immunopath

7/29/2019 immunopath

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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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SECTION B UERMMMC Class 2014 Pathology 2 | 10

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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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 ____.

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REFERENCES

Bone Marrow Transplant

Heart Transplant

Liver Transplant

immunopath

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