEEDS CARRIERCAN REACT WITH ANTIBODY AFTER INDUCED
ANTIBODY MEDIATED IMMUNE MECHANISMS
NEUTRALIZATION / INACTIVATION
LYSIS
PRECIPITATION
MAST CELL DEGRANULATION
ANTIBODY-ANTIGEN REACTION NEUTRALIZATION
ANTIBODY-ANTIGEN REACTION - AGGLUTINATION
ANTIBODY- ANTIGEN REACTION LYSIS
COMPLEMENT
COMPLEMENTMEDIATEDLYSIS
C3b Opsonization
Lysis
IgM ONE MOLECULE CAN ACTIVATE LYSIS
COMPLEMENT
IgG TWO MOLECULES TOGETHER ON CELL IgM ANTIBODY IS 600 TIMES MORE EFFICIENT IN ACTIVATING C’ FOR LYSISTHAN IgG ANTIBODY
ANTIBODY-ANTIGEN REACTIONS PRECIPITIN
ANTIBODY-ANTIGEN REACTION PRECIPITIN
QUANTITATIVE PRECIPITIN REACTIONTOTAL PROTEIN AT EQUILIVANCE MINUS AMOUNT OF ANTIGEN ADDED = AMOUNT OF ANTIBODY
JACQUES OUDIN
ANTIBODY-ANTIGEN REACTION DOUBLE DIFFUSION IN AGAR
AB
AG
ANTIBODY-ANTIGEN REACTIONARTHUS SKIN REACTION
PEAK REACTION 6 HOURS
ARTHUS REACTIONVASCULITIS DUE TO AG-AB REACTIONAT EQUILIVANCE IN VESSEL WALL LEADINGTO FIXATION OF COMPLEMENT ⃗ACTIVATION OF C3a, c5A
ANTIBODY-ANTIGEN REACTIONIgE MEDIATED MAST CELL DEGRANULATION
Atopic or anaphylactic reactions
IgE MEDIATED WHEAL AND FLARE REACTION
PEAK REACTIONIN MINUTES
MONOCLONAL ANTIBODIES
NORMAL RESPONSE IN ANIMAL ARTIFICALLY PRODUCED
myeloma
ORIGINAL METHOD FOR PRODUCINGMoAbS
“HUMANIZED” MONOCLONALANTIBODIES
GENE CLONING
Production of enginered monoclonal antibodies is accomplished using recombinant DNA to create constructs[3] capable of expression in mammalian cell culture.
Gene segments capable of producing antibodies are isolated and cloned into cells that can be grown in a bioreactor such that antibody proteins produced from the DNA of the cloned genes can be harvested en masse.
The step involving recombinant DNA provides an intervention point that can be readily exploited to alter the protein sequence of the expressed antibody. The alterations to antibody structure that are achieved in the humanization process are therefore all effectuated through techniques at the DNA level
http://en.wikipedia.org/wiki/Recombinant_DNAhttp://en.wikipedia.org/wiki/Expression_vectorhttp://en.wikipedia.org/wiki/Humanized_antibody#cite_note-pmid9202712-3http://en.wikipedia.org/wiki/Gene_expressionhttp://en.wikipedia.org/wiki/Mammalhttp://en.wikipedia.org/wiki/Cell_culturehttp://en.wikipedia.org/wiki/Molecular_cloninghttp://en.wikipedia.org/wiki/Bioreactorhttp://en.wikipedia.org/wiki/Proteins
VALORTIM RAXIBACUMAB ANTHRAXSYNAGIS PALIVZUMAB RESPIRATORY SYNCYTIAL VIRUSmAb-114 , Z-Mapp, RABIES REGN-COV2 2 MONOCLONALS SARS2 CORONAVIRUSUNDER DEVELOPMENT HIVUNDER DEVELOPMENT SNAKE VENOMHUMIRA ADALIMUMAB RHEUMATOID ARTH, PSORIASISBENLYSTRA BELIMUAB SLERITUXAN RITUXIMAB SCLERODERMAXOLAIR OMALIZUMAB ASTHMAMEPOLIZUMZB RESILIZUMAB ASTHMA FASENRA BENRALIZUMAB EOSINOPHILIC ASTHMADUPIXENT DUPILUMAB ATOPIC ECZEMAORTHOCLONE-Okt3 MUROMONAB-CD3 KIDNEY GRAFT REJECTIONSIMULECT BESILIXIMAB KIDNEY GRAFT REJECTIONTALZ IXCKIZUMAB PSORIASISCONSNTEX SECUKINUMAB PSORIASISSKYRIZA TILDRAKIZUMAB PSORIASIATREMFYA GUSELKUMAB PSORIASISRAPTIVA EFALIZUMAB ALOPECIAREMICADE INFLIXIMAB CROHN DISEASEENTYVIO VEDOLIZUMAB CROHN DISEASESTELARA USTEKINUMAB PSORIASIS, CROHNANTI-CTLA-4 IPILUMAB CANCERPROLIA DENOSUMAB OSTEOPOROSIS
SOME HUMANIZED MONOCLONAL ANTIBODIES USED IN THERAPY
DRUG ANTIBODY COMPLEXES
IMMUNOFLUORESCENT LABELLING
IMMUNOFLUORESCENT LABELLING
Proposed and established in the 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), in Paris in 1982. This system was intended for the classification of the many monoclonal antibodies(mAbs) generated by different laboratories around the world against epitopeson the surface molecules of leukocytes (white blood cells). Since extended toother cells types.
CLUSTERS OF DIFFERENTIATIONMARKERS FOR WHITE BLOOD CELLS
INDIRECT OR “PIGGY-BACK” LABELING OF CD ON CELL
HUMAN CD 4
http://en.wikipedia.org/wiki/Leukocytehttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Paris,_Francehttp://en.wikipedia.org/wiki/Monoclonal_antibodieshttp://en.wikipedia.org/wiki/Epitopehttp://en.wikipedia.org/wiki/White_blood_cell
CLUSTERS OF DIFFERENTIATION (CD’s)
B- CELL DIFFERENTIATION
CD19,CD22----------------------------
CD19,CD20----------------------------------
IDENTIFICATIONOF WBC LINEAGESBY CDDESIGNATION
http://en.wikipedia.org/wiki/File:Cluster_of_differentiation.svg
CD 45 PAN WHITE CELL
CD 34 STEM CELL
CD 3 PAN T-CELL
CD 4 HELPER T-CELL
CD 8 SUPPRESSOR T-CELL
CD19/20 EARLY B-CELL
CD 23
CD 38
LATE B-CELL
ACTIVATED CELL
MAJOR CD MARKERS FOR LYMPHOCYTES
T-CELL ACTIVATIONANTIGEN PRESENTATION BY DENDRITIC CELLS
T-CELL RECEPTOR RECOGNIZES PEPTIDE ANTIGENS
JAK-STAT PATHWAY
TW0 MAJOR T-CELL SUBSETS - CD4 AND CD8
DELAYED HYPERSENSITIVITY KILLER
CD8 T-CELL (KILLER CELL) LYSIS
T-CELL CYTOXICITY CONTACT DERMATITISPOISON IVY
PEAK REACTION - 24-48 HOURS
T-CELL KILLING OF SKIN EPITHELIAL CELLS
CONTACT DERMITITIS POISON IVY
CD4 + EFFECTOR T-CELLS
IgG1, IgG3COMPLEMENTFIXING ANTIBODIES
OPSONIZATION,PHAGOCYTOSIS
MACROPHAGE ACTIVATION
B-CELL
Th1
CTL
INF-γ
INF-γ
IL-2INF-γ
CD8+T
Th2
B-CELL
IgG2, IgG4IgAANTIBODY
IgE
MAST CELLDEGRANULATION
NEUTRA-LIZATION
EOSINOPHILS
DIFFERENTIATION AND ACTIVATION
INHIBITIONOF INFLAM-MATION
IL-4,-10, -13
IL-4Il-13
IL-5
CD4+T-CELL
ANTIGENIC STIMULUS
Th2 – VASCULAR EFFECTS SECRETORY ANTIBODY
Th1 – DIRECTED TO CELLULAR RESPONSES
CD4+T
DELAYED HYPERSENSITIVITY
TYPE I TYPE II
CELL-MEDIATEDCYTOXICITY
VASCULITISGLOMERULONEPHRITIS
ANAPHYLACTIC REACTIONS
HEMOLYSISTRANSFUSIONREACTIONS
CD 4 DELAYED HYPERSENSITIVITY T-CELLACTIVATION OF MACROPHAGES
PEAK REACTION 24-48 HOURS AFTER INJECTION OF ANTIGEN
PPD – PURIFIED PROTEIN DERIVED FROM CULTURESOF MYCOBACTERIUM TUBERCULOSIS
EARLY DTH SKIN REACTION
Th17 CELLS
T-REGULATORY CELLS
INTERLEUKINESAND
CYTOKINES
INTERLEUKIN – A GLYCOPROTEIN PRODUCED BY WHITE BLOOD CELLS, LYMPHOCYTES THAT ACTS UPON OTHER CELLS OF THE IMMUNE SYSTEM, e.g. BY ACTIVATING MACROPHAGES OR LYMPHOCYTES.
OVER 31 IDENTIFIED.
IL-2 ACTIVATES IMMUNE EFFECTOR CELLS
IL-6 MULTIPLE SOURCES AND EFFECTS
Th17 cells in intestine and skin submucosa
IL-17A and 17F targetinnate immune cells and epithelial cells to produce multiple cytokines
Attract neutrophis, NK and T-cells
Defend against fungi and bacteria
Also IL21 stimulates antibody productionIn draining lymph nodes, in particular IgA
Bacterial products
IL-17
CYTOKINE
- A BROAD CATEGORY OF SMALL PROTEINS (PEPTIDES) SUCH AS INTERFERON, GROWTH FACTORS, AND
INTERLEUKINS SECRETED BY CELLS OF THE IMMUNE SYSTEM AND HAVE AN EFFECT ON OTHER CELLS
.
CYTOKINE STORM - OVERREACTION
WILLIAM COLEY1892
1890’s WILLIAM COLEY COIEY’S TOXINSBACTERIAL TOXIN’S USEDN TO TREAT CANCER
SIGNOR ZOLA TREATED 1891 BY INFECTION WITH S. PYOGENES
AFTER LIFE THREATENING INFECTION, TUMORS GO AWAY!
STEPHEN S. HALL
A COMMOTION IN THE BLOOD
HENRY HOLT & CO.NEW YORK
1997
DOUBLE EDGED SWORDTHE SAME IMMUNE MECHANISMS THAT PROTECT US FROM INFECTIONS MAY BE USED AGAINST US TO CAUSE DISEASE
BAD GUYSGOOD GUYS
IMMUNOPATHOLOGY –HOW IMMUNE REACTIONS CAUSE DISEASE
1. OVERREACTION AND/OR COLLATORAL DAMAGE
FOR EXAMPLE – CYTOKINE STORM
One immune mechanism may be directed to more than one enemy
More than one immune mechanism may be directed to the same enemy
PLEOTROPHY
GENETICS WHEN 1 GENE INFLUENCES MORE THAN ONE PHENOTYPIC TRAIT
AUTOIMMUNITY (AUTOALLERGY)
Immune mechanisms may be directed to self
ADULT TOLERANCE T-REGULATORY CELLLS
ADULT TOLERANCE AND AUTOIMMUNITY
AUTOIMMUNITY - LOSS OF SELF TOLERANCE
TOLERANCE AND LOSS OF TOLERANCE IS ARGUABLY THE MOST DISCUSSED ASPECT OF IMMUNITY
MULTIPLE POSSIBLE MECHANISMS HAS LED TO MANY THEORIES
1. REIMMERGENCE OF SELF-REACTIVE CELLS IN NEONATAL THYMUS SELF-REACTIVE CELLS USUALLY ELIMINATED DURING NEONATAL DEVELOPMENT
2. CROSS REACTIVE EPITOPESFOREIGN ORGANISMS OR CHEMICALS MAY SHARE EPITPOES WITH NORMAL TISSUES
3. LOSS OF Tregs (REGULATOR T-CELLS) Tregs BLOCK SELF-REACTIVE T-CELLS
4. CYTOKINE STORM (DANGER HYPOTHESIS)DURING SEVERE INFLAMMATORY RESPONSE CYTOKINES MAY ACTIVATE SELF-REACTIVE CELLS
5. ALTERED PHENOTYPE OF DIFFERENTIATED CELLS (ECOIMMUNITY)IN ADLUT TISSUES NEW PHENOTYPES MAY APPEAR THAT ARE RECOGNIZED AS FOREIGN
Nevo U, Hauban E. Ecoimmunity: Immune tolerance by symmetric co-evolution. Evolution & Dev. 9:632-642, 2007
CLASSIFICATION OF
IMMUNE EFFECTOR MECHANISMS
PARTIAL LIST OF IMMUNE MEDIATED PHENOMONA – PRE 1968
ANAPHLAXIS ASTHMA ARTHUS REACTIONAUTO-IMMUNE THYROIDITIS POISON IVY GLOMERULONEPHRITISMYASTHENIA GRAVIS DIABETES SERUM SICKNESSTUBERCULIN TEST GvH REACTION RHEUMATOID ARTHRITISTRANSFULSION REACTION EAE SCHULTZ-DALE PHENOMONONERYTHROBLASTOSIS FETALIS MYOPATHY COLD HEMAGLOBINURIAMUTIPLE SCLEROSIS SCLERODERMA WHEAL AND FLARE REACTIONPEMPHIGUS SCHICK TEST ERYTHEMA MULTIFORMEDERMATOMYOSITIS HAY FEVER SCHWARTZMAN REACTIONGIANT URTICARIA SHOCK PSORIASISWEGNER GRANULOMATOSIS POLYMYOSITIS PERNICIOUS ANEMIAMASTOCYTOSIS HEPATITIS LUPUS ERYTHEMATOSISAMYLOIDOSIS MYELOMA LYMPHOCYTIC CHORIOMENINGITISTUMOR IMMUNITY ORCHITIS JONES-MOTE REACTIONSIALOADENITIS NEURITIS SIALOADENITISPHACOANAPHYLACTIS ENDOPTHALMITIS ALLERGIC UVITITSHASHIMOTO’S THYROIDITIS ANGIOEDEMA HYPOTHYROIDISMIDIOPATHIC THROMBOCYTOPENIC PURPURA HEREDITARY ANGIOEDEMAHYPERCOMPLEMENTEMIC GLOMERULONEPHRITIS HYPERTHYROIDISMHYPOCOMPLEMENTEMIC VASCULITIC URTICARIAL SYNDROME PALPABLE PURPURAHYPOGAMMAGLOBULINEMIA OF INFANCY IgA NEPHRITISEPIDERMOLYSIS BULLOSA ACQUISITA REGIONAL ENTERITISERYTHEMIA CHRONIC MIGRANS CELIAC DISEASE EXTRINISIC ALLERGIC ALVEOLITISCOLD AGGLUTININ DISEASE BERYLLIOSIS CHURG STRAUSS SYNDROMEANKYLOSING SPONDYLITIS ANGIOEDEMA ANKYLOSING SPONDYLITIS
Clinical Aspects of Immunology 1963/68
Type I ATOPIC OR ANAPHYLACTICType II CYTOTOXICType III IMMUNE COMPLEXType IV DELAYED HYPERSENSITIVITY
CLASSIFICATION OF “HYPERSENSITIVITY REACTIONS”
PHILIP GELLROBIN COOMBS
1972 2001
IMMUNOLOGY, IMMUNOPATHOLOGY AND IMMUNITY6 EDITIONS - 5 LANGUAGES
PRIMARYREACTION
SECONDARY REACTION
TERTIARY REACTIONS
ANTIBODY MEDIATED
CELL MEDIATED
Ag+Ab AgAb
in vitro in vivo
INACTIVATION
AGGLUTINATION LYSIS,OPSONIZATION
PRECIPITATION
MAST CELLDEGRANULATION
CYTOLYTIC
IMMUNE COMPLEX
ANAPHYLACTIC
+Ag->T-DTH
T-CTL
LYMPHOKINESMACROPHAGEACTIVATION
TARGET-CELL LYSIS
DELAYED HYPERSENSITIVITY
T-CELL CYTOTOXICITY
BLASTTRANSFORMATION
LEVELS OF REACTIONS OF ANTIGEN WITH ANTIBODY OR CELLS
IMMUNE EFFECTOR MECHANISMS
Ab or + INSOLUBLE ANTIGEN GRANULOMAS
NEUTRALIZATIONACTIVATION
MYASTHENIA GRAVISHYPERTHRYOIDISM GRAVE’SANTI-TOXIN NEUTRALIZATION
TRANSFUSION REACTIONSERYROBLASTOSIS FETALISBACTEROLYSIS
ARTHUS REACTIONGLOMERULONEPHRITISABCESS FORMATION ANAPHYLALCTIC SHOCKASTHMAINTESTINAL PARASITE IMMUNITY
TUBERCULIN SKIN TEST EAE, AUTOALLERGIC DISEASESCHANCRE OF SYPHILIS
AUTOIMMUNE THYROIDITISPOISON IVY, MEASLES
TB, SARCOID, BERYLLIOSIS, LEPROSYFOREIGN BODY GRANULOMA
EXAMPLES
THE DOUBLE-EDGED SWORD OF IMMUNE EFFECTOR RECTIONS
IMMNUE EFFECTOR MECHANISM PROTECTIVE FUNCTION DESTRUCTIVE FUNCTION
NEUTRILIZATIONINACTIVATION DIPHTHERIA, TETANUS, INSULIN RESISTENCE
CHOLERA, ETC.
RECEPTOR BLOCKADE VIRAL INFECTIONS MYASTHENIA GRAVISGRAVE’S DISEASE*
CYTOTOXIC BACTERIOLYSIS HEMOLYTIC ANEMIALEUKOPENIA
IMMUNE COMPLEX ACUTE INFLAMMATION VASCULITIS, ARTHRITISOPSONIZATION GLOMERULONEPHRITIS
ATOPIC/ANAPHYLACTIC VASODILATION ASTHMA, HAY FEVERINTESTINAL PARASITES ANAPHYLACTIC SHOCK
T-CELL CYTOXICITY VIRAL INFECTIONS CONTACT DERMATITISTUMOR IMMUNITY GRAFT REJECTION
DELAYED HYPERSENSITIVITY TUBERCULOSIS, LEPROSY AUTO-ALLERGIES SYPHILIS, LYME DIS. POST-VACCINIAL ENCEPH.
GRANULOMATOUS TUBERCULOSIS, LEPROSY SARCOIDOSIS, BERYLLIOSIS
Modified from: Sell, S. Introduction to symposium on immunopathology: Immune mechanisms in human disease.Human Pathology 1978; 9:23-24
1. INTRODUCTION
INFLAMMATIONINNATE (NATURAL) IMMUNITYADAPTIVE IMMUNITYIMMUNE EFFECTOR MECHANISMS
2. ANTIBODY-MEDIATED MECHANISMS
INATIVATION/NEUTRALIZATIONCYTOLYTICIMMUNE COMPLEXATOPIC/ANAPHYLACTIC
3. CELL-MEDIATED MECHANISMS
T-CELL CYTOTOXICDELAYED HYPERSENSITIVITY
GRANULOMATOUS REACTIONS
DEMYSTIFYING HUMAN IMMUNOLOGY