Type of Immune Disease

8/3/2019 Type of Immune Disease

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Hypersensitive reaction

Several important general features of hypersensitivity disorders :

Both exogenous and endogenous antigens may elicit hypersensitivity reactions. The development of hypersensitivity diseases (both allergic and autoimmune

disorders) is often associated with the inheritance of particular susceptibility

genes.

A general principle that has emerged is that hypersensitivity reflects animbalance between the effector mechanisms of immune responses and the

control mechanisms that serve to normally limit such responses.

1.Immediate (Type 1) Hypersensitivity

Mediated by immunoglobulin E(IgE) antibodies directed against

specific antigens

Many local type I hypersensitivity

reactions have two well-defined phases

The immediate or initial reaction1. Characterized by

vasodilation, vascular

leakage, and depending on

the location, smooth muscle

spasm or glandular

secretions.

2. become evident within 5 to30 minutes after exposure toan allergen and tend to

subside in 60 minutes

late-phase reactiono sets in 2 to 24 hours later

without additional exposure

to antigen and may last for

several days.

o characterized by infiltrationof tissues with eosinophils,

neutrophils, basophils,

monocytes, and CD4+ T cells

as well as tissue destruction,

typically in the form of

mucosal epithelial cell

damage.

Most immediate hypersensitivity reactions are mediated by IgE antibodydependentactivation of mast cells and other leukocytes.

- Mast cells are bone marrow-derived cells that are widely distributed in thetissues and activated by the cross-linking of high-affinity IgE Fc receptors

- Basophils are similar to mast cells in many respects, including the presence ofcell surface IgE Fc receptors as wellas cytoplasmic granules, and not normally

present in tissues but rather circulate in the blood in extremely small numbers.


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- TH2 cells play a central role in the initiation and propagation of immediatehypersensitivity reactions by stimulating IgE production and promoting

inflammation

Mediator

- Preformed (Primary) Mediator stored in the granules, and de novo synthesis3 categories of prefored (Primary) Mediator

1. Vasoactive amines. The most important mast cellderived amine ishistamine

2. Enzymes, cause tissue damage and lead to the generation of kinins andactivated components of complement by acting on their precursor

proteins

3. Proteoglycans, serve to package and store the amines in the granules.(e.g: Heparin)

- Lipid (Secondary) Mediator synthesized by sequential reactions in the mast cell membranes that lead to

activation of phospholipase

Component of secondary Mediator

1. Leukotrienes2. Prostaglandin D23. Platelet-activating factor (PAF

Condition important example of IgE mediated disease

1. Systemic Anaphylaxis- Follows parenteral or oral administration of an allergen (drugs, food)

- sign and symptom : pruritus, urticaria and erithema occur minutes after exposure

followed by bronchoconstriction and laryngeal edema obstruction

2. Local Immediated Hypersensitive Reactions

- These reactions are exemplified by atopic allergies

- local type response to common inhaled or ingested allergen

- symptom : urticaria, angioedema, rhinitis and asthma

2. Antibody-Mediated (Type II) Hypersensitive

This type of hypersensitivity is caused by antibodies that react with antigens present on

cell surfaces or in the extracellular matrix..There are 3 mechanism of antibody-

mediated injury.

a. Opsonization and Phagocytosis

- Cells opsonized by IgG antibodies are recognized by phagocyte Fc receptors, which are

specific for the Fc portions of some IgG subclasses.

- The net result is phagocytosis of the opsonized cells and their Destruction

- Antibody-mediated destruction of cells may occur by another process called antibody-

dependent cellular cytotoxicity (ADCC). Its mediated by monocytes, neutrophils,eosinophils, and NK cells

- antibody-mediated cell destruction and phagocytosis occur in the followingsituations :

o transfusion reactions,o hemolytic disease of the newborn (erythroblastosis fetalis),o autoimmune hemolytic anemia ,agranulocytosis, and thrombocytopenia


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o certain drug reactionsb. Inflammation

- When antibodies deposit in fixed tissues, such as basement membranes and

extracellular matrix, the resultant injury is due to inflammation

- due to both complement- and Fc receptordependent reactions

- Antibody-mediated inflammation is the mechanism responsible for tissue injury insome forms of glomerulonephritis, vascular rejection in organ grafts, and other

disorders

c. Cellular Dysfunction

- In some cases, antibodies directed against cell surface receptors impair or dysregulate

function without causing cell injury or inflammation

3. Immune Complex-Mediated (Type III) Hypersensitivity

- Antigen-antibody complexes produce tissue damage mainly by elicitinginflammation at the sites of deposition

- can be systemic, if immune complexes are formed in the circulation and aredeposited in many organs, or localized to particular organs, such as the kidney(glomerulonephritis),joints (arthritis), or the small blood vessels of the skin if

the complexes are deposited or formed in these tissues


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- The pathogenesis of systemic immune complex disease can be divided intothree phases :

1. Formation of antigen-antibody complexes in the circulationThe introduction of a protein antigen triggers an immune response that

results in the formation of antibodies, typically about a week after the

injection of the protein2. deposition of the immune complexes in various tissues, thus initiating3. an inflammatory reaction at the sites of immune complex deposition

- Local Immune Complex Disease (Arthus Reaction) is a localized area of tissuenecrosis resulting from acute immune complex vasculitis, usually elicited in the

skin. As the antigen diffuses into the vascular wall, it binds the preformed

antibody, and large immune complexes are formed locally. These complexes

precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed

thrombosis worsens the ischemic injury


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4. T-Cell Mediated (Type IV) Hypersensitivity

- initiated by antigen-activated (sensitized) T lymphocytes,including CD4+ andCD8+ T cells

- induced by environmental and self-antigens can be a cause of chronicinflammatory disease.- Reactions of CD4+ T Cells: Delayed-Type Hypersensitivity and Immune

Inflammation

o The same immunological events are responsible for chronic inflammatoryreactions against self-tissues

o Lead to granuloma formation- Reactions of CD8+ T Cells: Cell-Mediated Cytotoxicity

o In this type of T cellmediated reaction, CD8+ CTLs kill antigen -bearingtarget cells

o The killing of infected cells leads to the elimination of the infection, and isresponsible for cell damage that accompanies the infection (e.g., in viralhepatitis)

o Lead to apoptosis


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Summary Table

Autoimmune Diseaseat least three requirements should be met before a disorder is categorized as truly due

to autoimmunity:

(1) the presence of an immune reaction specific for some self-antigen or self-tissue;

(2) evidence that such a reaction is not secondary to tissue damage but is of primary

pathogenic significance; and

(3) the absence of another well-defined cause of the disease

- The diseases can be organ spesific disease or systemic or generalized disease


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Immunological ToleranceImmunological tolerance is the phenomenon of unresponsiveness to an antigen

as a result of exposure of lymphocytes to that antigen. Self-tolerance refers to lack of

responsiveness to an individual's own antigens, and it underlies our ability to live in

harmony with our cells and tissues.The mechanisms of self-tolerance can be broadly classified into two groups:

central tolerance and peripheral tolerance :

a. Central Tolerance

In this process, immature self-reactive T- and B-lymphocyte clones that recognize self-

antigens during their maturation in the central (or generative) lymphoid organs (the

thymus for T cells and the bone marrow for B cells) are killed or rendered harmless

b. Peripheral Tolerance

Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues;

these are best defined for T cells

-Anergy: This refers to prolonged or irreversible functional inactivation oflymphocytes, induced by encounter with antigens under certain conditions.

- Suppression by regulatory T cells- Deletion by activation-induced cell death


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Mechanism of AutoimmunityAutoimmunity arises from a combination of the inheritance of susceptibility genes,

which may

contribute to the breakdown of self-tolerance, and environmental triggers, such as

infections and tissue damage, which promote the activation of self-reactive lymphocytes

- Role of Susceptibility GenesSeveral autoimmune disease are linked with the HLA locus, especially class II

alleles (HLA-DR, -DQ)

- Role of InfectionTwo mechanisms have been postulated to explain the link between infections

and autoimmunity

o Induction of costimulators on APCs :If these cells are presenting self-antigens, the result may be a breakdown of anergy and activation of T

cells specific for the self-antigens.

o Molecular Mimicry: some microbes may express antigens that have thesame amino acid sequences as self-antigens.may result in the activation ofself-reactive lymphocytes

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Type of Immune Disease