Final Immunology 6

8/8/2019 Final Immunology 6

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Immunopathology

Diseases of immunity

The immune system is a defensive system whose primaryfunctions are to protect against infectious organisms such as

bacteria, viruses, fungi and parasites and development of cancer.

Immunity is the results of nonspecific or nature (innate or native)

and acquired (adaptive or specific).

I-Innate or natural immunity (Nonspecific immunity)

It considers the first line of defense mechanisms; are not

specific to antigen and lack memory.

It depends on individual species variation in susceptibility to

infection, for example horse and equine are resistant to infection

with canine distemper virus, a highly pathogenic agent to the dog.

Moreover, neutrophils and macrophages beside skin, mucous

membranes, and mucus covers respiratory epithelium, saliva and

gastric acid play an immportant role in nature immunity. Natural

antibodies, interferons and complement system are involved also in

the natural immunity.

II-Acquired immunity (Specific immunity)

Adaptive immunity in general consists of cell mediate

immunity (mediated by T lymphocytes) against intracellular

pathogens and humoral immunity (mediated by B lymphocytes)

against extracellular pathogens and toxin. The acquired immunity

characterized by; (1) previous exposure to the antigen, (2) highly

specific for certain antigens, (3) and memory.

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Cells involved in acquired immunity

1-Antigen-presenting cells (APCs)

Macrophages, Langerhans cells of skin and follicular dendritic cells

found in the germinal centers of lymph nodes and spleen are

considered antigen presenting cell. The APCs phagocylize the

antigens and degrade into antigenic peptides. The APCs then

connected the antigenic peptides to major histocompatibility

complex (MHC) and present the complex on the surface of the cell

in a form that can be recognized by other cells.

2-T-lymphocytes are another important class of cells involved

in the acquired immune response.

The most important subset of T-lymphocytes is the helper T

cells, which characterized by presence of CD4 molecules on their

surface. Those cells secrete a number of chemical substances, known

as cytokines that regulate the function of the immune system.

Another subset of T-cells are the cytolytic (cytotoxic) T

lymphocytes which have CD8 molecules on their surface, cytotoxic

cells are responsible for killing virus infected cells and cells

expressing foreign antigens on their surfaces.

Suppressor T cells are another subset that secretes cytokines

suppresses the activity of B lymphocytes and cytotoxic T cells.

Adhesion molecules involved in the immune system

Adhesion molecules are membrane-bound proteins that allow one

cell to interact with another. Adhesion molecules play an important role

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Immunopathology

in directed of the immune cells to a particular site to perform some

function. Three groups of adhesion molecules are recognized; (1)

immunoglobulin superfamily, (2) integrin and (3) selectin family

Acquired immunity classified to

1-Humoral immunity

The humoral immunity, is mediated by B lymphocytes against

intracellular pathogens, involves circulating antibodies and can passively

transfer with serum. Antibodies are glycoprotein substance present in the

body fluid that combat diseases and formed as a result of exposure to

foreign antigens. Antigens are substances that are foreign to the host.

Haptens are simple chemicals that can induce antibodies when coupled to

carrier protein.

2-Cell-mediated immunity

It is a form of acquired immunity, mediated by T lymphocytesagainst extracellular pathogens and toxin, requires a stimulus, highly

specific and has a memory. It depends on immune cells not

antibodies, so it cannot be transferred by serum. Cell mediated

immunity responsible for resistance and reaction associated with

granulomatous diseases, simple bacteria, some protozoa and

metazoan parasites. Also it involved in the mechanism of graft

rejection, certain viral diseases and destruction of neoplasm.

The cell mediated immune response resulted from interaction of

T lymphocytes and antigen presenting cells (APCs) as macrophages.

Antigens is processed by APCs and presented to T lymphocytes by

macrophages. Sensitize T lymphocytes release chemokines which

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Immunopathology

call additional macrophages (principle effector cells) that accumulate

at reaction site.

Microscopically, the delayed reaction of cell mediates

immunity is characterized by:

1. Proliferation of large lymphocytes in the paracortical regions

of lymph nodes. The lymphocytes may release chemokines to attract

macrophages or destroying the antigens with lysis of cells through

release of cytoplasmic granules or enhance apoptosis (cytotoxic or

cytolytic cells).

2. Macrophages, epithelioid cells, multi-nucleated giant cells,

and small numbers of neutrophils.

Disorders of the immune system

The diseases of immune system are broadly classified into

1- Autoimmune diseases

2-Immunodeficiency diseases

3- Hypersensitivity

4- Possible immune disorders classical example of this group

being amyloidosis.

1-Autoimmune diseases

It is defined as a specific immune response to self

antigens. Autoimmune diseases are occurs due to loss of

immunologic tolerance to self tissues or cellular antigens and

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Immunopathology

characterized by abnormal or excessive activity of self reactive

immune effector cells.

The etiology of most autoimmune diseases is still elusive

as they are often multifactorial and have a genetic and

environmental component.

Autoimmune diseases can be organ specific, localized or

systemic.

Several autoimmune diseases are recorded in animals such

as Lupus erythematosus, rheumatoid arthritis

2-Immunodeficiency syndromes

Immunodeficiency disease occurs when there is a failure of the

immune system to protect the host from infectious organisms or

cancer.

They consider a number of genetic and congenital acquired

defects in innate and acquired immune system render individuals

more susceptible to infectious agents and neoplasm.

An immunodeficiency syndrome that results of a congenital or

genetic defect in a component of the immune system is called a

primary immunodeficiency, but the one result from complication of

infections, malnutrition, or aging or a side effect of

immunosuppressant, irradiation or chemotherapy of cancer is called

secondary immunodeficiency diseases.

I-Primary immunodeficiency

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Immunopathology

1. Neutrophils disorders

A-Canine cyclic neutropenia: it is characterized by cyclic

neutropenia every 8-12 days due to defect in bon marrow stem cell

maturation. The animals are more susceptible to bacterial infection

of digestive and respiratory system.

B-Chediak-Higashi disease (CHD)

It is characterized by partial albinism and increase susceptibility

to bacterial infection and a tendency to hemorrhage. The disorders is

characterized by presence of large granules in the cytoplasm of

neutrophils, macrophages, NK cells and melanocytes.

2. Adhesion molecules deficiencies

Leukocyte adhesion deficiency syndromes are characterized by

recurrent bacterial and fungal infections.

3. Complement deficiencies

Animal with C3 and C5 deficiencies is unable to opsonize and

destroy bacterial organisms.

4. B-lymphocytes deficiencies

Agammagloblinemia and hypogammaglobulinemia may resultfrom defective synthesis, increase catabolism or excessive loss of

immunoglobulines.

5. T-lymphocytes deficiencies

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Immunopathology

Deficiencies of T-lymphocytes generally result in more serious

susceptibility to infection than defects involving B-cells, owing to

the essential contribution of T cells to normal B-cell function.

II. Secondary immunodeficiency disorders

1-Failure of passive transfer of maternal immunoglobulin

It is the one of the most common acquired forms of

immunodeficiency in veterinary medicine due to failure of animal to

consume colostrum.

2-Virus induced immunosuppression

The virus induce suppression through direct effect on the cell of

immune system especially macrophages and lymphocytes.

Immunosuppression usually accompanies diseases as canine distemper,

hog cholera, bovine virus diarrhea and others.

III-Hypersensitivity (Allergy)

Definition:

A hypersensitivity is defined as the altered reactivity to a

specific antigen that results in pathologic reaction when exposure toof a sensitized host to that specific antigen. Also hypersensitivity is

defined as an abnormal, exaggerated immune reaction to a foreign

agent (antigen), with resulting injury to host tissues.

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Immunopathology

Antigens which produce such a harmful effect calledallergens.

They may be bacterial, nonbacterial or even simple chemical

substance.

There are four different mechanisms of hypersensitivity (TypeI,

II, III and IV). All forms, except type IV, are mediated by

antibodies. Type IV is mediated by T lymphocytes and

macrophages. All forms need initial exposure (sensitizing or

preparatory dose) followed by second dose of the same antigen after

1 or more weeks (challenge or eliciting dose). An immediate violent

response may be seen within few seconds or minutes (immediate

hypersensitivity). On the other hand, the reaction to the challenge

dose may appear several hours or days or even months later (delayed

hypersensitivity).

A. Immediate hypersensitivity

It is characterized by an allergic reaction that occurs

immediately following contact with the antigen (challenge dose).

Histamine is a mediator in immediate hypersensitivity for the

following reasons.

1-Histamine injection reproduces the clinical manifestation of

immediate hypersensitivity.

2-Histamine is higher in tissue severely affected in

hypersensitivity as liver in dog.

3-Antihistamine injection decreases the intensity of the

anaphylactic shock.

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Immunopathology

4-Histamine can be demonstrated in blood during shock except

in rabbit because its platelets adhere to endothelium and disappear

from the circulation during shock.

1. Type I (Cytotropic anaphylactic)

It is an inflammatory reaction results from IgE mediated

immune response directs against environmental antigen (allergens)

and parasite antigen. The basic pathogenesis includessensitization

phase and an effector phase.The sensitization phase develops

when IgE become fixed on specific Fce receptors on surface of mast

cells and basophils. The host is now sensitized, and either through a

second exposure or prolonged exposure, combination of antigen with

fixed antibodies to mast cells and basophils, leading to release of

vasoactive (Histamine, leukotriene and prostaglandine D2),

chemotactic(Eosinophil chemotactic factor and inflammatory factor

of anaphylaxis) and spasmogenic substances (Histamine and

prostaglandins) that act on vessels and smooth muscle, results in

effector phase. Complement is not necessary.

Cytotropic anaphylactic may be localized or systemic

(anaphylactic shock).

A. Systemic or Anaphylactic shock

Anaphylaxis refers to an acute systemic hypersensitivity

reaction to an antigen that is mediated by IgE and involves mast cell

activation, resulting in a shock like state often involving multiple

organs. Release of vasoactive amine into the circulation causes

smooth muscle contraction, generalized vasodilation, and increase

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permeability.The clinical signs and pathology are varying by

species. This variation reflects differences in distribution of the mast

cells.The primary target tissues are blood vessels and smooth

muscle. It can be demonstrated experimentally in guinea pig, rabbit,

dog and cattle, these species react differently as follows.

1- Guinea pig: It dies within 10 minutes due to spasm of

bronchial muscles (Mast cells concentrated around bronchioles in

guinea pig).

2- Dog shows epileptiform fits, coma and death within 1-2

hours of restlessness, diarrhea and vomiting due to pooling of blood

in the liver and mesenteries due to contraction of venous passages,

especially the hepatic vein.

3- Cattle show cutaneous edema, particularly around the eyes,

valva and dyspnea.

4- Rabbit shows constriction of pulmonary artery and dilatation

of the right heart.

5- Rat shows increase vascular permeability and intestinal

hemorrhage.

The lesions of anaphylactic shock can be summarized as

Spasm of the smooth muscles of blood vessels and

bronchioles.

Damaged endothelium of blood vessels with increase

permeability.

Damaged connective tissue fibers

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Immunopathology

B- Local anaphylaxis or Atopy

In local types the clinical signs and pathological lesions are

restricted to a specific tissue or organ. Atopy means genetically

controlled predisposition to develop localized anaphylactic reaction

to inhaled or ingested allergens. Specific diseases include urticaria

and hay fever.Before we closed the discussion of type 1

hypersensitivity, it should be noticed that there are several beneficial

function for type I as antigen elimination and play a role in

resistance to parasites

2. Type II Hypersensitivity (Cytotoxic)

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Immunopathology

In the original Gill and Combs classification, the type II

hypersensitivity was define as antibody mediated cytotoxic

hypersensitivity. It is characterized by an antigen-antibody reaction

on the surface of a host cell that causes the destruction of such cell.

The antigen involved may be endogenous (normal cell or tissue

protein) to the cell or exogenous (drugs or microbial protein) and

attached to the cell surface. Specific antibody, commonly IgG and

IgM, is produced against the antigen and interact with it on the cell

surface. This cell interaction causes cell damage in several ways.

A- Complement dependent reactions

There are two mechanisms by which antibody and complement

mediate type II hypersensitivity.

1-Antibody reacts with the antigen present on the surface of the

cells causing activation of the complement system and resulting in

formation of membrane attack complex, resulting cell lysis.

2- The cells become susceptible to phagocytosis (opsonization)

by fixation of antibody or C3b fragment to the cell surface.

B- Antibody-dependent cell-mediated cytotoxicity

It does not involve fixation of the complement but instead

requires the cooperation of leukocytes. The target cell, coated with

antibody, are killed by a variety of non-sensitized cells (monocytes,

neutrophils, eosinophils and NK cells) that have Fc receptors, the

later bind to the target by their receptors for the Fc fragment of IgG

and cell lysis proceeds without phagocytosis.

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Immunopathology

Clinically type II hypersensitivity occurs in the transfusion

reaction, erythroblastosis fetalis, equine infectious anemia,

autoimmune hemolytic anemia and certain drug reaction.

3-Type III hypersensitivity (Aggregate)

Type III hypersensitivity is designated as immune complex

hypersensitivity. Interaction of antigen and antibody may result in

the formation of immune complexes, either locally or systematically,

which deposit at various sites in the body and activate complement

causing acute inflammation and injury. In type III hypersensitivity,

the cells or tissues are destroyed not because the antibody become

directed to that tissue, but rather because the immune complexes

either stuck to that cells or are deposited in that tissue.

Pathogenesis

Immune complex are capable of producing a wide variety of

acute inflammation through:

1-Interact withcomplement system to generate C3a and C5a

which stimulate the release of vasoactive amines and chemotactic

factors.

2-Stimulate macrophages to release cytokines that are very

important during inflammation.

Types of immune complex injury

1- Arthus phenomenon (Local form)

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Immunopathology

It is immediate hypersensitivity characterized by vasculitis.

Pathogenesis: The

subcutaneously injected

antigen into

hyperimmunized animal

diffuses away from the site

of injection into the vessel

walls and formed immune

complex beneath the

endothelial cells, when this

complex activate the

complement system, C3a

and C5a are produced and

neutrophils are attracted to

the site of injection.

Lesions:

Massive aggregation of neutrophils within the blood vessels

and in their wall.

Fibrinoid necrosis in the wall of the blood vessel.

Hemorrhage and edema.

Thrombosis

Serofibrinous inflammation.

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Immunopathology

2-Serum sickness (General type III immediate

hypersensitivity)

It may be acute or chronic

A-Acute serum sickness: It develops without previous

sensitization to the responsible antigen. Injection of a large amount

of antigen into the blood stream, as horse serum allows a part of

antigen to circulate in blood after development of the specific

antibody, thus antigen bind with antibody and form antigen-antibody

complex. The large complexes are removed from the blood by

phagocytic cells. The small complex is deposited in the vessels with

the complement. Release chemotactic factors from complement

invite neutrohpilic infiltrations which lead to necrotizing vasculitis.

Many vessels are affected but mostly the major arteries,

endocardium and renal glomeruli.

B-Chronic serum sickness: It results of repeated interavenous

exposure to antigen which results in immune complex formation in

blood. It is important in pathogenesis of many diseases-in man and

animals. It results in deposition of immune complexes on the

epithelial side of basement membrane of glomeruli. It may or may

not contain complement which leads to immune complex

glomerulonephritis(GBM-nephritis). Deposition of this complex in

vessel walls leads to vasculitis (similar to arthus phenomenon).

B. Delayed hypersensitivity

(Type IV hypersensitivity)

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Immunopathology

Type IV hypersensitivity is also known as cell mediated

hypersensitivity because it is the results of interaction of T

lymphocytes and the specific antigen to which they have been

sensitized. The resulting immune response is mediated either by

direct cytotoxicity by CD8 T lymphocytes or by the release of

soluble cytokines from CD4 lymphocytes, which act through

mediator cells (macrophages) to produce chronic inflammatory

reaction. Type IV hypersensitivity reaction take more than 12 hours

to develop (24-28 hours needed to develop because it depend in

sensitized lymphocytes) and involve cell mediate immune reaction

rather than humoral one, so it cannot be transferred by serum but can

transferred by T cells- The best example for Type IV

hypersensitivity is tuberculin reaction.

Types of delayed hypersensitivity

1-Infectious hypersensitivity

It is the prototypical types of delayed hypersensitivity as occurs

in localized tuberculin response. Moreover, it occurs in facultative

intracellular organisms, e.g. mycobacteria and fungi. It is the most

important form of type IV hypersensitivity. The best example is

Koch phenomenon.

Koch phenomenon is the reaction of the normal and

tuberculous guinea pigs to injected tubercle bacilli. The normal one

develops hard nodules at the site of injection within 2 weeks. The

nodule ulcerated and the animals die from generalized tuberculosis.

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Immunopathology

The tuberculous guinea pig develops inflammatory edema and

necrosis at the site of injection which heal later.

Microscopically, granulomatous reaction is seen

(Macrophages, lymphocytes and epithelioid cells)

2-Allergic contact dermatitis

Contact dermatitis is characterized by eczematous reaction at

the point of contact with an allergen.

Cause:

Contact with agents such- as nickel, dichromate compounds,

dyes, formaldehyde and synthetic fibers. A contact dermatitis has

two stages.

A-Sensitization: It takes 10-14 days and involved presentation

of the antigen by Langerhans cells and producing a populationofCD4 T cells.

B-Ellcitation: During this phase degranulation of mast cells

and cytokines release from other cells are potent inducer of

endothelial adhesion molecules and migration of mononuclear cells

toward the antigen.

Microscopically, the dermis infiltrated with mononuclear cells

beside hyperemia and edema of the dermis.

Table (4): Differences between immediate and delayed

hypersensitivities

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Immunopathology

Immediate Delayed

-Immediate onset (up to 12 hours). -Delayed onset (after 12 hours).

-Circulating antibodies (humoral). -Cellular immunity (no antibodies).

-Passive transfer by serum. -Passive transfer by cells.

-Affect smooth muscle, blood

vessels and collagen.

-Affect any tissue.

-Not affected by the rout of

administration.

- Almost through the skin.

-Types include: Type I,II and III. -Types include: Type IV.

3-Transplant rejection

The frequency of tissue transplantation has increased

dramatically since 1970. Immunologic reactivity against transplanted

cells may be directed against many antigens on the surface

membrane of cells such as

1-Antigens on erythrocytes

2-Antigens on surface of nucleated cells as MHC class I, II and III.

Mechanism of transplant rejection

1- Direct pathway of graft rejection is mediated by CD8 cytotoxic

T lymphocytes which cause cell injury and tissue damage

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Immunopathology

2-Indirect pathway of graft rejection: It mediated by recipient's T

lymphocytes that recognize antigen on the graft presented by

the antigen presenting cells of the recipient. It is depend on the

activation of CD4 lymphocytes and elaboration of cytokines

and development of delayed hypersensitivity.

Table showing mechanisms of immunologic tissue injury

Type Mechanisms Examples

Type I

(Anaphylactic,

atopic)

Humoral Abs of IgE type resulted

in basophils/mast cell sensitize

and release of anaphylactic

Systemic anaphylaxis

Local anaphylaxis such as hay

fever, bronchial asthma

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Immunopathology

mediators

Type II

Cytotoxic

i-Cytotoxic auto and iso-

antibodies to blood cells

ii-Cytotoxic Abs to tissue

components

iii-Ab dependent cell mediated

cytotoxicity (ADCC)

i. Autoimmune hemolytic

anemia, transfusion reaction

ii. Myasthenia gravis

iii. Tumor cells and parasites

Type III i. Local (|Arthus

reaction) Ag-Ab

complexes

ii. Systemic (circulating)

Ag-Ab complexes or

serum sickness

i. Injection of ATS

ii. Glomerulonephritis

Type IV

(Cell mediated)

i. Classical delayed hyper

sensitivity mediated by CD4 T

cell

ii. T cell mediated cytotoxicity by

CD8 T cells

i-Tuberculin reaction

ii-Virus infected cells,

transplant rejection

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Final Immunology 6