Diseases of the Immune System - مخزن مركز تحميل صور ملفات ... Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases 1. Autoimmunity:

Dr. Huda Hammad

Dr. Wael Swelam

OBC 231 General Pathology

Diseases of the Immune System

12/22/2012

Hypersensitivity Diseases:

Mechanisms of Immune Mediated Injury

Individuals who mount immune responses against an antigen are said to be “sensitized” to that antigen.

When these responses are pathologic or excessive, the manifestations are called “hypersensitivity”.

Normally, a system of checks and balances optimizes the eradication of infecting organisms without serious injury to host tissues.

However, immune responses may be inadequately controlled or inappropriately targeted to host tissues.

In these situations, the normally beneficial response is the cause of disease.

12/22/20122


Mechanisms of Immune Mediated InjuryCauses of Hypersensitivity Diseases

Pathologic immune responses may be directed against different

types of antigens, and may result from various underlying

abnormalities:

1. Autoimmunity.

2. Reactions against microbes.

3. Reactions against environmental antigens.

12/22/20123



Causes of Hypersensitivity Diseases

1. Autoimmunity:

Normally, the immune system does not react against an individual's own antigens (self-tolerance).

Sometimes, self-tolerance fails, resulting in reactions against one's own cells and tissues that are called autoimmunity.

The diseases caused by autoimmunity are referred to as autoimmune diseases.

12/22/20124



2. Reactions against microbes:

Many types of reactions against microbial antigens may cause

disease.

In some cases, the reaction may be excessive or the microbial

antigen is unusually persistent.

12/22/20125



Reactions against microbes

Antibodies produced against

microbial immune complexes

Inflammatory Poststreptococcal

glomerulonephritis

T-cell responses against persistent microbes

sever inflammatory response

Granulomas, e.g.

Tuberculosis

Antibodies / T cells cross-react

with a host tissue

Rheumatic heart disease

During the process of eradicating the

infection host tissues injury

Cytotoxic T cells try to eliminate infected cells, and this

normal immune response damages liver cells e.g. Viral

hepatitis

12/22/20126



Poststreptococcal

glomerulonephritis

Tuberculos granuloma

Rheumatic heart disease

Viral hepatitis

12/22/20127



3. Reactions against environmental antigens:

Most healthy individuals do not react strongly against common

environmental substances (e.g., pollen, animal dander, or dust

mites), but almost 20% of the population is "allergic" to these

substances.

12/22/20128



Causes of Hypersensitivity Diseases

These hypersensitivity diseases tend to be chronic, often

debilitating, and pose therapeutic challenges.

Since chronic inflammation is a major component of these

disorders, they are sometimes grouped under the term

immune-mediated inflammatory diseases.

12/22/20129


Mechanisms of Immune Mediated InjuryTypes of Hypersensitivity Diseases

Hypersensitivity reactions are traditionally subdivided into four types.

1. Immediate (type I) hypersensitivity.

2. Antibody-mediated (type II) hypersensitivity.

3. Immune complex-mediated (type III) hypersensitivity.

4. T-cell-mediated (type IV) hypersensitivity.

The first three are variations on antibody-mediated injury, whereas the fourth is

cell mediated.

This classification of immune-mediated disease is not perfect, because several

immune reactions may coexist in one disease.

12/22/201210

12/22/201211



Types of Hypersensitivity Diseases

Immediate (type I) hypersensitivity

Some of these mediators are released

within minutes from sensitized mast

cells causing the intense immediate reactions associated with conditions

such as systemic anaphylaxis.

Others, such as cytokines, are

responsible for the inflammation seen

in late-phase reactions.

12/22/201212

Sequence of events in immediate (type 1)

hypersensitivity

Action Mediator

Vasodilation, increased

vascular permeability

Histamine

PAF (platelet activating Factor)

Leukotrienes C4, D4, E4

Neutral proteases that activate

complement and kinins

Prostaglandin D2

Smooth muscle spasm Leukotrienes C4, D4, E4

Histamine

Prostaglandins

PAF

Cellular infiltration Cytokines (e.g., chemokines,

TNF)

Leukotriene B4

Eosinophil and neutrophil

chemotactic factors (not defined

biochemically)

12/22/2012

13





Often, the IgE-triggered reaction has two well-defined phases:

(1) the immediate response: vasodilation, vascular leakage, and

smooth muscle spasm, within 5 to 30 minutes after exposure to an

allergen and subsiding by 60 minutes.

(2) a second, late-phase reaction: in 2 to 8 hours later and may last

for several days, inflammation and tissue destruction, such as

mucosal epithelial cell damage. Dominated by neutrophils,

eosinophils, and lymphocytes, especially TH2 cells.

12/22/201214





Clinical and Pathologic

Manifestations :

Systemic anaphylaxis:

Within minutes of an exposure in a

sensitized host, itching, urticaria

(hives), and skin erythema appear,

followed in short order by profound

respiratory difficulty caused by

pulmonary bronchoconstriction and

accentuated by hypersecretion of

mucus.

Laryngeal edema may exacerbate

matters by causing upper airway

obstruction.

12/22/201215





Clinical and Pathologic Manifestations :

Systemic anaphylaxis:

The musculature of the entire gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea.

Without immediate intervention, there may be systemic vasodilation with fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes.

12/22/201216





Clinical and pathologic manifestations :

Local reactions generally occur when the antigen is confined to a particular site, such as :

1. Skin (contact urticaria),

2. Gastrointestinal tract (ingestion diarrhea), or

3. Lung (inhalation bronchoconstriction).

12/22/201217

12/22/201218




Antibody-mediated (type II) hypersensitivity

Caused by antibodies directed against target antigens on

the surface of cells or other tissue components.

The antigens may be normal molecules intrinsic to cell

membranes or extracellular matrix, or they may be

adsorbed exogenous antigens (e.g., a drug metabolite).

12/22/201219





Antibody-mediated abnormalities are the underlying cause of many human diseases; examples include:

1. Autoimmune hemolytic anemia.

2. Autoimmune thrombocytopenic purpura.

3. Pemphigus vulgaris.

4. Vasculitis caused by ANCA.

5. Goodpasture syndrome.

6. Acute rheumatic fever.

7. Myasthenia gravis

8. Graves disease (hyperthyroidism).

9. Insulin-resistant diabetes.

10. Pernicious anemia.12/22/201220

Mechanisms of Antibody-Mediated Diseases:

A.





12/22/201221





Mechanisms of Antibody-Mediated Diseases:

C. Antibodies can bind to cell surface receptors or essential molecules, and cause

functional derangements (either inhibition or unregulated activation) without cell

injury, e.g. myasthenia gravis, Grave’s disease (hyperthyroidism).

12/22/201222




Immune complex-mediated (type III)

Caused by antibodies binding to antigens to form complexes

that circulate and may deposit in vascular beds and stimulate

inflammation, typically secondary to complement activation.

Tissue injury in these diseases is the result of the inflammation.

The antigens in these complexes may be exogenous antigens,

such as microbial proteins, or endogenous antigens, such as

nucleoproteins.

It is only when these complexes are produced in large amounts,

persist, and are deposited in tissues that they are pathogenic.

12/22/201223




Imm

un

e co

mp

lex-

med

iate

d

(typ

e II

I)

Systemic

1) Formation of antigen-antibody complexes in the circulation.

2) Deposition of the immune complexes in various tissues, thus initiating

3) An inflammatory reaction in various sites throughout the body

Local

Excess amount of initial antibody immune complexes precipitated at

the site of injection and trigger the same inflammatory reaction as in

systemic immune complex disease

12/22/201224




Immune complex-mediated (type III)

Disease Antigen Involved Clinicopathologic

Manifestations

Systemic lupus

erythematosus

Nuclear antigens Nephritis, skin lesions,

arthritis, others

Poststreptococcal

glomerulonephritis

Streptococcal cell wall

antigen(s); may be "planted"

in glomerular basement

membrane

Nephritis

Polyarteritis nodosa Hepatitis B virus antigen Hepatitis B virus antigen

Reactive arthritis Bacterial antigens (Yersinia) Acute arthritis

Serum sickness Various proteins, such as

foreign serum protein (horse

anti-thymocyte globulin)

Arthritis, vasculitis, nephritis

Arthus reaction

(experimental)

Various foreign proteins Cutaneous vasculitis

12/22/201225




T-cell-mediated (type IV) hypersensitivity

Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions:

12/22/201226





Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions:

B. Direct cell cytotoxicity, mediated by CD8+ T cells.

12/22/201227





This group of diseases has received great interest because many

of the newly designed biologic therapies developed to target

abnormal T-cell reactions.

Several autoimmune disorders, as well as pathologic reactions to

environmental chemicals and persistent microbes, are now

known to be caused by T cells.

12/22/201228

Disease Specificity of Pathogenic T

cells

Clinicopathologic

Manifestations

Type 1 diabetes mellitus Antigens of pancreatic islet βcells

(insulin, glutamic acid

decarboxylase, others)

Antigens of pancreatic islet βcells

(insulin, glutamic acid

decarboxylase, others)

Multiple sclerosis Protein antigens in CNS myelin

(myelin basic protein, proteolipid

protein)

Demyelination in CNS with

perivascular inflammation;

paralysis, ocular lesions

Rheumatoid arthritis Unknown antigen in joint

synovium (type II collagen?); role

of antibodies?




Peripheral neuropathy; Guillain-

Barré syndrome?

Protein antigens of peripheral

nerve myelin




Inflammatory bowel disease

(Crohn's disease)

Unknown antigen; may be derived

from intestinal microbes

Chronic inflammation of ileum

and colon, often with granulomas;

fibrosis, stricture

Contact dermatitis Environmental chemicals, e.g.,

poison ivy (pentadecylcatechol)

Dermatitis, with itching; usually

short-lived, may be chronic with

persistent exposure

12/22/201229

12/22/201230

12/22/201231

Surgical difficulties

Graft rejection

Organ shortage

Rejection of transplants

Transplantation problems

12/22/201232

Transplant Immunology Outline: Graft compatibility

Rejection = Recipient recognizes graft as foreign, and destroys it

Autograft Within same person

Isograft Between identical twins

Allograft Between genetically different people

Xenograft Between different species

12/22/201233

Histocompatible: antigenically similar to the host

Histoincompatible: antigenically different from the host

MHC antigens are the MOST IMPORTANT

ABO antigens are also important

Minor histocompatiblity antigens are less important

Histocompatibility

12/22/201234

Gene collection on chromosome 6

Three regions: class I, class II,

class III

Class I gene products

• HLA-A, HLA-B, HLA-C

• expressed on nearly all cells

• present antigen to TC cells

Class II gene products

• DP, DQ, DR

• expressed on antigen-

presenting cells

• present antigen to TH cells

Compatibility: HLA complex

12/22/201235

12/22/201236

12/22/201237

Compatibility

MHC class I II III

Region A B C DP DQ DR C4, C2, BF

Gene

products

HLA-

A

HLA-

B

HLA-

CDP DQ DR

C' proteins

TNF-

TNF-

12/22/201238

Compatibility

parents

four possible

haplotype

combinations of

children

a/b c/d

a/c a/d b/c b/d

♂ ♀

12/22/201239

Compatibility

1 7 w3 2 1 1

2 8 w2 3 2 2

11 35 w1 7 3 4

3 44 w4 4 1 3

A B C DR DQ DP

haplotypes

a

b

c

d

HLA alleles

12/22/201240

Compatibility

ice

cream

haplotypes

a

b

c

d

pop fruit veggiecookieyum

yum

Vault

De

w

12/22/201241

The more matching alleles between donor and host, the better!

Matching the class II antigens is more important than matching the

class I antigens.

One or two class I mismatches = no big deal

One or two class II mismatches = big deal

Mismatches in both class I and II = very big deal

Compatibility: HLA inheritance

12/22/201242

gra

ft s

urv

ival, %

50

100

63 12

time after transplant, months

0 0

1 or 2 0

3 or 4 0

0 1 or 2

1 or 2 1 or 2

3 or 4 1 or 2

number of mismatches

Class I Class II

12/22/201243

Transplant Immunology Outline

Introduction

Graft compatibility

Graft rejection

12/22/201244

Any two people (except identical twins) will express some

HLA proteins that are different.

Every recipient will recognize, and react against, at least

some foreign antigens in the graft

Rejection is complex, with lots of killing mechanisms.

Rejection

12/22/201245

Rejection

How do recipient cells know which cells to kill?

12/22/201246

T-cell-mediated rejection

Antibody-mediated rejection

Rejection

Two mechanisms of rejection

12/22/201247

CD8+ CTLs kill graft cells directly

CD4+ cells trigger a delayed hypersensitivity reaction

T-cell mediated rejection

12/22/201248

CTL Killing

Delayed Hypersensitivity

12/22/201249

Preformed antibodies

• Anti-HLA or anti-ABO

• Rejection occurs immediately

(“hyperacute”)

• Antibodies cause thrombosis

• Rare these days

Newly-made antibodies

• Appear within days to years

• Usually directed against graft

endothelium

• Cause damage by: Helping complement kill graft cells

Opsonizing graft cells (yummy!)

Antibody-mediated rejection

12/22/201250

Target cell is coated with IgG

Effector cell* has receptors for Fc fragment

Effector cell binds to target cell

Target cell is lysed

Antibody-dependant cell-mediated cytotoxicity (ADCC)

* Macrophage, Neutrophil, or NK Cell 12/22/201251

Clinical types of Rejection

Hyper-acute rejection

• Within hours

• Preexisting anti-donor antibodies

• Rare these days

• “Accelerated” is similar

Acute rejection

• Starts at about 10 days

• Cell-mediated

Chronic rejection

• Months to years after transplant

• Humoral and cell-mediated mechanisms

• Hard to prevent

• Hard to treat

12/22/201252

Acute cellular (t) Acute humoral

Chronic12/22/201253

12/22/201254

12/22/201255

Autoimmune Diseases

The immune reaction to self-antigens, or autoimmunity, is

the cause of certain human diseases.

A growing number of entities have been attributed to

this process (see table in next slide).

12/22/201256

Organ-Specific Systemic

Hashimoto thyroiditis Systemic lupus erythematosus

Autoimmune hemolytic anemia Rheumatoid arthritis

Autoimmune atrophic gastritis of pernicious

anemia

Sjögren syndrome

Multiple sclerosis Reiter syndrome

Autoimmune orchitis Inflammatory myopathies*

Goodpasture syndrome Systemic sclerosis (scleroderma)*

Autoimmune thrombocytopenia Polyarteritis nodosa*

Insulin-dependent diabetes mellitus

Myasthenia gravis

Graves' disease

Primary biliary cirrhosis*

Autoimmune (chronic active) hepatitis*

Ulcerative colitis *The evidence supporting an autoimmune basis

of these disorders is not strong. 12/22/201257

Autoimmune Diseases The evidence that the diseases listed in the previous table are the

result of autoimmune reactions is more persuasive for some than

for others.

For example, the presence of multiple autoantibodies accounts for

many of the clinical and pathologic manifestations of SLE.

Moreover, these autoantibodies can be identified within lesions by

immunofluorescence and electron-microscopic techniques.

12/22/201258

Autoimmune Diseases

In many other disorders, an autoimmune etiology is

suspected but is unproven.

In some cases of apparent autoimmunity, the response may be

directed against an exogenous antigen, such as a microbial

protein.

Autoimmune diseases range from those in which specific

immune responses are directed against one particular organ

or cell type, to multisystem diseases.

In the systemic diseases, the lesions affect principally the

connective tissue and blood vessels of the various organs

involved. These diseases are often referred to as "collagen

vascular" or "connective tissue" disorders.12/22/201259

Autoimmune Diseases: Self-Tolerance

Autoimmunity implies loss of self-tolerance.

Immunological tolerance is unresponsiveness to an antigen

that is induced by exposure of specific lymphocytes to that

antigen.

Self-tolerance refers to a lack of immune responsiveness to

one's own tissue antigens.

12/22/201260

Autoimmune Diseases

Self-Tolerance

During the generation of billions of antigen receptors in

developing T and B lymphocytes, receptors are produced that

can recognize self-antigens.

Several mechanisms work in concert to prevent immune

reactions against one's own antigens.

These mechanisms are broadly divided into two groups:

central tolerance and peripheral tolerance.

12/22/201261

Autoimmune Diseases

Self-Tolerance

Central tolerance

• Immature lymphocytes that recognize self-antigens in the central (generative) lymphoid organs are killed by apoptosis.

• In the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive

Peripheral tolerance

• Mature lymphocytes that recognize self-antigens in peripheral tissues undergo one of the following:• They become functionally

inactive (anergic),

• Or are suppressed by regulatory T lymphocytes,

• Or die by apoptosis.

12/22/201262

Autoimmune Diseases

Self-Tolerance

The variables that lead to a failure of self-tolerance and the

development of autoimmunity include:

1. Inheritance of susceptibility genes that may disrupt different

tolerance pathways.

2. Infections and tissue alterations that may expose self-

antigens and activate APCs and lymphocytes in the tissues,

altering the recognition of self-antigens.

12/22/201263

Pathogenesis of

autoimmunity

Autoimmunity arises from many

causes, including:

1) Inheritance of susceptibility genes

that may interfere with self-

tolerance,

2) Environmental triggers

(inflammation, other inflammatory

stimuli) that promote lymphocyte

entry into tissues,

3) Activation of self-reactive

lymphocytes, and tissue injury.

12/22/2012

64

Autoimmune Diseases

Systemic Lupus Erythematosus

The fundamental defect in SLE is a failure to maintain

self-tolerance.

A large number of autoantibodies is produced, classically

including antinuclear antibodies (ANAs),that can

damage tissues either directly or in the form of immune

complex deposits.

12/22/201265

12/22/2012

Lupus erythematosis pathogenesisGenetic factors

B cell

reactivity

autoantibody

productionB cells to enhance the

function of other cells

Organ damage

alter the function of T cells,

antigen-presenting cells &

cytokines production

66

Autoimmune DiseasesSystemic Lupus Erythematosus1997 Revised Criteria for Classification of Systemic Lupus Erythematosus

Malar rash

Malar rash

Discoid rash

Photosensitivity

Oral ulceration

Arthritis12/22/201267


Serositis

Renal disorders

Neurologic disorder

12/22/201268


Hematologic disorder

• Hemolytic anemia: with reticulocytosis,

• Leukopenia: <4.0 ×109 cells per liter (4000 cells per mm3) total on two or more occasions

• Lymphopenia: <1.5 ×109 cells per liter (1500 cells per mm3) on two or more occasions

• Thrombocytopenia: <100 ×109

cells per liter (100 ×103 cells per mm3) in the absence of offending drugs

Immunologic disorder

• Anti-DNA antibody to native DNA in abnormal titer

• Anti-Sm: presence of antibody to Sm nuclear antigen

• Positive finding of antiphospholipid antibodies

12/22/201269


11. Antinuclear antibody:

An abnormal titer of antinuclear antibody by

immunofluorescence or an equivalent assay at any point in

time and in the absence of drugs known to be associated with

drug-induced lupus syndrome.

12/22/201270

12/22/201271

Immune deficiencies

primary (inherited)

secondary (to infection, immunosuppression, etc.)

Patients more susceptible to infections and cancer

Type of infection varies:

Ig, C’ or phagocytic cell defect: bacterial infection

T cell defect: viral and fungal infections

Immune Deficiencies: Basic Concepts

12/22/201272

Rare!

Genetic

Can affect any part of immune system:

Adaptive (humoral or cellular)

Innate (C’, phagocytes, NK cells)

Typical patient: infant with recurrent infections

Primary importance for our class: boards

Primary Immune Deficiency Diseases: Basic

Concepts

12/22/201273

X-linked agammaglobulinemia

SCID

SCID

DiGeorge syndrome

SCID

Hyper-IgM syndrome

IgA deficiency

12/22/201274

Primary immune deficiencies

X-Linked Agammaglobulinemia

Common Variable Immunodeficiency (CVID)

Hyper-IgM Syndrome

Selective IgA Deficiency

Combined T-cell and B-cell (antibody)

deficiencies

12/22/201275

Pre-B cells can’t differentiate into B cells

Patients have no immunoglobulin

Affects males

Presents at 6 months of age (maternal Ig gone)

Recurrent bacterial infections

Treatment: intravenous pooled human Ig

X-linked Agammaglobulinemia

12/22/201276

Common variable immunodeficiency

Group of disorders characterized by

defective antibody production

Affects males and females equally

Presents in teens or twenties

Basis of Ig deficiency is variable (hence the

name) and often unknown

Patients more susceptible to infections, but

also to autoimmune disorders and

lymphoma!

12/22/201277

Severe Combined Immunodeficiency

12/22/201278

Examples of Infections in Immunodeficiencies

Pathogen Type T-Cell-Defect B-Cell DefectGranulocyte

Defect Complement Defect

Bacteria Bacterial sepsis Streptococci,

staphylococci,

Haemophilus

Staphylococci,

PseudomonasNeisserialinfections, other

pyogenic bacterial

infections

Viruses Cytomegalovirus, Epstein-Barr

virus, severe varicella, chronic

infections with respiratory and

intestinal viruses

Enteroviral

encephalitis

Fungi and

parasitesCandida, Pneumocystis carinii Severe intestinal

giardiasis

Candida, Nocardia, Aspergillus

Special features Aggressive disease with

opportunistic pathogens, failure

to clear infections

Recurrent

sinopulmonary

infections, sepsis,

chronic meningitis

12/22/201279

Disease Transmission Defect Clinical stuff

XLA X-linkedNo mature B cells;

no Ig

Infant with recurrent

bacterial infections

CVID

IgA deficiency

Hyper-IgM

DiGeorge

SCID

A good way to study immune deficiencies

12/22/2012 80

Etiology: HIV

Pathogenesis: Infection, Latency, Progressive T-Cell loss

Morphology: MANY

Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load)

AIDS(SECONDARY IDS)

12/22/201281

Homosexual: (40%, and declining)

Intravenous drug usage (25%)

Heterosexual sex (10% and rising)

Epidemiology

12/22/201282

The enzyme reverse transcriptase (RT) is used by retroviruses to transcribe

their single-stranded RNA genome into single-stranded DNA and to

subsequently construct a complementary strand of DNA, providing a DNA

double helix capable of integration into host cell chromosomes.

Reverse transcriptase

12/22/201283

Attaching Budding

Pathogenesis

12/22/201284

Early budding

Pathogenesis

Late budding

Mature new

virions

12/22/201285

Lymphopenia

Decreased t-cell function

B-cell activation, polyclonal

Altered monocyte/macrophage function

General immune abnormalities

12/22/201286

Protozoal/Helminthic: Cryptosporidium,

PCP (Pneumocystis Carinii Pneumonia),

Toxoplasmosis

Fungal: Candida, and the usual 3

Bacterial: TB,

Nocardia,

Salmonella

Viral: CMV, HSV, VZ (Herpes Family)

AIDS related Infections

12/22/201287

PCP12/22/201288

CRYPTOSPORIDIUM 12/22/201289

Caseating granuloma 12/22/201290

Kaposi sarcoma

B-cell lymphomas

CNS lymphomas

Cervix cancer, squamous cell

Cancers related to AIDS

12/22/201291

12/22/201292

Documents

Diseases of the Immune System - مخزن مركز تحميل صور ملفات ... Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases 1. Autoimmunity: