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Chapter 6 - Immune Diseases (Part I) (Robbins and Cotran Pathologic Basis of Disease )

Chapter 6 - Immune Diseases (Part I) (Robbins and Cotran Pathologic Basis of Disease )

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Published by: Ernie G. Bautista II, RN, MD on Nov 12, 2011
Copyright:Attribution Non-commercial

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11/15/2014

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 Prepared by:
EGBII; 8-13-11
Immunity
General Features of Immune System
 Deficiency
infections, tumorHyperactive
fatal diseaseAutoimmunity - immune reaction against own tissues& cells
Two Mechanisms of Immunity
1. Innate immunity2. Adaptive immunityInnate Immunity
natural, native immunity
defense mechanism that are present evenbefore infection
first line of defense
Skin/epithelial barriers, phagocytic cells,natural killer cells, plasma proteins
2 most imp cellular rxn
Inflammation
Phagocytic cells
Antiviral defense
Dentritic & NK cellsAdaptive Immunity
acquired, specific immunity
mechanisms that are stimulated bymicrobes and capable of recognizing nonmicrobial substances (Ags)
develop later
after exposure
to microbes
 
more powerful “immune response”
 
Consists of lymphocytes and their (ex.Antibodies)
Can be: cellular or humoral immunity1.
Cell Mediated or Cellular Immunity
 
against intracellular and extracellularmicrobes, parasites and ab normal cells
mediated by T lymphocytes2.
Humoral Immunity
 
against extracellular microbes & toxins
mediated by B lymphocytes(Immunoglobulin)
Cells of immune system
Lymphocytes
CD4 + T4 & C8 + T8
Naïve lymphocytes
 –
immunologicallyinexperienced
Effector cells
 –
eliminates microbes
Memory cells
 –
With Previous exposure
 –
With Heightened awareness
Cells and Tissues of the Immune System
T lymphocytes
B lymphocytes
Macrophages
Dendritic cells
Natural killer cells
T lymphocytes
From BM stem cells
Maturation in thymus
Found 60-70% in blood and T cell zones(paracortical/ parafollicular area)
Recognize by peptides presented by MHCof Antigen presenting cells
express receptors for chemokines
recognizes spec. cell bound Ag by TCR
cannot be activated by soluble Ags
presentation of Ag is required
B lymphocytes
From BM precursors
Found 10-20% in blood
recognizes Ag thru B-cell Ag receptorcomplex
IgM & IgD -Ag binding component
form plasma cells that secrete Igs
requires help of CD4+ Tcells
Stimulated by Ags and other signals
Plasma cells
Immunoglobulin production
Monodimer
 –
IgD, E, G
Dimer
 –
IgA
Pentamer
 –
IgM (biggest & hasmore binding site)
Macrophages
Function as APCs in T cell activation
Key effector cell -- in Cell med. immunity
Involved in effector phase -- in humoralimmunity
role in induction of cell mediated immunity
role as effector cells in cell mediatedimmunity eg. delayed hypersensitivity
role in effector phase of immunity
Dendritic cells
Aka: Interdigitating DC
Most important APC
Located under epithelia and interstitial
 
“Langerhans cells” (note langhans –
amacrophage)
 –
An immature dendritic cells
 –
Found in skin
Follicular dendritic cells
Found in germinal centers of lymphoidtissues
Has Fc receptors for IgG & receptors forC3b
Natural killer cells
 
AKA: “large granular lymphocytes”
 
10-15% of blood lymphos
w/ abundant azurophilic granules
innate ability to
kill w/o previous
sensitization to Ags
 
tumor
cells,
 
virally infected
cells, somenormal cells
part of
innate immune system
 
CD 16 & CD 56 (+)
Ab dependent cell mediatedcytotoxicity
Fxn balanced by activating/inhibitingreceptors
Secrete Cytokine
 –
ex: IFN-gamma
Tissues of the Immunes System
Generative lymphoid organs
Thymus (Primary) and BM
Peripheral lymphoid organs
LN, spleen, mucosal & cutaneouslymphoid tissues, mucosal associatedlymphoid tissue (MALT)
Lymphocyte recirculation
More on T cells
B cells stay; antibody circulates
T cells
T cell zone (LN)
Ag from APC
activation
circulation
Targetmicrobes/ tissues
Cytokines
Messenger molecules of immune system
A short acting soluble mediators
Example: Interleukins
Secreted in bursts similar to mediators
Regulate lymphocyte growth
Activate inflammatory cells
 
Mediate innate immunity 
IL-1, IL-12, TNF, type Iinterferons, chemokines, IFN
 –
 gamma
 
 
Adaptive responses 
IL-2,4,5,17. IFN-gamma
 
 
Stimulate hematopoiesis 
CSFs
 –
colony stimulatingfactors
 
Structure and Function of Histocompatibility Complex (MHC)molecules
Important in the antigen recognition by T-cells
Associated with many autoimmunedisease (ex. In the case of allografts)
Products of genes that evoke rejection oftransplanted organs
bind peptide fragments of foreign CHONsfor presentation to Ag specific receptors
chromosome 6
major histocompatibility complex (MHC) orhuman leukocyte antigen (HLA)
occur in 2 forms:
class I
class II
MHC locus has genes that encodes:
Complement components
TNF
Lymphotoxin
Class I MHC
 
Imp in Ag recognition by T cells 
 
Display peptide fragments of CHON to recognized by Ag Spec T cells 
Expressed on all nucleated cells &platelets
Composed of polymorphic heavy chainglycoprotein encoded in the following:
HLA-A, HLA-B, HLA-C
Bind peptides derived from endogenousCHONs
Ex. Viral antigen in thecytoplasm & present to andrecognized by CD8+ cytotoxic Tcells
Class II MHC
Confined to APCs, including:
 –
Dendritic cells
 –
Macrophage
 –
B-cells
 –
Activated T-cells
Noncovalently associated with alpha- &beta- chains coded in
HLA-D
with 3defined subloci
 –
DP, DQ, DR
Bind peptides derived from exogenousCHONs
 –
& present to CD4+ helper Tlymphocytes
 
 Prepared by:
EGBII; 8-13-11
HLA and Disease association
1. Inflammatory diseases
 –
HLA-B27 associated
 –
eg. Ankylosing spondylitis2. Inherited errors of metabolism
 –
HLA-BW47 - 21 hydroxylase disease
 –
HLA-A - hereditary hemochromatosis3. Autoimmune diseases
DR locus- AA endocrinopathies
Hypersensitivity
MECHANISM OF HYPERSENSITIVITYREACTIONS
Altered reaction
 –
2
nd
exposure
Exogenous and endogenous antigens maybe triggered hypersensitivity rxns
Often associated w/inheritance ofsusceptibility genes
Imbalance between effector mechnisms ofimmune responses and controlmechanisms
TYPES
1. Immediate hypersensitivity (type I)2. Antibody-mediated (type II)3. Immune complex mediated (type III)4. Cell mediated (type IV)
Immediate Hypersensitivity (Type I)
rapid immunologic reaction (w/in mins.)after combination of Ag with Ab bound tomast cells of previous sensitizedindividuals
most mediated by IgE antibodies
release of vasogenic, spasmogenic subst.,cytokines (recruitment of inflam. cells)
 
Usually, “Allergy”
 
Most mediated by TH2m IgE ab, & mastcells
Release of mediators & pro inflammatorycytokines
Synthesis of IgE
 –
requires induction ofCD4+ helper T cells of TH2 type (w/cproduce multiple cytokines)
IL-4
 –
produced by TH2 cells is essentialfor IgE synthesus
IL-3, 5, GM-CSF
 –
promotes production &survival of eosinophilsA. Systemic
Usually follows injection of Ag (parenteralor oral administration)- skin testing done to loweroccurance
Maybe in state of shock w/in mins(anaphylactic shock)B. Local
Exemplified by atopic allergies1. Immediate or initial phase
5-30 mins after exposure
Primary mast cell mediators
 –
resp. forinitial phase
Includes
o
Biogenic amines (histamine)
o
Chemotactic mediators(eosinophil & neutrophil)
o
Enzymes (chymase & tryptase)2. Late phase
2-24 hours after initial allergen exposure
Driven by lipid mediators & cytokines
o
Produces by mast cells
Lipid mediators include
o
LT-B4,C4,D4,E4
o
Prostaglandin D2
o
PAF
Cytokines include
o
TNF-a
o
Interleukines
o
GM-CSF
o
ChemokinesPrimary mediators/ degranulation contentsSecondary mediators/ membranephospholipids.Histamine.Protease.Chemotactic factors;ECF &NCF.Leukotrienes B,C,D4.Prostaglandin-D2.PAFMasts cells
BM derived
near b.v., nerves, subepithelium
have
cytoplasmic
membrane boundbasophilic granules containing
mediatiors
IgE Fc receptors
 –
where the allergennormally boundBasophils
similar to mast cells
found in the circulation
can be recruited to inflammatory sitesTH2 cells
Initiation & propagation
IL-4
 –
B cells switch to IgE & TH2production (autocrine)
Promotes inflammationEosinophils
Important in late phase
Recruited by chemokines
IL-5
 –
most potent eosinophil activatingcytokine
Liberate:
o
Proteolytic enzymes
o
Major basic proteins
o
Eosinophilic cationic protein
IMMEDIATE HYPERSENSITIVITY
Susceptibility is genetically determined
Basis not clear/ hereditary predisposition in
o
CHROMOSOME 5q31 & 6p
Where genes for TH2are located
ATOPY
 –
predisposition to developlocalized immediate hypersensitivity
NON-ATOPIC ALLERGY
o
Triggered by extremetemperature & exercise
o
NO TH2 cells nor IgE involved
SYSTEMIC ANAPHYLAXIS
Vascular shock, edema, difficulty ofbreathing
May go into shock
Ex: penicillin, food allergies, insect
IV or oral
LOCAL IMMEDIATE HYPERSENSITIVITY
Allergic reactions
Atopic allergy
Diseases:
o
Bronchial asthma
o
Angioedema
o
Allergic rhinitis
o
Urticarial/ pruritus
o
Inhaled or ingested
Preformed mediators/ Primary mediators:
Found in initial response1. Biogenic amines (eg. Histamine)2. Enzymes (eg. Neutral proteases, acid hydrolases)3. Proteoglycans (eg. Heparin, chondroitin sulfate)
Lipid mediators/ Secondary mediators:
1. Lipids mediators1. Syn in mast cell membrane2. Activates phospholipase A23. Leukotrienes4. Prostoglandin D2 P5. Platelet activating factorLeukotrienes
o
C4 & D4
most potent (thanhistamine) vasoactive &spasmogenic agents
o
B4
chemotatic for neutrophils,eosinophils and monocytesProstaglandin D2
o
most abundant mediator fromcyclooxygenase pathway
o
intense bronchospasm
o
increased mucus secretionPlatelet Activating Factor
o
platelet aggregation
o
histamine release
o
bronchospasm
o
increased vascular permeability
o
vasodilation
o
Chemotactic for neutrophils andeosinophils2. Cytokines
Many are from mast cells
o
TNF, IL-1,4, chemokines
Different types of hypersensitivity
Disease Ag involved ManifestationsSLE Nuclear Ag Nephritis, skinlesion, arthritisPGN Strep. Cell wallAgNephritis
 
 Prepared by:
EGBII; 8-13-11
PAN(polyarthritisnodosa)Hep.B virusantigen insomeSystemicvasculitisReactivearthritisBacterial Ag Arthritis,vaasculitis,nephritisArthur reaction Various foreignproteinsCutaneousvasculitis
Antibody Mediated Hypersensitivity (TypeII)
Mediated by Abs directed toward Antigenson cell surfaces or extracellular matrix
(3) mechanisms
o
Opsonization & Phagocytosis
o
Complement and Fc mediatedInflammation
o
Antibody-Mediated CellularDysfunction
Cells opsonized by IgG Ab are recognizedby phagocyte Fc receptors
Phagocytosis and destruction of opsonziedcell follows
Activation of complement also occurs
Formation of membrane attack complex(MAC) C5b-C9
cell lysis
Classical, alternative, lectin pathways
1.OPSONIZATION & PHAGOCYTOSIS
Transfusion reaction (type A patienttransfused with type B blood)
Erythroblastosis fetalis(HDN)
o
Rh Ag of baby + anti-Rh ofmother
autoimmune hemolytic anemia
agranulocytosis
thrombocytopenia
drug reactionsAb Dependent cellular w/o phagocytosis
can occur by nonsensitized cells bearingFc receptors called ADCC or by naturalkiller cells
Ex. NK cells, IgG or IgE
2.COMPLEMENT & Fc RECEPTOR MEDIATEDINFLAMMATION
Abs deposit into fixed tissues, injuries isdue to inflammation
Complement is activated (C3a, C5a)
Fc receptor involvement
Ex.
o
Glomerulonephritis
o
Vascular rejection
3.ANTIBODY MEDIATED CELLULARDYSFUNCTION
Impairment/ dysregulate function
NO cell injury, NO inflammation
o
Compared to ADCC &opsonization
NO tissue damage
Only activate or block normal cellular orhormonal function
Example:
o
Myasthenia gravis
o
Pemphigus vulgaris
o
 
Grave’s disease
 *memorize each examples
Immune Complex MediatedHypersensitivity (Type III)
Mediated by Ag-Ab complexes
 –
immunecomplexes
Forming either in the circulation or at siteof Ag deposition
Enhanced by increased vascularpermeability resulting from inflammation
Cell activation by immune complex bindingto Fc/ C3b receptors
tissue damage by inflammation at the siteof deposition of the immune complex (IC)
Ag-Ab w/in circulation (circulating immunecomplex) deposited in vessel walls
o
Releases vasoactive mediators+ cytokines
Some at extravascular sites (in situ IC)
2 types of Ag:
o
exogenous
o
endogenous
2 types of type 3:
o
Generalized/ Systemic
o
Localized
SYSTEMIC/ GENERALIZED
Circulating IC that are systemicallydepositedEx:
GN
Vasculitis
Serum sickness
o
Results from recruitment orprolonged antigen exposure &ongoing IC deposition = there isthickening of intimal layer
LOCALIZED
Arthus reaction
o
Characterized by localized tissuevasculitis with necrosisIC & complement can be visualized by:
IMMUNOFLUORECENCE microscopy
o
Granular fluorescence
 –
 exogenous
o
Linear fluorescence
 –
 endogenous
Ie. Glomerularbasement membrane
Immune Complex MediatedHypersensitivity (Type IV)
Initiated specifically by sensitized T-lymphocytes
Initiated by antigen activated T-lymphocytes
o
DELAYED type
CD4+ T cells with fewCD8+
Only stimulateinflammation &activate phagocytosis
o
DIRECT cell toxicity
CD8+ T cells
Directly kill tissue cell
DELAYED type (CD4+)
 
 –
principal pattern to:
*Granulomatous diseases
o
*myocobacterium, fungi
o
TB skin test sensitivity
o
Transplant rejection/ allograftrejection
o
Contact dermatitis
Causing granuloma:
o
Macrophage activation
o
Inflammation
o
Tissue injury
CYTOTOXIC T-LYMPHOCYTE (CTL) mediated(CD8+)
 
 –
involved in:
Neoplastic cell lysis
Transplant rejection/ allograft
Virus infected cells (hepatitis)
Type 1 DM
CTL
 –
mediated by perforin-granzyme &Fas-FasL pathways including apoptosis*Transplant rejection
 –
can be both delayed & direct
Autoimmune Diseases
Immune reactions against self-Ags
 
3 requirements:
1. presence of autoimmune reaction2. reaction is not secondary to tissuedamage3. Absence of another well definedcause of dse.
From tissue injury caused by T cells or Absreacting to self-Ags
types: >organ specific>generalized or systemic
TOLERANCE
 –
 lackof reaction to selfantigens
AUTOIMMUNE DSE.
 –
 lossof selftolerance
IMMUNOLOGICAL TOLERANCE
o
Phenomenon ofunresponsiveness to an antigenas a result to exposure oflymphocytes to that antigen
SELF TOLERANCE
 –
unresponsiveness
to an individual’s own antigen and can be:
 
o
CENTRA tolerance
o
PERIPHERAL tolerance
CENTRAL TOLERANCE
death of self reactive T & B lymphocyteclones during their maturation in lymphoidorgans (in thymus & BM)
THYMUS
o
Immature T cells w/TCRsencounters by Ag and die byapoptosis by:
o
Negative selection or deletionAIRE (autoimmune regulator)
o
Required for the development ofT cell tolerance
o
Stimulates expression of some
“peripheral tissue restricted”
antigen
o
Is critical for deletion ofimmature T cells specific for theantigens
o
Mutation in this gene
 –
leads toautoimmune polyendocrinopathy
BONE MARROW
o
B cells receptor editing
 –
rendersB cell NOT to be specific for selfantigen
o
Apoptosis
 –
happens if receptorediting does not occur
Many self reactive T/B cell escape this.

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