DEMYSTIFYING HUMAN IMMUNOLOGY · DEMYSTIFYING HUMAN IMMUNOLOGY. What is the alternative to understanding the complexity of the world? Atul Gawande 1. COMPLEXITY 2. LACK OF KNOWLEDGE

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