Immuno Pathology 222

7/29/2019 Immuno Pathology 222

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IMMUNOPATHOLOGY

NORMAL IMMUNE RESPONSE

OVERVIEW OF IMMUNE SYSTEM

Immunity is a state where an individual is protectedagainst a particular dx. Such individual is resistant todx cos of:

• formation of humoral antibodies or

• development of cellular immunity or

• development of both humoral and cellular

immunity or

• other mechanisms such as interferon activity inviral infection

Normally the immune system protects against agentsthat r foreign or non-self

However, abnormal situations may occur in:

• Immunodeficiency state: individual is susceptibleto infection and possibly tumor

• Hyperactive immune state /system: there‟s

overwhelming allergic rxn to a foreign substance.Such individual r said to be hypersensitive

• Autoimmunity: where in the immune system losesits ability to distinguish self from non-self against

individual tissue and cells.DIVISION OF IMMUNE SYSTEM:

• INNATE/ NATURAL/ NAÏVE/ NON-SPECIFICIMMUNE SYSTEM

• ADAPTIVE/ ACQUIRED/ SPECIFIC IMMUNESYSTEM

INNATE IMMUNITY:

First line of defense cos:

• the actions of its component do not depend on

prior sensitization to or priming by the antigen

present on their target cell (microbes or tumorcells) and

• They do not possess the fine antigen specificity that is characteristic of the adaptive or specificimmune responses. E.g. a macrophage can wet itsappetite by ingesting a wide variety of antigenically distinct bacteria or viruses at its 1st encounter.

It has 2 componentS:

• Humoral component: Complements whichinclude chemotactic subst, opsonins, MAC,…

• Cellular comp. : neutrophils, Macrophages,Natural Killer cells (NKCs)

The complement cascade

• Triggered directly by the invading organism

(alternate pathway) or by Antibodies(Abs) formeddirectly in the course of specific immune response

• The Complements in turn plays an impt. Role inmodulating role in regulating cellular immunity

Macrophages function as

• Phagocyte

• Antigen presenting cells(APC): impt role in

– triggering specific immune response mediatedby T- & B-lymphocytes

– Mediating cellular immunity

– Regulating fxn of Ab-producing B cells as wellas that of macrophages and NK cells

ADAPTIVE IMMUNITY:

There r 2 forms: Cellular and Humoral Immunity

• CELLULAR COMPONENTS: r T- & B-lymphocytes

– Display antigenic specificity: by means of antigen-specific receptor on their surface thatrecognize only 1___.

– Unprimed ones r extremely small in number

– Primed ones r large in number: whenchallenged with foreign antigen(Ag), theydivide and expand (clonal expansion; Takesfew days to weeks b4 the process is completed) to handle the offending organism

– Fights against intracellular microbes

• HUMORAL COMPONENT: are the

Immunoglobulins (Igs) produced by Plasma cells(differentiated B lymphocytes) that fights against

extracellular microbes and their toxins



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CELLS AND TISSUES OF THE IMMUNE SYSTEM

• LYMPHOCYTES

• MACROPHAGES

• NATURAL KILLER CELLS

• DENDRITIC CELLS

T- LYMPHOCYTES

ORIGIN: Derived from immature precursors in thethymus

ANATOMIC SITES of mature Naïve T cells:

• Blood: where they constitute 60-70% of

circulating lymphocytes

• T-cell zone in peripheral lymphoid organs such as

Paracortical regions of Lymph nodes andperiarteriolar zone of the spleen

– Reason for locating in these organs: these cellsexpress receptors for the chemo-attractants,cytokines (chemokines), that r produced onlyin these regions.

It Expresses Ag specific T-cell Receptor (TCR)

• αβ TCR in 95%, and ɣδ TCR in 5% of T cellpopulation

– αβ TCR = disulphide linked heterodimer of α & β polypeptide chain each having a variable(Ag binding) region and a constant region); ɣδ

TCR also = ɣ+δ polypeptide chain

heterodimer

• TCR Exhibits diversity that is generated by somatic

rearrangement of TCR GENES, that occurs duringdevelopment of the T-cells in the thymus, andserve as a (i) molecular marker of T-cell lineage

and (ii) a distinguisher of polyclonal (non-reactive/non-neoplastic) T-cell proliferations frommonoclonal (neoplastic) T-cell proliferations (i.e.analysis of antigen receptor gene rearrangements

is a valuable assay for molecular marking T-cell

lineage & detecting lymphoid tumors )

It also expresses a num. of non-polymorphic functionassociated molecules (a.k.a Accessory molecules/co-

receptors) in conjunction with the TCR, during T celldevelopment in the thymus. They include:

• CD2, CD3, CD4 (in Helper T Cells), CD8 (incytotoxic T cells), intergrins, and CD28. CD4 andCD8 r expressed in 2 mutually exclusive subsets of T cells: CD4 in ≈ 60% and CD8 in ≈ 30% of mature T cells (so, CD4:CD8 = 2:1)

Unlike B cells, it cannot be activated by soluble Ag.There4 APC must present processed form of the Ag to

the T cell in order to induce a cell-mediated immunity

• Thus, during d Ag presentation,

– αβ TCR binds to Ag presented by (thepolymorphic portion of) the MHC on thesurface of the APC; CD4 binds to d non-polymorphic portion of Class II MHC, whileCD8 binds to non-polymorphic portion of class

I MHC molecule on the APC,

– when the TCR recognizes d Ag, the CD4 OR CD8 co-receptor initiates signals that arenecessary for activation of the T cells.

– Thus, CD4 + helper T cells can recognize and

respond to Ags displayed only by MHC-II

molecules, whereas CD8 + cytotoxic T cells

recognize Ags displayed by MHC-I molecules

• Activated T cells then secrete cytokines (cytk).One of d cytk, IL-2, causes self-proliferation,generating large num. of the Ag specificlymphocyte (autocrine effect). Some of these cellsdifferentiate into:

– effector cells that perform the fxn of eliminating the Ag that started the response;

– Memory cells that r long-lived and r poised torespond rapidly to repeated encounter

– Supressor cells:

T-cells also Have 2 fxnally distinct population of CD4+ helper-T cell (HTC):

• HTC-I or TH1 cells: synthesizes and secrete IL-2and IFN-ɣ (but not IL-4 or IL-5); facilitates(i)delayed hypersensitivity, (ii) macrophage

activation and (iii) synthesis of opsonizing and

complement fixing Abs (such as IgG2A in mice) allof which r actions of IFN-ɣ

• HTC-II or TH2 cells produces IL-4, IL-5 and IL-13(but not IL-2 or IFN-ɣ); aids in synthesis of other

classes of Igs, notably IgE, (mediated by IL-4 & IL-13) and in the activation of eosinophils (mediatedby IL-5)

• CD8+ T CELLS: fxns as cytotoxic cells to kill othercells BUT similar to CD4+ T cells, they can secretecytk primarily IL-2 and INF-ɣ of HTC-I



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B LYMPHOCYTES

Develop from immature precursors in the bonemarrow

ANATOMICAL SITE:

Blood: Mature B cells are ≈10 – 20% of circulatinglymphocytes

Lymphoid tissue in: spleen, tonsils, extra-lymphaticorgans (like GIT), Lymph nodes (in superficial cortex),spleen (in white core). Here they r aggregated in the

form of lymphoid follicles (which on activationdevelop staining germinal centre) that occupy the Bcell zone of these organs

• Reason for locating in these organs: the B cellsexpress receptors for chemokines produced inthe follicle

They Express Ag specific B cell receptors (which r IgM and IgD) on the surface of all mature, naive B cells

• These receptors have a unique antigen

specificity, derived from somatic

rearrangements of Ig genes. Thus, as in T cells,

analysis of Ig gene rearrangements is useful for

molecular marking of B-lineages and

identifying monoclonal B-cell tumors

• After antigenic stimulation, B cells mature in

plasma cells that secrete Igs, mediators of humoral Immunity.

They Also expresses co-receptors, Igα & Igβ, aheterodimer of the 2 non-polymorphic proteins.

• Similar to CD3 proteins of TCR, Igα & Igβ donot bind but are essential for signal

transduction through the Ag receptor

Also expresses other non-polymorphic molecule essential for B cell fxn

:• (i) Complement receptors, (ii) Fc receptors &

(iii) CD40

• CD21 (OR complement receptor-2 – CR2) is areceptor for Epstein-Barr virus (EBV) & henceEBV readily infect B cells.

Are activated by Protein and non-protein Ags

• END result: differentiation into Ab-secreting

cells (plasma cells) which reside in lymphoidorgans and mucosal tissue; some migrate tobone marrow and live there 4 several yrs

• Secreted Abs enter mucosa and the blood andr able to neutralize and eliminate the Ags

Responses to protein Ags require help from CD4+ Tcells (HTCs)

• HTCs activate B cells by engaging CD40, amember of the TNF-receptor family and by

secreting cytokines

• This interaction is essential for B cell

maturation and secretion of IgG, IgA and IgEAbs. Ig secretions is mediated by cytk frm

HTCs

MACROPHAGES (Mphs)

Dominant cells in chronic inflammation

One of the components of mononuclear phagocytesystem (or RE system)

• RES consist of closely related cells of bone

marrow including blood monocytes and tissueMPhs

• Tissue Mphs r diffusely scatterd in C.T. orlocated in organs such as liver (Kupfer cells),spleen (sinus histiocytes), brain (micorglia),bone (osteoclast)

Derived from common precursors of in the bonemarrow that give rise to blood monocytes thatcirculate in blood for abt ½ a day b4 migrating toextravascular tissue to differentiate in Mphs, whose ½-life(or life-span) can be months/years.

• Extravasation of Monocytes,

– Occurs quite early during Acuteinflammation & in 48hrs, these cellsconstitute the predominant cell typein that tissue

– is governed by the same factors thatcause neutrophil emigration (i.e.

Adhesion molecules & chemicalmediators with chemotactic ndactivating properties

express an array of specific cell surface molecules thatare important for their host defense functions.

• MHC-II molecules,

• CD14 (a receptor that binds bacteriallipopolysaccharide and can trigger cellactivation),

• several types of Fc immunoglobulinreceptors,

• toll-like receptors,



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• adhesion molecules and

• a variety of cytokine receptors that participatein regulating monocyte/macrophage function

r ACTIVATED by various stimulants including cytkslike INF-ɣ secreted by sensitized T lymphocytes &NKCs, Bacterial toxins and other mediators

• END result:

– increase in cell size and level of lysosomal enz.

– more active metabolism

– greater ability to phagocytize and killingested microbes.

– Tissue injury & fibrosis (OR chronicinflammation) if activity of the

activated Mph is unchecked

DENDRITIC CELLS

R of 2 types, each with different functions and bothhaving dendritic cytoplasmic processes (hence theirname)

• Interdigitating dendritic cells A.K.A Dendriticcells

• Follicular Dendritic cells

Interdigitating (Dendritic) Cells

• Most important APC

• For initiating primary immune responseagainst Ag

• Features accounting for this function:

1) Location in the right place to capture Agslike:

• Underneath Epithelia surfaces, thecommon site of entry of microbesand foreign Ag

• In interstitia of all tissues where Agmay b produced

• With the Epidermis: epidermal

Langerhans cells

2) Expression of many receptor forcapturing and responding to microbes andother organisms

3) Expression of chemokine receptors thatrecruits the dendritic cells to the T-cellzones of lymphoid organs, in response tomicrobes, where they r ideally locatedand present antigens to T cells.

4) Expression of high level of MHC-IImolecules needed for presenting antigens

to and activating CD4+ T cells.

Follicular dendritic cells

• Present in the germinal centers of lymphoidfollicles in the spleen and lymph nodes (hencetheir name)

• Bears Fc receptors for IgG and receptor forC3b (opsonin) and so and can trap Ag bound

to Abs or complement proteins.

• Play a role in humoral immune responses bypresenting antigens to B cells and selecting theB cells that have the highest affinity for theantigen, thus improving the quality of theantibody produced.

NKCs

• make up approx. 10% to 15% of peripheral

blood lymphocytes and

• do not express TCRs or cell surface Ig

• Morphology:

– Larger than small lymphocytes

– Contain abundant azurophilicgranules; hence are called LargeGranular Lymphocytes

• Are part of the innate immune system

– They r endowed with ability to kill avariety of infected and tumor cells,without prior exposure to oractivation by these microbes ortumors

– This ability makes them an early lineof defense against viral infections and,perhaps, some tumors.

• Are commonly identified by Two cell surfacemolecules, CD16 and CD56. CD16 is an Fcreceptor for IgG, and it confers on NK cellsthe ability to lyse IgG-coated target cells. Thisphenomenon is known as anti-body-dependent cell-mediated cytotoxicity (ADCC).



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HYPERSENSITIVITY REACTIONS (hps rxn)

INTRODUCTION and DEFINITION

It is the adverse immune response to Ags OR animmune response that leads to tissue injury or disease

GENERAL FEATURES

1. It is elicited by both Exogenous antigens (food, drugs, dust, pollen, microbes, chemicalsand many blood products used in chemicalpractice) and Endogenous Ags (or Self-Ags orAutologous Ags, to cause Autoimmune dx).

2. Some of these immune rxns r triggered by homologous Ags that differ among individualsof different genetic background (i.e.isoantigens – isomers of an Ag). Transfusion

rxns and Graft rejection r examples of immunologic disorders evoked by

homologous Ags3. The development of hypersensitivity diseases

(both allergic and autoimmune disorders) is

often associated with the inheritance of particular susceptibility genes (HLA and Non-

HLA Ags).4. It reflects an imbalance between the effector

mech-anisms of immune responses and thecontrol mechanisms that serve to normallylimit such

CLASSIFICATION OF HYPERSENSITIVITY RXN

TYPE I HYPERSENSITIVITY – ImmediateHypersensitivity

~ is a rapid immunologic reaction occurring within

minutes after the combination of an antigen withantibody bound to mast cells in individuals previouslysensitized to the antigen.

Also called ALLERGY

The Ag eliciting this rxn: ALLERGEN. The Antibody(that is bound to FC receptors on the mast cell andBasophils) to which the Allergen binds is IgE

2 forms: System Hps Rxn and Localized hps Rxn

• Systemic rxn/Systemic Anaphylaxis/ Generalized

Anaphylaxis; the immediate response, that follows intravenous injection of foreign Ag (antisera,hormone, enz., polysaccharides, drug,…) to whichthe host has been sensitized.

• Example: Systemic Anaphylaxis (immediateresponse involving smooth muscles and capillariesthroughout the body of a sensitized individual…) – Characterized by vascular shock, widespread

edema and difficulty in breathing



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• Local Immediate Hps rxn/Local Anaphylaxix: – It is the immediate, transient response that is

limited to the area surrounding the site of

entry of the Ag.

– i.e. this rxn Varies depending on port of entryof Ag (like on skin, thru eye, resp. airway,…)

– Characterized by Cutaneous swelling (Skin allergy)

Hay fever Bronchial asthma Allergic gastroenteritis (food poisoning)

– Occurs In 10-20% of the population – E.g. Ectopic allergy – localized rxn to common

environmental allergens such as pollen, animaldanola, house dusts and food materials,…

• Specific Dx include: Urticaria, Angioedema,Allergic Rhinitis, some form of Asthma

2 PHASES: Immediate/initial Phase & Late/secondPhase rxn

• Initial Phase

o Within 5 – 30 min after exposureo CAUSED by release of histamine,

chemotactic factors for eosinophils,proteases,… from IgE triggered Mast

cellso Characterized by vasodialation and

bronchoconstriction

o Depends on the location, smooth

muscle spasms or glandular secretion• Late Phase

o Sets in 2 – 24 hrs later without

additional exposure to Ag o CAUSED by synthesis & release of PGs

and Leukotrienes by the IgE triggeredMast cells

o Characterized by Infiltrations of tissuewith Eosinophils, neutrophils,monocyte, CD4+ T cells, as well as

Tissue Degradation

STEPS in the development of HPs rxns: see diagrambelow

NOTE:

IL4: essential for turning off the IgE producing B cellsand for sustaining TH2 development. IL-4 causesplasma cells to switch from IgM to IgE synthesis.

IL5: activate Eosinophils which are effectors of Type Ihypersensitivity

IL13: promotes IgE production and acts on epithelialcells to stimulate mucus secretion

In addition, TH2 cells (as well as mast cells andepithelial cells) produce chemokines that attract moreTH2 cells, as well as other leukocytes, to the reactionsite.

TYPE II HYPERSENSITIVITY REACTION (Antibody

Mediated)

~ is a rxn caused by antibodies that react withantigens (intrinsic and/or Exogenous Ags) present oncell surfaces or in the extracellular matrix.

FEATURES:

a. Mediated by IgG and IgMb. Cells involved: Phagocytes and NK cells

3 MECHANISMS:

1. OPSONIZATION and COMPLEMENT and FCreceptor mediated PHAGOCYTOSIS (a.k.aAntibody mediated OPSONIZATION &

PHAGOCYTOSIS)



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2. COMPLEMENT and FC receptor mediatedINFLAMMATION (Antibody mediated

INFLAMMATION) 3. ANTIBODY mediated cellular DYSFUNCTION

Antibody mediated OPSONIZATION &

PHAGOCYTOSIS

a. Abs (IgG + IgM) binds to Ags intrinsic to thebody cells, causing the Classic Pathway activationof complement system that leads to

i. Formation of MACs that disrupts membraneintegrity by “drilling holes” through the

lipid bilayer, thereby causing osmotic lysisof the cells. E.gs are seen in autoimmune

hemolytic anemia, Erythroblastosis Foetalis and Transfusion rxn

ii. Formation of OPSONIN, by-product of thepathway, which coats the cells, thus

attracting phagocytes that hv receptors forthese opsonins. E.gs are seen Certain types

of autoimmune hemolytic anemia and some

drug reactions

End result : phagocytosis of the cells

b. Antibody-dependent cellular cytotoxicity (ADCC) is another Ab mediated destruction of cells thatdoes not require fixation of complements butrather, the activity of Cytolytic Leukocytes

(which include Monocytes, Neutrophils,eosinophils and NK cells). These effectors cellsPhagocytize & kill cells coated (or opsonized)with low conc. of antibodies (also called Specificor immune Opsonins), particulary IgG, Theyrecognize the Ab-coated cells via their Fcreceptors that bind to the Fc portion (ordomain) of these Abs

Antibody mediated INFLAMMATION

a. Caused by Ab deposited in structural connective

tissues e.g. basement membranes andextracellular matrix.

b. The resultant injury is due to inflammation andnot due to phagocytosis

c. Deposited antibodies activate complement,generating by-products, such as chemotacticagents (mainly C5a), which direct the migrationof polymorphonuclear leukocytes andmonocytes, and anaphylatoxins (C3a and C5a),which increase vascular permeability. Theseleukocytes are activated by binding to the Absvia their Fc receptors and so, release injurioussubstances like enzymes and reactive O2metabolites with resultant damage to the tissue.

d. E.gs of Type I hypersensitivity due toINFlammation are

i. glomerulonephritis,ii. vascular rejection in organ grafts

iii. Goodpasture syndromeiv. Bullous skin diseases

ANTIBODY mediated cellular DYSFUNCTION

a. Here Ab deposited against a cell surface causesneither cell destruction nor inflammation but

a change in the cells fxn.b. E.g. Myasthenia gravis (Abs binds to Ach

receptors, impairing Neuromusculartransmission and causing muscular weakness);Graves dx (Abs bind to TSH receptors inthyroid gland, causing hyperthyroidism);Pemphigus vulgaris (Abs deposited againstdesmosome, disrupting intercellular adhesionsin epidermis and leading to formation of skinvesicles or gully).



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TYPE III HPS RXN (Immune Complex Mediated rxn)

Here, immune complexes (Antigen-antibodycomplexes) r formed which are deposited in tissueswhere they elicit an inflammatory rxn and cause tissueinjury.

THE ABS INVOLVED: IgG and IgM and, occasionally,IgA

THE AGS INVOLVED: r either

Exogenous Ag like foreign particles, bacteria,streptococcal antigens, hepatitis B virus, andheroin … OR

Endogenous Ag: self-components which maybe circulating Ags present in the blood orAgenic (or immunogenic) component of one‟s

own cells and tissues, immunoglobulins andnuclear antigens

THE IMMUNE COMPLEXES formed are either

Circulating Immune complexes formed in theblood vessels and deposited on the vascularwall

In situ Immune complexes that r formed atextravascular sites.

EFFECTOR CELLS: Polymorphonucleic cells & theimmunocompetent cells

2 FORMS: Systemic Immune complex dx & Local

immune complex dx

SYSTEMIC IMMUNE COMPLEX DX

Prototype Example: Acute SERUM SICKNESS

Serum sickness is an acute, self-limited disease thattypically occurs 6 to 8 days after injection of aforeign serum or serum protein, with both local andsystemic reactions such as:

Pathogenesis : is in 3 phases

i. Formation of immune complexes: introductionor Ag in the body leads to interaction withimmunocompetent cells (T- and B-lymphocytes) and a later release of Abs into theblood, 6-8 days after injecting the Ag. These Abs(which were not preformed) react with Ags toform Ag-Ab complexes.

ii. Deposition of Immune Complexes: the immunecomplex are transported via the circulation, tomany tissues where they r deposited.

iii. Acute inflammatory rxn by the immunecomplex that causes Tissue injury. How? look

below – Arthus rxn

Clinical features: Urticaria, Fever, Generallymphadenopathy, Edema, Arthritis + joint pain,Proteinuria and severe Glomerulonephritis

LOCAL IMMUNE COMPLEX DX

Prototype E.gs: Arthus Rxn – a form of Type I

hypersensitivity demonstrated experimentally byintracutaneous injection of an antigen into an

individual that has been previously sensitized andhas specific Abs against the Ag. The Ag diffusing intothe blood vessels binds to the preformed Abforming the immune complex thatdeposits/precipitate in walls of these vessels.

Here, u see that this deposition prevents the

immune complex from travelling far to other tissue.

So the resulting injury mediated by this complex is

Local – within the skin

Resulting vascular injury is mediated by complementfixation, followed by recruitment and activation of

polymorphonucleic cells that phagocytize thedeposits and release of their tissue-damaging

mediators like proteases, Arachidonic acid productsand O2 radicals (same mechanism as in Serumsickness).

Arthus lesion develops over a few hrs and reaches apeak, 4-10 hrs after injection

Clinical Features: erythema, edema, hemorrhage,

and necrosis

MORPHOLOGY OF IMMUNE COMPLEX INJURY

a. Acute necrotizing inflammation (a.k.a necrotizing

vasculitis) with necrosis of the vessel wall andintense neutrophilic infiltrations.

b. Fibrinoid necrosis which hv a smudgyeosinophilic appearance: caused by immunecomplexes, + complement + plasma protein

DXs OF TYPE III HPS RXN:

1. Serum sickness2. Systemic lupus erythematosus (SLE)3. Polyarteritis nodosa4. Acute (OR Acute post-streptococcal)

glomerulonephritis5. Membranous nephropathy

Difference btw type I hps and Arthus rxn:

i. Type I hps rxn occurs immediately; Arthus rxn,occurs within hrs

ii. Cells involved: mast cell & eosinophils (type Ihps); all leucocytes (arthus rxn)





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AUTOIMMUNE DISEASES

AUTOIMMUNITY – immune rxn against self-antigen.

Antibodies involved:

- Autoantibodies found in Serum of apparentlynormal individuals, particularly in older agegroups.

- Innocuous (harmless) Abs formed afterdamage to tissue and may serve a physiologicrole in the removal of tissue breakdownproducts

Antigens involved:

- Self-Ags/autoantigens which are recognized asnon-self if modified by infection,inflammation, or complexing with a drug.

- Antigens usually isolated from the immune

system which are exposed by trauma orinflammation and become recognized asforeign. Examples include thyroglobulin, lensprotein, and spermatozoa.

- A foreign antigen that shares a common

structure with a host antigen

3 requirements for classifying autoimmune dx OR 3

features of autoimmune dx:

a) the presence of an immune reaction specific for some self-antigen or self-tissue

b) evidence that such a reaction is not secondary to

tissue damage but is of primary pathogenicsignificance

c) The absence of another well-defined cause of the

disease.

However, Autoimmunity could result from tissueinjury caused by T cells or antibodies that react againstself-Ag.

The spectrum of Autoimmunity has 2 extremes: on

one end is Organ specific autoimmunity; on the otherend is the generalized autoimmunity. In the middle isGoodpasture syndrome.

- Organ specific Autoimmune dx. Examples:o type I Diabetes Mellitus: in which the auto-

reactive T cells and Abs attach specific β cells of the pancreatic islet

o Multiple sclerosis: autoreactive t cells reactagainst CNS myelin

o Addison‟s dx: immune destruction of

adrenal cortexo Pernicious anemia: immune destruction of

Parietal cells in the stomacho Hashimoto's thyroiditis: immune destruction

of the thyroid

- Generalized OR Systemic Autoimmune dxs:o Systemic Lupus Erythematosus: in which a

diversity of Abs directed against DNA,platelets, RBCs and Protein phospholipidcomplexes result in widespread lesionsthroughout the body.

o Rheumatoid arthritiso Systemic sclerosis

An abnormal autoimmune response to self-antigensimplies a loss of immune (or immunologic) tolerancei.e. the body cannot tolerate „Self‟ & and there is lossof suppressor T cell control over B cell fxn.

IMMUNOLOGIC TOLERANCE

Immunologic tolerance is a condition or state whereinan individual is incapable of developing an immune

response to a specific Ag.

Self-tolerance refers to lack of responsiveness to an

individual‟s own antigens, and it underlies our abilityto live in harmony with our cells and tissues.

2 Forms of Tolerance;

- CENTRAL TOLERANCE- PERIPHERAL TOLERANCE

CENTRAL TOLERANCE

Refers to death (lesion) of self-reactive T- & B-Lymphocyte clones during their maturation in the central/primary lymphoid organ (Thymus and Bone)

Evidence show that T-lymphocytes that bear receptor

for self-Ag undergo apoptosis within the thymusduring the process of cell maturation

It is proposed that many autologous protein antigens,

including antigens thought to be restricted toperipheral tissues, are processed and presented by thymic APCs in association with self-MHC moleculesand can, therefore, be recognized by potentially self-reactive T cells.A protein called AIRE (autoimmune regulator),present in medullary thymic epithelial cells (mTEC)

mediate the transcription of many self-Ags that r

secreted (by these same thymic cells) in order to

stimulate expression of receptors for these Ags by theT-cells. Those developing T cells that express high

affinity receptors for such Self-Ag are negativelyselected or deleted (by apoptosis) and there4, theperipheral T-cell pool are lacking in self-reactive T-cells.



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Mutations in AIRE gene are the cause of anautoimmune polyendocrinopathy (A disease usuallycaused by insufficiency of multiple endocrine glands)

Some immature T-cells that encounter self-Ag in thethymus develop into regulatory T-cells.

As with T-cells, clonal deletion is also operative in B-

cells. When developing B cells encounter a membranebound Ag within the bone marrow, they undergoapoptosis.

However, clonal deletion of Self-reactive lymphocytesis not perfect. Many self-Ags may not be present in thethymus, hence, T-and B- cells bearing receptors for Self – Ag escape into the periphery.

B cells bearing self-Ag receptors for Ags (likeThyroglbulin, collagen & DNA) can be found in theperipheral blood of an individual.

PERIPHERAL TOLERANCE

Self-reactive T-cells that escape intra-thymic – veselection can cause tissue injury unless they are deletedin the peripheral tissue.

MECHANISM OF ELIMINATING AUTOREACTIVE T-

CELLS FROM the PERIPHERY

ANERGY: refers to prolonged or irreversible

functional inactivation of lymphocytes, induced by

encounter with antigens under certain conditions.If the self-Ag is presented by competent APCs thatdo not bear the co-stimulators (that supposed tobind to the co-receptors on the Lymphocytes) a

negative signal is delivered, and the lymphocytes

becomes anergic.Since most dendritic cells in normal tissue weaklyexpresses or do not express co-stimulatorymolecules, many of these auto-reactive T-Lymphocytes will become anergic once theyrecognize specific self-antigens displayed by thesedendritic cells.

Anergy also affects mature B cells in peripheraltissues. It is believed that if B cells encounter self-

antigen in peripheral tissues, especially in the

absence of specific helper T-cells, the B-cells becomeunable to respond to subsequent antigenicstimulation and may be excluded from lymphoidfollicles, resulting in their death.

SUPPRESSION BY REGULATORY T CELLS: RegulatoryT cells develop mainly in the thymus, as a result of recognition of self-antigens, but they may also beinduced in peripheral lymphoid tissues.

The best-defined regulatory T cells are CD4+ cells thatconstitutively express CD25, the α-chain of the IL-2

receptor. Evidence suggests that theinhibitory/suppressive activity of these cells may bemediated by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibitlymphocyte activation and effector functions.

CLONAL DELETION BY ACTIVATION-INDUCED

CELL DEATH: CD4+T cells that recognize self-antigens

may receive signals that promote their death byapoptosis. This process has been called activation-

induced cell death, because it is a consequence of T-

cell activation.

ANTIGEN SEQUESTRATION : Some antigens are

hidden (sequestered) from the immune system,because the tissues in which these antigens are locateddo not communicate with the blood and lymph. Thisis believed to be the case for the testis, eye, and brain,all of which are called immune-privileged sites (areas

of Physiological barriers) because it is difficult toinduce immune responses to antigens introduced intothese sites.

If the antigens of these tissues are released, forexample, as a consequence of trauma or infection, theresult may be an immune response that leads toprolonged tissue inflammation and injury. This is thepostulated mechanism for post-traumatic orchitis anduveitis.

Mechanisms of Autoimmunity

Autoimmune dx results when self-tolerance is lost orby-passed

2 factors relevant to the development of autoimmunedx:

1. inheritance of susceptibility genes, which maycontribute to the breakdown of self-tolerance,and

2. environmental triggers, such as infections andtissue damage, which promote the activation of self-reactive lymphocytes

Role of Susceptibility Gene (HLA and MHC genes)

- Best characterized susceptibility genes – HLAand MHC gene

- Postulation: the presence of particular MHCalleles affects the negative selection of T cells inthe thymus or the development of regulatory Tcells but there is little proof for either possibility .

- However, many people inherit MHC genes thatdisease-associated but still have normal MHCmolecules capable of presenting self-antigens.



- Therefore, the presence of particular MHCalleles is not, by itself, the cause of autoimmunity

- In several autoimmune dxs e.g. SLE, Type ID.M., many non-MHC genes hv bin shown tobe involve.

Role of infection

- 2 mechanisms have be postulated to relateinfection with A.I. dxo Infections may up-regulate the expression

of costimulators on APCs. If these cells arepresenting self-antigens, the result may be abreakdown of anergy and activation of Tcells specific for the self-antigens.

o Some microbes may express antigens thathave the same amino acid sequences asself-antigens. Immune responses against the

microbial antigens may result in theactivation of self-reactive lymphocytes.This phenomenon is called molecular

mimicry. A clear example of such mimicryis rheumatic heart disease, in whichantibodies against streptococcal proteinscross-react with myocardial proteins andcause myocarditis

Once an autoimmune disease has been induced it

tends to be progressive, sometimes with sporadicrelapses and remissions (on & off), and the damagebecomes inexorable (continuous and irreversible).

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Immuno Pathology 222