Disorders of the immune system

Disorders of the Immune System Hypersensitivity

Caused by excessive immune activity

Autoimmunity Caused by a misdirected attack against ‘self’

Immunodeficiency Caused by reduced responsiveness of the

immune system

Persistent inflammation Caused by absence of the normal dampening of

the inflammatory response

Hypersensitivity Hypersensitivity reactions are defined as an

inappropriate response to an antigen that causes damage to an individual.

Four Types of Hypersensitivity Reactions: Type I (Anaphylactic) Reactions

e.g. Hay fever, hives, asthma

Type II (Cytotoxic) Reactions e.g. Transfusion reactions

Type III (Immune Complex) Reactions e.g. glomerulonephritis (inflammatory kidney damage)

Type IV (Cell-Mediated) Reactions e.g. tuberculosis skin test, latex sensitivity

HypersensitivityType I (Anaphylactic)

Reactions Occur in within minutes of exposure to antigen.

IgE binds to mast cells and basophils causing degranulation and release mediators: Histamine: Dilates and increases permeability of blood

vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi).

Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion.

Leukotrines: Bronchial spasms.

Large and widespread output of histamine can also cause contraction of smooth muscle in the lung tubules, making breathing difficult (anaphylaxis).

Hayfever

Plasma cell

Interleukins

Mature helper T cell

B cell

IgEAllergen

SymptomsMediators

Mast cell

Allergies such as hay fever and hives are related to the antibody known as IgE. The first time an allergy-prone person is exposed to an allergen--for instance, grass pollen--the individual’s B cells make large amounts of grass pollen IgE antibody. These IgE molecules attach to granule-containing cells known as mast cells, which are plentiful in the lungs, skin, tongue, and linings of the nose and gastrointestinal tract. The next time that person encounters grass pollen, the IgE-primed mast cell releases powerful chemicals that cause the wheezing, sneezing, and other symptoms of allergy.

Mast celldegranulation

HypersensitivityType II (Cytotoxic)

Reactions Involve activation of complement by

IgG or IgM binding to an antigenic cell.Antigenic cell is lysed.

Example – Transfusion Reactions ABO Blood Groups – O is the universal donor.

Incompatible donor cells are lysed as they enter the blood stream.

Rh Blood Group – 85% of population is Rh+. Those who are Rh- can be sensitised to destroy Rh+ blood cells. Haemolytic disease of the newborn: foetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta.

HypersensitivityType III (Immune Complex)

Reactions Immune complexes are clusters of interlocking

antigens and antibodies. Involve reactions against soluble antigens

circulating in the serum. Usually involve IgA antibodies. Normally they are rapidly removed from the

bloodstream. In some circumstances, however, they continue

to circulate, and eventually they become trapped in, and damage, the tissues of the kidneys, or the lungs, skin, joints, or blood vessels.

Immune Complex Mediated Hypersensitivity

HypersensitivityType IV (Cell Mediated)

Reactions Involve reaction by T memory cells

First contact sensitizes, subsequent contacts elicit a response

Reactions are delayed by one or more days (delayed type hypersensitivity) Delay due to migration of macrophages and T cells to the site of

foreign antigen

Reactions are frequently displayed on the skin: itching, swelling, redness, pain Tuberculosis skin test Poison ivy Metals Latex in gloves and condoms (3% of healthcare workers)

Anaphylactic shock may occur

Allergic contact dermatitis response to poison ivy

AutoimmunityLoss of self tolerance leads to production

of antibodies or T cells that react against one’s own antigens.

Immune system response to self antigens causes damage to organs.

Three types of autoimmune disorders: Cytotoxic (type II reactions)

e.g. Grave’s disease Immune complex (type III reactions)

e.g. Lupus, rheumatoid arthritis Cell-mediated (type IV reactions)

e.g. type I diabetes, pernicious anaemia, multiple sclerosis

AutoimmunityType II (Cytotoxic) Reactions

Involve antibody reactions to cell surface molecules, without cytotoxic destruction of cells.

Graves Disease: Antibodies attach to receptors on thyroid gland and

stimulate production of thyroid hormone. Symptoms: Goiter (enlarged thyroid) and bulging eyes.

Myasthenia gravis: Progressive muscle weakness. Antibodies block

acetylcholine receptors at neuromuscular synapse. Affects higher percentage of women than men. Today most patients survive when treated with drugs or

immunosuppressant.

AutoimmunityType III (Immune Complex) ReactionsSystemic Lupus Erythematosus 90% of those affected are women Name derived from red skin rash on face Autoantibodies react against DNA, blood cells, neurons, and

other tissues When cells die, immune complexes form and deposit under

skin, joints, in kidneys, blood vessels, and central nervous system

Inflammation interferes with normal function of these sites (arthritis, rash, kidney damage)

Most patients die from kidney damage No cure Symptoms treated with anti-inflammatory and

immunosuppressive drugs.

AutoimmunityType III (Immune Complex) ReactionsRheumatoid Arthritis 70%+ of those affected are women Cause unknown, but microbial mimicry may be

involved IgM autoantibodies (rheumatoid factors) against IgG

form complexes in joint, leading to inflammation and cartilage damage

Often causes finger and joint deformities No cure Symptoms treated with anti-inflammatory (aspirin)

and immunosuppressive drugs. Physical therapy keeps joints movable. Surgical replacement of joints may be necessary.

AutoimmunityType IV (Cell-mediated) ReactionsDiabetes Mellitus Insulin-dependent (Type I or Juvenile)

diabetes.Makes up 10% of diabetes cases.Characterized by insufficient insulin

production due to immunological destruction of insulin-secreting cells of the pancreas by T cells.

Usually develops before the age of 15. Treated with insulin injections.

Autoimmune Disease: Diabetes

Cytotoxic T cell

Pancreas

Beta cell

ImmunodeficiencyTwo main forms of immunodeficiency

disease.

Primary immunodeficiency Congenital (baby is born with deficiency) May be result of genetic defect or developmental

abnormality Examples: DiGeorge syndrome, SCIDS (Severe

combined immunodeficiency)

Secondary immunodeficiency Acquired as a result of severe stress or other diseases

i.e. AIDS

Primary immunodeficiencySCIDS

Inherited X-linked genetic disease. Bone stem cells are defective so neither T or B cells are

produced. Non-existent immune system means that even trivial

infections are fatal to SCID babies. Need to live in tightly controlled sterile environments in

order to survive. Conventional treatment has been bone marrow transplant

to replace defective stem cells – requires lifelong regime of immunosuppressive drugs to prevent rejection.

Gene therapy is new approach – bone marrow cells extracted and infected with virus carrying normal form of defective gene. Cells then transplanted back into patient. New normal cells are found in the circulation after a few weeks.

Secondary immunodeficiencyAIDS

Acquired immunodeficiency syndrome. Results from human immunodeficiency virus (HIV). HIV destroys helper T cells. The virus copies itself incessantly and invades helper

T cells and macrophages, the very cells needed to organize an immune defense.

HIV splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses.

Death from AIDS is usually due to infections such as pneumonia that rage unchecked because the helper T cells are unable to activate normal immune responses.

Persistent inflammation Inflammation is an important component

of the innate immune response.

Research suggests that continued presence of the cells and molecules of the inflammatory response may contribute to a wide variety of diseases – not causing the disease, but causing a continuing problem.

Examples include: heart disease, rheumatoid arthritis, severe asthma, Alzheimer’s disease and cancer.