Hypersensitivity Reactions

Disorders of Immunity Hypersensitivity Reactions

Dr. Mehzabin Ahmed

THE IMMUNE SYSTEM IN HEALTH & DISEASE  The immune system enables

us to recognize self from non-self and thereby confer protection against disease  It is made up of complex network of  Lymphocytes  in tonsils, lymphnodes, thymus, spleen and bone marrow,  Monocytes and macrophages  Plasma proteins  Cytokines (Chemical messengers)

 The most common clinical

problems are:  Overactivity of the immune response leading to allergic and autoimmune disease.  Underactivity resulting in immunodeficiency.  Inappropriate activity of the immune system resulting in autoimmune disorders

The immune system in health:  Innate immunity: Consists of the rapidly acting (front line) host

defense mechanism and includes both physical as well as elements of immune system. They are: a) Physical or chemical barriers: Skin and mucus membrane, Gastric acid, lactoferrin, nitric oxide in secretions b) Mechanical removal: Sneezing, coughing, Secretions and urine, Ciliary escalator of respiratory mucosa c) Non specific immune system: Phagocytes, NK cells, Complement, Interferon d) Colonization resistance: Present in the skin and G.I.T. of normal flora preventing colonization by pathogenic organism.

Phagocytes: They provide the first line of defense.

 •

Neutrophils - is microbe killing phagocyte. These cells are released in the large numbers during acute infection.

•

Eosinophils - used selectively for fighting parasitic infection. Eosinophils also participate in immediate hypersensitivity (allergic) reactions.

•

Macrophages – destroy bacteria and foreign bodies

Disorders of the Immune System 1.

Hypersensitivity reactions

2.

Autoimmune diseases

3.

Immunologic deficiency syndromes

4.

Amyloidosis

Hypersensitivity reactions •

Type I hypersensitivity (Immediate Hypersensitivity)

•

Type II hypersensitivity (Antibody-mediated disorder)

•

Type III hypersensitivity (Immune complex-mediated disorder)

•

Type IV hypersensitivity (Cell-mediated immune disorder)

Immediate, or Type I, Hypersensitivity  occurring within minutes after the

combination of an antigen with an IgE antibody bound to mast cells in individuals previously sensitized to the antigen  Activation of the mast cells in type I

hypersensitivity causes release of their mediators  Common examples are bronchial

asthma, urticaria/ hives, anaphylactic shock

Many local type I hypersensitivity reactions have two well-defined phases  The immediate, or initial, response within 5 to 30 minutes is

characterized by 

vasodilation,



vascular leakage, and



smooth muscle spasm or



glandular secretions.



Due to release of primary mediators.

 The late-phase reaction sets in 2 to 24 hours later is characterized by 

infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as



tissue destruction, typically in the form of mucosal epithelial cell damage due to release of secondary mediators.

Type II hypersensitivity

 Type II hypersensitivity is mediated by antibodies

directed toward antigens present on cell surfaces or extracellular matrix.

 Three different antibody-dependent mechanisms

involved in this type of reaction are described.

1. Opsonin and Complement-and Fc Receptor-Mediated Phagocytosis When antibodies are deposited on the surfaces of cells, they may activate the complement system (if the antibodies are of the IgM or IgG class). Complement activation on cells also leads to the formation of the membrane attack complex, which causes lysis of the cells In addition, 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 the phagocytosis of the opsonized cells and their destruction

A. Complement-dependent reactions that lead to lysis of cells or render them susceptible to phagocytosis.

Clinically, antibody-mediated cell destruction and phagocytosis occur in the following situations: •

transfusion reactions

•

erythroblastosis fetalis

•

autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia

•

certain drug reactions

2. antibody-dependent cellular cytotoxicity (ADCC)

 Antibody-mediated

destruction of cells may occur by another process

 IgG coated target cells

are killed by cells that bear Fc receptors for IgG (e.g., NK cells, macrophages).

3. Antibody-Mediated Cellular Dysfunction  In some cases, antibodies directed against cell-surface receptors

impair or dysregulate function without causing cell injury or inflammation.  For example, in myasthenia gravis, 

antibodies reactive with acetylcholine receptors in the motor endplates of skeletal muscles impair neuromuscular transmission and therefore cause muscle weakness.

 The opposite i.e., antibody-mediated stimulation of cell function is

noted in Graves disease. 

In this disorder, antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

Antireceptor antibodies disturb the normal function of receptors. In this example, acetylcholine receptor antibodies impair neuromuscular transmission in myasthenia gravis.

Type lll hypersensitivity reaction  Two general types of antigens cause immune complex-mediated

injury: (1) The antigen may be exogenous, such as a foreign protein, a bacterium, or a virus; or (2) Under some circumstances, the individual can produce antibody against self-components-endogenous antigens

Examples of Immune Complex-Mediated Diseases

Disease

Antigen Involved

Clinicopathologic Manifestations

Systemic lupus erythematosus

DNA, nucleoproteins, others

Nephritis, arthritis, vasculitis

Polyarteritis nodosa

Hepatitis B virus surface antigen (in some cases)

Vasculitis

Poststreptococcal glomerulonephritis

Streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane

Nephritis

Acute glomerulonephritis

Bacterial antigens (Treponema); parasite antigens (malaria, schistosomes); tumor antigens

Nephritis

Reactive arthritis

Bacterial antigens (Yersinia)

Acute arthritis

Arthus reaction

Various foreign proteins

Cutaneous vasculitis

Serum sickness

Various proteins, e.g., foreign serum (antithymocyte globulin)

Arthritis, vasculitis, nephritis

The pathogenesis of systemic immune complex disease can be divided into three phases

•

formation of antigen-antibody complexes in the circulation;

•

deposition of the immune complexes in various tissues, thus initiating; and

•

an inflammatory reaction at the sites of immune complex deposition

Schematic illustration of the three sequential phases in the induction of systemic type III (immune complex) hypersensitivity.

Circulating immune Complexes (CIC)  Large complexes formed in great antibody excess are

rapidly removed from the circulation by the mononuclear phagocyte system and are therefore relatively harmless.

 The most pathogenic complexes are of small or

intermediate size (formed in slight antigen excess), which bind less avidly to phagocytic cells and therefore circulate longer.

Deposition of CICs  In addition to the renal glomeruli, the favored sites of

immune complex deposition are joints, skin, heart, serosal surfaces, and small blood vessels.  They produce vasculitis, arthritis, endocarditis,

glomerulonephritis, pericardial and pleural effusions

Cell-Mediated (Type IV) Hypersensitivity  The cell-mediated type of hypersensitivity is initiated by

antigen-activated (sensitized) T lymphocytes.  It includes the



delayed type hypersensitivity reactions mediated by CD4+ T cells



direct cell cytotoxicity mediated by CD8+ T cells.

Delayed type hypersensitivity reactions  The reaction is mediated by CD4+

helper T cells  T cell–derived cytokines give rise

to the formation of

granuloma

in type IV hypersensitivity reactions.  Commonly seen in TB, Leprosy

A section of a lymph node shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleate giant cells.

Mantoux Test  The classic example of delayed hypersensitivity is the

tuberculin reaction, 

It is produced by the intracutaneous injection of tuberculin, a protein-lipopolysaccharide component of the tubercle bacillus.



In a previously sensitized individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside.