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SECTION B UERMMMC Class 2014
Dr. Joselli c. Rueda-cu July 26- 28, 2011
PATHOLOG
Immunopathology 1
Pathology 1 | 10
The Immune systemo Vital for survival that protects us from the environment
filled with deadly microbes and infectious pathogens Immunopathologic States
o Immunodeficiency Renders and individual an easy prey of infections and
tumourso Hyperactive
May cause fatal disease, as in the case of anoverwhelming allergic reaction
Hypersensitivity diseaseso Autoimmune
Immune reaction against self Immune system loses its normal capacity to
distinguish self from non-self
Fig 1. Innate and Adaptive Immunity
A. Innate (Natural/Native) Immunity First line of defense
Recognizes microbes, protection against infections
Present before infection Components:
a. Epithelial BarriersMechanical barriers against entry of microbes
from external environment Produce anti-microbial molecule such as
defensins and lymphocytes
b. Phagocytic CellsMostly neutrophils and macrophagesOne of two cellular reactions of innate immunity
that causes inflammationIf absent, a persons immune system is
congenitally impaired
c. Dendritic Cells Produce type I interferons which inhibit viral
infection and replicationOne of two important cellular reactions of innateimmunity as anti-viral defensetogether with NKcells
d. Natural Killer Cells Protect against viruses and intracellular bacteria
e. Plasma ProteinsComplement system proteins Lysis
f. Lung Surfactant Lowers surface tension of the lungsComponent of innate immunity Provides protection against inhaled microbes.
B. Adaptive (Acquired/Specific) Immunity Stimulated by antigens/ microbes
Antigens (Ag) Foreign bodies accessed by theimmune system as substance to be destroyed.
B lymphocytes Most responsible for destruction ofthe antigen by maturing to a plasma cell thenreleasing antibodies
Recognition of microbial and non-microbial substances Develops after exposure to microbes More powerful than innate immunity in combating
infections
Component ofboth Innate and Adaptive Immunityo Cause cell lysis
o In Innate Immunity: It is activated by binding to microbes
Uses Alternate and Lectin pathways
Mannose-binding Lectin and C-reactiveproteinCoat microbes for phagocytosis and
complement activationC reactive protein indication of an
inflammatory processo In Adaptive Immunity:
Activated by binding to antibodies using Classicalpathways
Thymus derived cellular immune response 60-70% of lymphocytes Anatomic residence:
a. Thymusb. Found in paracortical areas of lymph nodesc. Periarteriolar sheaths of the spleen
Contain T-cell receptors which bind Major HistocompatibilityComplex (MHC) molecules on the surface of Antigen-presenting cells
The Complement System
T-Lymphocytes
Cell and Tissues of the Immune System
Mechanisms of Protection
General Features of the Immune SystemTHE IMMUNE SYSTEM
I. The Immune Systema. General Featuresb. Mechanisms of Protection
c. Cellular Componentsd. Categories of the Immune
Systeme. MHC Molecules
II. Hypersensitivity Reactionsa. Type Ib. Type IIc. Type IIId. Type IV
III. Transplant Rejections
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Subsets:1. Cytotoxic T cells
70% to 80% of circulating blood lymphocytes Majority of the T-lymphocytes Express CD8+ surface receptors Destroy infected and tumour cells
2. Helper T cells Help/ facilitate in microbial destruction
Express CD4+ surface receptors Contain T-cell receptors (TCRs) which:
Are polymorphic antigen-binding molecules Bind antigens associated with MHC on other
cells Analogous to surface immunoglobulins (Ig) of B
cellsCan rearrange their genes to respond to
antigenic stimuli
3. Suppressor T cells Express pan T-markers (pan- means everything/ a lot)
including CD2, CD3 and CD5
Note:CD3are invariant molecules (meaning, its identical in all T
cells) which bind to the TCR forming the TCR complex Signaltransduction pathways in T cells once antigen is presented inthese complexes T cell responses.
TCRsare Polymorphic Ag-binding molecules, analogous tosurface Ig that binds Ag associated with MHC on other cells.
Bone marrow derived humoral immune response 10-20% of lymphocytes Anatomic residence:
a. Bone marrowb. Bloodc. Cortex of lymph nodes and germinal centersd. Splenic white pulpe. Lymphoid follicles
Responses to protein antigens require help from CD4+ T cells Engages CD40, necessary for B cell maturation andsecretion of IgG, IgA and IgE antibody
CD40 Member of the Tumor Necrotic Factor (TNF)-receptorfamily and by cytokines activated helper T lymphocytesexpress CD40 ligand, which specifically binds to CD40expressed on B cells
B cells express several molecules on their surface (just likeTCRs in T cells) responsible for response activation (ex.CD40, Fc receptors, CD21 etc.)o CD4+ T cells engage CD40, a member of the TNF
receptor familyo CD40 is necessary for B cell maturation and the secretion
of IgA, IgE and IgG antibodieso
Activated helper T lymphocytes express the CD40 ligand(CD40L), which specifically binds to CD40 expressed on Bcells.
o Mutations in the gene encoding CD40 ligands may resultto X-linked hyper-IgM syndrome No IgG production
o The 3 types of mutation in CD40 ligands areTranslocation, Amplification and Point Mutation. (TAP)
Note:Ig and Ig are 2 invariant proteins of B cell antigen
receptor complex (much like CD3 of T cells) needed for signaltransduction pathwaysB cell responses.
Fc receptors are proteins found on the surface of cells thatcontribute to the protective functions of the immune system.
Second line of defense Seen in cellular immune response They can serve as APCs and they can be Activated Activated Macrophages
o Express MHC class II receptoro Cytokine activation of CD4+ cells enhances microbicidal
properties of macrophages and augments their ability to
kill tumor cells Antigen Presenting Cell
o Induction of cell mediated immune response Process the antigens in phagocytosed microbes and
present peptide fragments to T cells T-cells become more sensitive to the bacteria that the
macrophage caries T-cells then produce cytokines that enable
macrophages to destroy the bacteria In Effector phase of humoral immunity
o They phagocytose microbes opsonised (Making microbesmore palatable/ edible by macrophage) by IgG or C3b
MLE Q: Only cytokines are involved, no antibodies
Note:According to Dr. Cu Macrophage (when presentingantigens to T cells) tells T-Lymphocytes Im carryingsomething I cannot destroy, will you help me?
Fig 2. The role of dendritic cells in capturing microbial antigens from epithelia and
transporting them to regional lymph nodes. Immature DC (ex. Langerhans cell inepithelia) respond to microbes and are activated Migrate to lymph nodes vialymphatic vessels DC recruited to T- cell zones of lymphoid organs to function asAPCs to T cells. Please refer to Fig. 6-10 p. 194 of Robbins for a clearer image.
Resident phagocytes Found under the lining epithelium which is the most common
entry site of antigens 10-20% of circulating peripheral lymphocytes Most important antigen presenting cells for initiating primary
immune response against protein antigens
Location: (MLE Q)o Under epithelia, the most common entry site of antigens
and interstitial of all tissues where Ag maybe produced
Dendritic Cells
Macrophages
B-Lymphocytes
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Types:1. Interdigitating dendritic cells/ simply dendritic cells
Most important antigen presenting cells for initiatingprimary IR against protein antigens
2. Langerhans cells Immature dendritic cells within the epidermis.
3. Follicular dendritic cells Germinal centers of lymphoid follicles in spleen and
LN Bears Fc receptors for IgG and C3b Trap antigen bound to antibody (Ab) or complement
proteins Improving quality of humoral immuneresponse Play a role in the pathogenesis of
AIDS
Note:Two major types according to Robbins namely interdigitating
and follicular
10-15% of peripheral lymphocytes Kill variety of tumor cells, virally infected cells, some normal
cells without previous sensitization Do not bear T-cell receptors, surface Ig nor the traditional T
or B markers Nucleus is not segmented Morphologic name: Large granular lymphocytes Histological appearance: Huge lymphocytes Has two receptors: Inhibitory receptor and activating
receptor Cancer patients take interferon for the possibility that NK cells
will destroy the foreign bodies. Cytokines IL-2, IL-15 and IL-12 regulate NK cells activity
o IL-2 and IL-15 Proliferation of NK cellso IL-12 Activates killing and secretion of IFN-
MLE Q: Killing dependent on cell to cell contact enhanced byinterferon and IL-12
MLE Q: Antibody Dependent Cell mediated Cytotoxicity(ADCC):
Ability to lyse IgG coated target cells due to CD16 cellsurface molecules secrete cytokines such as IFN-
MLE Q: What receptor enhances NK cell killing? Answer: CD16
Note:CD16 is an Fc receptor of NK cells for IgG. It confers the
ability on NK cells to lyse IgG-coated target cell. This reaction iscalled ADCC.
NK cells are early line of defense because of the ability to killa variety of infected and tumor cells. It activates macrophages bysecreting IFN- which provides an early defense againstintracellular microbes.
Activation of B lymphocytes and elimination ofextracellular microbes
B-cell lymphocyte mediated via production of antibody
MLE Q:Often develops as a response to soluble antigens B cells account for about 20% of circulating lymphocytes Immunoglobulin gene rearrangements allow tremendous
diversity of responses to many antigens. Protects against extracellular microbes and toxins Can mutate/change in genetic coding to have different
responses
Fig 3. Immunoglobulin molecule. Note that there are two heavy (H) chains andtwo light (L) chains linked by disulfide bonds. Each heavy and light chain has aconstant (C) and a variable (V) region. It is the variable regions in the Fab portiothat react with a specific antigen and give rise to the diversity of immunologicresponse. Immunoglobulin can attach via the Fc portion to a variety of cells with Freceptors.
Steps in Humoral Immunity1. Naive IgM and IgD B cell binds microbe2. Helper T cells help B cells via:
a. CD40 on B cells recognize CD40L of T cellsb. IL-4 (secreted by TH2 helper cells) lead to matured B
cells/ plasma cells IgE productionc. TH1 helper cells stimulated IgG Ab production
3. Class switching and affinity maturation occurs mainly ingerminal centers
4. Antibody secretion by plasma cells Abs b ind to microbes neutralizing them, preventing
them from infecting cells. IgG act as opsonins
Activation of T lymphocytes and elimination ofintracellular microbes
Mediated by T lymphocytes T-cell receptors (TCR)
o Genetically programmed to recognize specific antigenso Can rearrange their alpha and beta genes to respond to
antigenic stimuli Macrophages process the antigen and present it with class II
Human Leukocyte Antigen (HLA) to the CD4+ cells
Cytokines such as interleukin (IL) and tumor necrosis factor(TNF) are elaborated by activated T cells to enhance cellularimmune reactions
A. CD4+ helper lymphocytes Help B cells make antibody (therefore B cells are not
exclusively for humoral immunity) Help generate cytotoxic T cells Macrophages process antigen and present it with class II
HLA to the CD4+ cells Participate in delayed hypersensitivity reactions (TYPE IV) 60% of peripheral T lymphocytes Secrete and respond to growth factorIL-2 cytokine
Proliferation and increase in number of CD4+ T cells
II. Cell-Mediated Immunity
I. Humoral ImmunityTwo Broad Categories of the Immune System
Natural Killer Cells
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Table 1. Characteristics of the different CD4+ Subsets
CD4+Subsets
TH1 TH2TH17
(Recentlydiscovered)
Cytokinesecreted
IFN-- potentmacrophage
activator
IL-4Stimulate B
cells todifferentiateinto IgE-
secretingplasma cells
IL-5Activateseosinophils
IL-13Mucussecretion
IL-17- play arole inseveral
inflammatory
diseases
Induced by IFN- and IL-12 IL-4TGF-, IL-1
etc
Function
Macrophageactivation
IgGproduction
IgE
production
Mast cell
andeosinophilactivation
Recruitmentof
neutrophilsandmonocytes
Hostdefenseagainst
Intracellularmicrobes
Helminthicparasites,allergens
Extracellularbacteria and
fungi
Role indisease
Immune-mediated
chronicinflammatory
diseases (often
autoimmune)
Allergies
Immune-mediated
chronicinflammatory
diseases
(oftenautoimmune)
B. CD8+ suppressor lymphocytes Cytotoxic (mostly occur during cell-cell contact) 30% of circulating T lymphocytes Destroy infected and tumour cells
Physiologic function: To display peptide fragments of proteinsfor recognition by antigen-specific cells.
Play key roles in regulating T cell-mediated IR
MLE Q: MHC or human leukocyte antigen (HLA) complex is onchromosome 6
Two Classes of MHCs1. Class I Antigens: A, B and C
Present on all nucleated cells and platelets (thereforeis not seen in RBCs) Only class A and B are important in blood typing Encoded in loci/ regions HLA A, B and C Tested for and detected by serologic means "C" antigens unimportant A number of alleles are present and each person
inherits one from each parent Thus, a person might be HLA typed as:
a. A 5, 10b. B 11, 41
2. Class II MHC Molecules: In the D region (DR) Narrowly distributed Mostly on mononuclear inflammatory cells
(macrophages, B cells and dendritic cells) Help induce CD4+ cells Encoded in loci/region: HLA D (3 subregions: DP, DQ
and DR) Recognized by CD4+ T lymphocytes
Detected by mixed lymphocyte assay
Importance of HLA Transplantation Regulation of some immune responses
Virus-infected cells with class I antigen are lysed byCD8+ cells that can recognize the virus-cell complex
MLE Q: Class II antigens help induce CD4+ cells Its association with a variety of diseases
Inheriting HLA-B27 90% of developing ankylosingspondylitis and several postinfectiousarthropaties
HLA-DR 2, -DR3 andDR4 with autoimmune diseases
Notes: HLA system is highly polymorphic Meaning there are
many alleles of each MHC gene in the population. Eachindividual inherits one set of these alleles, which is differenfrom the alleles of other individuals. This is why there is abarrier in organ transplantation.
No 2 individuals (other than identical twins) are likely toexpress the same MHC molecules and therefore graftsexchange between these individuals are recognized asforeign and attacked by the immune system.
An individualinheriting a specific MHC molecule has itsown consequences/ advantages.Ex. Inheriting MHC Class II specific for Ragweed pollenwould be genetically prone to pollen allergies. In contrastinheriting MHC Class II for bacterial antigens provideresistance to infection by evoking a protective antibodyresponse.
Major Histocompatibility Complex (MHC) Molecules
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Table 2. Mechanisms of Immunologically Mediated Diseases
TypePrototypeDisorder
ImmuneMechanisms
PathologicLesions
Immediate(type I)
hypersensitivity
Anaphylaxis;allergies;bronchial
asthma (atopicforms)
Production of IgEantibody
Immediate release ofvasoactive amines
and other mediators
from mast cells Recruitment of
inflammatory cells(late-phase reaction)
Vasculardilation,edema,
smooth muscle
contraction,mucusproduction,
inflammation
Antibody-mediated(type II)
hypersensitivity
Autoimmunehemolytic
anemia; Goodpasture
syndrome
Production of IgG,IgM Binds to
antigen on target cellor tissue
Phagocytosis or lysisof target cell by
activatedcomplement or Fc
receptors;Recruitment of
leukocytes
Cell lysis;inflammation
Immunecomplex-mediated(type III)
hypersensitivity
Systemic lupuserythematosus;some forms of
glomerulonephritis; serum
sickness; Arthusreaction
Deposition ofantigen-antibody
complexes
Complementactivation
Recruitment ofleukocytes bycomplement
products and Fcreceptors Release
of enzymes andother toxicmolecules
Necrotizingvasculitis(fibrinoidnecrosis);
inflammation
Cell-mediated(type IV)
hypersensitivity
Contactdermatitis;
multiplesclerosis; type I,
diabetes;transplantrejection;
tuberculosis
Activated Tlymphocytes
i. Release ofcytokines andmacrophageactivation
ii. T cell-mediatedcytotoxicity
Perivascularcellular
infiltrates;edema; celldestruction;granulomaformation
Occurs within minutes after an antigen combines with anantibody (IgE) bound to mast cells in previously sensitizedindividuals
Anaphylaxiso Occurs in individuals with prior sensitizationo Promotes mast cell proliferation and IgE production of
plasma cellso IgE and mast cells bind in places such as the respiratory
tract mucosao Most threatening if person has it in the respiratory tract
because patient can die due to asphyxia. It can causevasodilation and bronchoconstriction which decreases
effective blood circulation and may lead to shock
Mast cells Found near blood vessels and nerves Almost same with Basophils, except that it does not roam
around the circulation Contains granules:
1. Preformed and Stored in Cytoplasm (1 mediators)a. Vasoactive amines Histamine and serotonin
(vasodilation and bronchoconstriction)b. Enzymes Cause tissue damage and kinin
productionc. Proteoglycans Heparin
2. Lipid Mediators - de novosynthesis and release (2mediators)a. Leukotrienesb. Prostaglandinc. Platelet-activating factord. Bradykinins
Steps:1. 1
stexposure: Allergen binds to antibody
2. TH2 cells secrete IL-4
Stimulate IgE production3. IgEs Fc portion binds to mast cells4. 2
ndexposure: Allergen binds to IgEs Fab portion (This
same IgE is the one bounded to a mast cell due to 1st
exposure to allergen)5. Bridging of Fc receptorsMast cell degranulation
(Release of histamine and serotonin, leukotrienes,prostaglandin and bradykinin)
Fig 4. TYPE I hypersensitivity
Remember: 1
stexposure to antigen produces IgE but NO degranulation
of mast cell 2
nd/re-exposure: Bridging of IgE to mast cell with antigen
Degranulation Inflammatory cell infiltrates
Immediate Reaction (In minutes) Vasodilation, vascular leakage, smooth muscle spasm and
glandular secretions
Late Phase Reaction (2-24 hours)
Leukocyte infiltration, epithelial damage, bronchospasms In late phase reaction, eosinophils are particularly importan
1. Systemic Characterized by vascular shock, widespread edema
and difficulty in breathing Cx: Itching, hives skin erythema, laryngeal edema,
vomiting, abdominal cramps, diarrhea, laryngealobstruction. Patient may go into shock and die in anhour
Ex. Drug allergies (anaphylaxis), Food allergies(peanuts), Asthma, Insect toxins (bee sting), hay fever
Fig 5. Acute laryngeal edema due to anaphylactic reaction to penicillin. A formof Type I hypersensitivity reaction where preformed IgE antibody on mast cellsquickly reacts with antigen. Mast cells release histamine and other mediatorsleading to edema.
Types of AnaphylaxisType I (Immediate) Hypersensitivity
HYPERSENSITIVITY REACTIONS
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2. Local (Atopy) Affects 10% of people Allergens include: Pollen, animal fur, dust, food etc. Easily sensitized to allergens that cause a localized
cutaneous swelling when inhaled or ingested Specific diseases include: Urticaria (hives),
angioedema, allergic rhinitis (hay fever), bronchialasthma, skin allergy, conjunctivitis and food allergies.
Fig 6. Hay Fever. A form of localized anaphylaxis with Type I hypersensitivity whereallergens in plant pollens contact IgE bound to mast cells then causing the releaseof granules containing mediators such as histamine that promote vasodilation andedema. Beneath the nasal mucosa at the left, eosinophils have been attracted. Theplasma cells seen here have collected due to the chronic nature of the antigenicstimulation.
Caused by antibodies that react with antigens present oncell surfaces or in the extracellular matrix or altered cellsurface antigens
Complement dependent reactions: Antibody directed againstantigen on cells (circulating red blood cells) or extracellularmaterials (basement membrane).
Resulting Ag-Ab complexes activate complement (via theclassic pathway) causing cell lysis and extracellular tissuedamage.
Fig 7. In the above diagram, a red blood cell has antigen fixed on its surface towhich antibody attaches. The attached antibody sets off the complement cascade,which ends with the formation of the "membrane attack complex" of C5-9 whichcauses lysis of the cell. Other complement components may be generated, such asthe opsonin C3b.
1. Phagocytosis and Opsonization Examples:
a. Transfusion reactionswherein incompatible redblood cells (RBCs) or serum is transfused
b. Autoimmune hemolytic anemiain which antibodiesare made against ones own RBCs
c. In erythroblastosis fetalis, there is an antigenicdifference between the mother and the fetus Whenmaternal IgG crosses the placenta, it destroysfetal RBCs
2. Inflammation Abs are deposited to fixed tissues (bas ement
membrane and extracellular matrix) Activatecomplement system Formation of the membraneattack complex which disrupts membrane integrity
Examples:Good Pasteurs syndrome Ab targets kidney
glomerular basement membrane/ GBM.
Immunofloresces of GBM show a linear patternbecause GBM becomes antigenic Lineardeposition of cells.
3. Cellular Dysfunction/ Stimulation In some cases, antibodies directed against cell surface
receptors impair or dysregulate function without causingcell injury or inflammation.
Examples:a. Dysfunction: In myasthenia gravis, there are
acetylcholine receptor antibodies in the motor endplates of skeletal muscles which blockneuromuscular transmission and diminishmuscular response Muscle weakness. Ach hasno receptor to bind to since the receptors areoccupied by Ab thus no contraction occurs.Manifestations:
1st: Ptosis (bilateral)2
nd: Difficulty in breathing
b. Stimulation: In Graves disease, antibodiesagainst the thyroid-stimulating hormone receptorantibodies on thyroid epithelial cells stimulate thecells, leading to hyperthyroidism
c. Dysfunction: In pernicious anemia, anti-parietalcell antibodies are present Decreasedabsorption of Vit. B12.
Antibody-mediated cell destruction may also occur via ADCC
o Low concentrations of IgG or IgE (in the case of parasites)Coat target cells Inflammatory cells such as NK (naturakiller) cells, monocytes, and granulocytes bind to theimmunoglobulin Fc receptors Lyse, but DO NOTphagocytize, the target cells
Fig 8.A macrophage with Fc receptors on its surface is able to recognize a targecell coated with antibody via the Fc receptor portion of the attached antibody. Themacrophage can then demolish the targeted cell by elaboration of proteases(Macrophage releasing proteases) tissue necrosis; inflammation
Examples of ADCCa. Transplant rejectionb. Immune reactions against neoplasmsc. Immune reactions against parasites
Antireceptor antibodies: IgG antibody is directed againstreceptors in target cells, resulting in complement-mediateddestruction of the receptors.
Antibody-Dependent Cell-mediated Cytotoxicity
(ADCC)
Mechanisms of Type II Hypersensitivity
Type II (Antibody-Mediated) Hypersensitivity
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Fig 9. In the diagram, antibody is directed against acetylcholine receptors at themotor end plate of a muscle, blocking the receptors and diminishing the muscularresponse. This is the mechanism for muscle weakness in myasthenia gravis.
Diseases caused by this mechanism include: Myasthenia gravis: Ach receptor antibody. Grave's disease (thyrotoxicosis): Anti-TSH receptor antibody Pernicious anemia: Anti-parietal cell antibody.
Mediated by immune (Ag-Ab) complexes (IC) which
promote tissue damage primarily through complementactivation (alternate pathway)oC3b, as an opsonin, attracts neutrophils, which then
release lysosomal enzymes.oC5a as a chemoattractantbrings in neutrophils.o Serum complement is reduced as it is used up in this
process.
Fig. 10.Antibody-Antigen complex promotion
Antigen-antibody complexes are circulating and becomingtrapped beneath the basement membrane of a small bloodvessel, setting off the complement cascade and generatingcomponents that attract PMN's to generate an ongoinginflammatory response (Figure above).
In this type of hypersensitivity reaction, there is a markelement of VASCULITIS.
Immune complexes can be deposited systemically orlocally(deposited nearBasement membranes)
Pathogenesis ofSystemic Immune Complex Disease
1. Ag-Ab complexesform in the circulatory system Protein/ Ag is introduced leading to formation of Abs
in blood
2. Deposition of Immune Complexes in various tissues Larger immune complexes are quickly phagocytized
by macrophages and removed. The larger they are,they are more easily recognized and phagocytized.
The smaller to intermediate complexes formedwithin antigen excess may escape removal. They arethe most pathogenic and are not recognized hencethey are opsonized. These complexes are depositedto organs w/c filter at high pressure. (Glomeruli, Jointsand BV)
This may lead to:Glomerulonephritis Serum sickness Vasculitis
3. Initiating Inflammation caused by deposition of IC Because small ICs are opsonised, they trigger
complement system The resultant inflammatory lesions are the ff:
Glomerulonephritis Red/white cell becomesimmunogenic to own system, circulate anddeposited in glomerular capillaries
Vasculitis Deposited in and around small bloodvessel inciting an inflammatory reaction
Arthritis In joints
Note:A single large exposure to antigen/ Ag excess in circulation
leads to Acute Serum Sickness.Repeated or prolonged exposure Chronic form of Serum
Sickness ex. Systemic Lupus Erythematosus (SLE).
Local immune complex disease: "Arthus" reaction
oArthus reaction Localized area of tissue necrosis fromacute IC vasculitis.
o Local injection of the antigen Immune complexformation Acute inflammatory hemorrhagic reaction andlocal dermal vasculitis.
o Role in the development ofhypersensitivity pneumonitis("farmer's lung")Small complexes are deposited in thebasement membrane of alveolar wall
No anti-body formation Sensitization of T-lymphocyte CD4 containing leukocytes The lymphocyte with then secrete cytokines to act on the
macrophage
Delayed Mediated by sensitized CD4+ T lymphocytes,which process antigens in association with class II HLAmolecules and release lymphokines
The lymphokines promote a reaction (especially mediatedthrough macrophages) beginning in hours but reaching apeak in 2 to 3 days.
Hypersensitivity reactions with this mode of action include:oGranulomatous diseases (MycobacteriaTuberculosis,
fungi)
Fig 11. Sequence of events in granuloma formation in response to Mycobacteriumtuberculosis (MTB). The key cell in the process is the epithelioid macrophage.
CD4+ Lymphocyte-Mediated Responses
Local Immune Complex Disease
Systemic Immune Complex Disease
Type IV (Delayed) Hypersensitivity
Type III (Immune Complex-Mediated)
Hypersensitivity
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MLE Q: What produces caseation in TB?Answer: Its the Immune Response, NOT the organism
MLE Q: What is the hallmark of granuloma formation?Answer: Activation of macrophage Epitheloid cell
formation
oTuberculin skin reactionsProduced by intracutaneousinjection of protein tuberculin from Bacillus in previouslysensitized patient Accumulation of CD4+ T cells andmacrophages around venules (perivascular cuffing)
MLE Q: Would HIV in chronic stage have caseousnecrosis?
Answer: NO, because no epitheloid formation thatcould destroy the organism.
o Transplant rejectiono Contact dermatitis Pre-sensitized lymphocytes led to
this inflammatory reaction a couple of days after contactwith the offending agent (poison oak, poison ivy)
CD8+ T cells generated Lyse specific cells Role of Class I HLA molecules: CTL bind MHC I Ag of cells,
kill them, enacting cell mediated immune response Reactions with this mode:
o Neoplastic cell lysiso Transplant rejectiono Virus-infected cell lysiso Viral Hepatitis
Note:Difference of Type 4 vs. Type 3
Greater phagocytosis, no deposition in basementmembrane, no Ig participation
Rejection of graft or donor organ Graft versus Host (GVH) disease Graft accepted but is
manifesting symptoms, host reacting to transplanted organ
A. HLA systemis a key factor. Reactions mediated by either T lymphocytes (cellular) or
Ab (humoral) Major types of hypersensitivity reactions involved: II & IV
B. The ABO system: Best characterized as the major blood group antigens Expressed on all cells except in the CNS Thus, matching for ABO compatibility is important for
transplantation.
C. T-cell mediated reactions: CD4+ cellsgenerating delayed hypersensitivity reactions
after recognizing foreign HLA class II (DR) antigens(seenin mononuclear cells)
Cytotoxic CD8+ cellsrecognizing foreign HLA class I(A,B, or C) antigens (in all nucleated cells). The donortissue or donor lymphocytes within the transplanted tissuecarry the offending HLA antigens. Involves suppressorreactions.
Note:According to Robbins, T-cell mediated rejection has 2
pathways, Indirect and Direct. Direct pathways involve bothCD4+ and CD8+ recognizing the donors APCs. Indirecpathways involve only CD4+ (type IV hypersensitivity) respondingto recipients own APCs presenting donors antigen.
D. Antibody mediated reactions: Mediated through:
Complement-mediated cytotoxicity Antibody-dependent cytotoxicity (ADCC) Immune complexesCan also be termed rejection vasculitis, because the
1st
target of the antibodies seems to be the graftvasculature
Note:According to Dr. Cu, there is no granuloma in HIV because
HIV kills CD4+ responsible for granuloma formation.
3 Classic modes of rejection
1. Hyper-acute rejection: Occurs within minutes or hours after transplantation Kidney becomes cyanotic, mottled, flaccid and may
excrete blood in urine (needed: erythropoietin tests) Ig and complement deposited in vessel wall Thrombi
endothelial injury and accumulation of neutrophils thesite May lead to kidney infarction
Preformed antibodycauses immediate (minutes tohours) vascular injury via ADCC
Due to previous sensitization through transfusion,pregnancy, or infections (through HLA cross-reactingbacterial or viral antigens)
2. Acute rejection Both cell mediated and humoralimmunity involvement Acute Cellular rejection:
Occurrence sometimes within days, usually withinmonths, even sometimes years later whenimmunosuppressive therapy is discontinued.
Cellular infiltrates with both CD4+ and CD8+ cells.Primarily T cell mediated cytotoxic damage There is tubular damage and vascular injury due to
CD8+Density of the infiltrateand extent of parenchymal
damagedetermine severity (more inflammatoryreaction, more tissue destruction due to dissolutionof immune complex)
Acute Vascular (or Humoral) Rejection (rejectionvasculitis)Rejection primarily at the vasculature of the graft
because of anti-donor antibodies 3 general stages:
1. Early: Subendothelial inflammation andhypertrophy of endothelium
2. Intermediate: moderate intimal proliferationwith more significant wall inflammation
3. Severe: Significant fibrinoid necrosis(indicator of immune damage) and intimalproliferation.
CD8+ Lymphocyte (CTL)-Mediated Responses
Renal TransplantOrgan System Pathology
Immunologic Mechanisms
Two Important Pathologies in Transplant Rejection
TRANSPLANT REJECTIONS
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Fig 12. This is an Acute renal transplant rejection known as acute cellulartubulointerstitial rejection because most of the inflammation is in the interstitium.The glomerulus seen here is normal, but the tubules are infiltrated by manylymphocytes at the upper right (coagulative necrosis). Organ is still discernible.
Fig 13.At high magnification, the lymphocytes and plasma cells are seen around arenal tubule in a renal transplant patient with acute cellular rejection. This type ofrejection can occur at any time following transplantation when immunosuppressionis diminished. This is treated by administering cyclosporine and otherimmunosuppressive agents.
3. Chronic rejection (Chronic transplant Glomerulopathy) More tissue fibrosis/ scar formation Scar formation Vessel obliteration Chronic rejection Renal failure Increase serum
creatinine Tubular atrophy and shrinkage of renal parenchyma Intimal fibrosis with vascular thickening Renal
ischemia Mononuclear infiltrates with prominent plasma cells and
eosinophils Both T-cell and humoral mechanisms leads to
increasingintimal fibrosis and ischemia Obliterates vessels, almost no blood supply to
surrounding structures Hallmark of chronic rejection is increased fibrosis
Fig 14. Immunologic disease can also complicate solid organ transplantation. Hereis a renal biopsy that demonstrates marked interstitial fibrosis in a patient withchronic vascular rejection.
Fig 15. Chronic vascular rejection at high magnification: thickened and fibrotic renaarteries; obliterated lumen. There is interstitial fibrosis and chronic inflammationSuch chronic rejection usually occurs slowly over several months to years followingtransplantation. This form of rejection, unlike acute cellular rejection, is difficult totreat.
Graft vs. Host Disease
An immune reaction of the host against a graft(e.g. organ) 2 phases
1. Acute: Cell necrosis of skin and GI tract, cholestasis2. Chronic: Over 100 days post transplant
Dermal fibrosis, desquamative esophagitis, portal
tract fibrosis Cholestasis 3 organs prominently involved:
a. Liver (cholestasis)b. Intestinec. Skin (apoptosis of squamous epithelium and thickening
of subepidermal region with increased hyalinization) In BM transplant, GvH is the greatest problem, however, in
case ofbone marrow malignancy transplant, graft vs. tumoreffect is therapeutic
Recall difference of necrosis and apoptosis( Board examquestion)
Fig 16. Liver cholestasis. Seen above are large collections of yellow-green bilepigment within the bile canaliculli
Fig 17. Thickness of subepithelial region; hyalinization of skin. Besides theicterus (yellow color, or jaundice) in this skin there is a fine scaling rash in thispatient following bone marrow transplantation with a 5 out of 6 antigen match. Thisis an example of graft versus host disease (GVHD) where donor lymphocytes attackhost tissues.
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SECTION B UERMMMC Class 2014 Pathology 10 | 10
Fig 18. Apoptosis or single cell necrosis there is vacuolization and dissolution ofepidermal cells along the basal layer, along with lymphocytes. At the arrow is arounded pink apoptotic body.
HLA is less important than simple matching of organ size(since most of these are done in children).
Two modes of rejection:a. Acute rejection
Seen within two months Mixed inflammatory portal and central vein
infiltrates.b. Chronic rejection
Continued inflammation, portal fibrosis, arteriolarthickening, and bile ductular necrosis
Note:In heart liver and lungs, HLA matching is usually not even
done, because anatomic compatibility (ex. Size), severity ofunderlying illness and minimizing the time of organ storage havemuch more benefits over HLA matching.
HLA is less important than simple matching of organ size. Immunosuppressive therapy is carefully monitored in
relationship to signs of rejection on endomyocardial biopsy.
Two modes of rejection:oAcute cellular rejection:
Lymphocytic infiltrates
Possible myocardial fiber necrosis.oAcute vascular rejection:
Immunoglobulin deposition in small arteries Vasculitis.
Fig 19. This is acute vascular rejection in a myocardial transplant tissue. Theinflammatory reaction consists mostly of mononuclear infiltration (lymphocytes) andis seen mainly around small arteries, a vasculitis. Such a reaction can occur whenthe dose of immunosuppressive drugs is decreased in the months followingtransplantation. Increasing immunosuppressive therapy in these patients is not aseffective as for acute cellular rejection.
Fig 20. By immunoperoxidase staining with antibody to CD3, the T-lymphocytes ithe myocardium involved in this acute cellular rejection phenomenon in a heartransplant recipient can be identified here.
Two problems that are unique to bone marrow transplant areGraft versus host disease and immunodeficiency.
HLA matching important to minimize GvHD. (GVHD) Donor lymphocytes attack recipient tissues having
the offending HLA antigens. Chemotherapy agents used to prepare patient for marrow
transplantation may result in hepatic veno-occlusive diseasein the weeks following transplantation.
Robbins Pathologic Basis of Disease: Disease ofImmunity
2013B Trans: Immunopathology Dr. Cus Lecture
1. One of the two important cellular reactions of innateimmunity as anti-viral defense together with NK cells
2. This is necessary for B-cell maturation and secretion of IgA,IgG, and IgE
3. Most important antigen presenting cells
4. MHC Class II can be detected by _______5. In type I hypersensitivity, this causes mast cell
degranulation.6. What mechanism causes autoimmune hemolytic anemia in
type II Hypersensitivity7. TRUE/FALSE: In type III Hypersensitivity, deposition should
takes place first before formation of immune complexes.8. Would HIV in chronic stage cause caseous necrosis?9. What type of classic mode of rejection is where
fibrosis/scarring are predominantly seen?10. The 3 organs predominantly involved in GVHD are skin, liver
and ____.
ANSWERS TO QUESTIONS
REVIEW QUESTIONS
REFERENCES
Bone Marrow Transplant
Heart Transplant
Liver Transplant
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