Dental Microbiology 211 IMMUNOLOGY 2006 Lecture 6 Adverse

Dental Microbiology #211 IMMUNOLOGY 2006 Lecture 6 Adverse Immune Reactions and Immune Deficiencies

Topics • Hypersensitivity reactions • Ig. E-mediated hypersensitivity (Allergy) • T cell-mediated reactions (Delayed-type hypersensitivity) • Autoimmune disorders • Inherited and acquired immunodeficiency disorders • Impact on the oral cavity

Hypersensitivity (Allergy) Definition: Altered capacity of the immune system to react to a foreign substance The hypersensitivity states or allergies can be divided into four categories: Type I (Ig. E antibody-mediated) Type II (Ig. G and Ig. M-mediated) Type III (Immune complex-mediated) Type IV (T cell-mediated)

Over 30% of individuals in the western hemisphere have the tendency to produce increased Ig. E levels-and suffer from Ig. Emediated reactions. They are called atopic individuals. The atopic state is influenced by both genetic and environmental factors. The prevalence of atopic allergy and bronchial asthma is affected by air pollution and exposure to infectious diseases of the respiratory tract

The Ig. E molecule Fig 1

Type I (Ig. E-mediated hypersensitivity reactions) There are certain antigens and routes of Ag exposure that favour Ig. E Ab production Antigens that evoke Ig. E responses are collectively called allergens The symptomatology is different depending on whether the Ag is injected, inhaled or ingested i. e. depending on the tissue where the pharmacologic mediators of allergy i. e histamine and serotonin are released (the target tissue).

Ig. E-mediated reactions Fig 2

Mediator release Fig 3 Ig. E is present in low concentrations in the plasma (<50 nannograms/ml) The Fc segment of Ig. E binds with extremely high affinity to an Fc receptor, called Fc, RI, on mast cells and basophils. Basophils are circulating polymorphonuclear leukocytes. Mast cells reside in tissues Ig. E has a half life of only two days in the plasma but over 30 days when bound to a Fc, RI on basophil or mast cell surface. The biological effector mechanism is triggered when mast cell- (or basophil-) bound Ig. E molecules are cross-linked by multivalent Ag. The cross-linking induces membrane modifications resulting in the release of granules containing powerful pharmacologic mediators such as histamine and serotonin

Allergens Most allergens are relatively small molecular weight soluble proteins carried on desiccated particles (pollen, dander, dried animal saliva, house mite faeces, etc) which become released from the particles, and penetrate the respiratory or the gastro-intestinal mucosa, depending on whether they are airborne or ingested.

House-dust Mites Fig 4 Fecal pellets

Consequences of mediator release Fig 5 Two major pathological consequences: contracti of smooth muscles and increase in vascular permeability. All symptoms of Ig. Emediated allergic reactions can be explained based on the two effects

Oral Allergy Syndrome In the oral cavity a specific condition called Oral Allergy Syndrome appears when an allergen (from foods or drugs) makes contact with the oral cavity in sensitive patients. This syndrome is characterized by a rapid swelling of the lips, tongue, gums, palate and pharynx.

Early and Late phases An Ig. E allergic reaction is divided into an immediate response (seconds to minutes) and a late-phase response (8 -10 hr). Ig. E-mediated reactions have also been termed Immediate -type hypersensitivity reactions. The intradermal injection of a minute amount of allergen into an allergic (atopic) individual gives rise to a local reaction called cutaneous anaphylaxis characterized by the immediate appearance of a blister full with histamine called a wheal, and redness around it called erythema or flare

The Wheal and Flare, and the Latephase responses Fig 6 Immediate: appearance of a blister containing histamine called a wheal, surrounded by redness called erythema or flare Late: Only erythema

Systemic anaphylaxis Allergen given in high doses and reaching the circulation, or given intravenously, triggers the sudden release of large quantities of mediators from the mast cells, and by the basophils in the circulation, and may cause a generalized or systemic reaction called systemic anaphylaxis or anaphylactic shock. These reactions can be fatal: insect venoms or drugs (antibiotics, sulphonamides or even foods) Oral cavity: Anaphylactic shock to local anaesthetics such as lidocaine or novocaine although rare, are encountered in dental practice

Treatment Allergy can be treated: a) by inhibiting Ig. E production through immune deviation, called also desensitization therapy or b) by interfering with the release of mediators or with their pharmacologic effects, such as administration of anti-histamines and topical steroids (Fluticasone propionate), or of drugs that prevent mast cell/basophil degranulation (cromolyn sodium). c) Epinephrine injection (against anaphylactic shock)

Type-II Hypersensitivities Triggered by Ig. G or Ig. M Ab directed against cells and tissues. These Ab activate the complement cascade which in turn induces target inflammation and cell death. E. g. Ig. G or Ig. M Antibodies against red blood cells Haemolytic anemia

Type-III Hypersensitivities Soluble Antigen reacting with soluble Ab in the circulation activate the complement cascade leading to powerful inflammatory reactions due to the release of anaphylatoxins. E. g. glomerulonephritis (the immune complexes are deposited on the glomerular basement membrane of the kidney)

Type-IV Hypersensitivities Due to the activation of Th-1 cells. The typical type-IV reaction is called also delayed-type hypersensitivity (DTH) The intradermal administration of antigen recognized by an effector CD 4+ Th-1 cell local cutaneous reaction. “delayed”: takes 12 -24 hr to appear. The aspect of the lesion is different from the wheal and flare of Ig. E. Typical examples of DTH reactions are cutaneous reactions to tuberculin in individuals that were in previous contact with tubercle bacilli (Mycobacterium tuberculosis), and reactions to poison ivy

DTH Reaction to Poison Ivy Fig 7

Autoimmune diseases Chronic inflammatory conditions that arise as a result of either Ab- or T cell-mediated responses to self-antigens (auto-antigens). Typical examples: Juvenile Diabetes: Target tissue: Beta islets (produce insulin) of the pancreas Multiple Sclerosis. Target tissue: CNS white matter (Myelin) Systemic Lupus Erythematosus (SLE): anti-DNA Ab. Target tissue: Kidney, Joints, Leukocytes Graves disease. Target tissue: Thyroid gland. Rheumatoid arthritis. Target tissue (joints).

Immune deficiencies Occur when one or more components of the immune system are defective. Immune defects can be inherited or acquired. The immune defects can involve the T cell, the B cell or both compartments of the immune system, the Complement or the APC.

Inherited (Genetic) Immune defects Genetic defects can occur in almost any molecule involved in the immune response. T cell defects: Di. George syndrome: Failure of the thymus to be formed (thymic aplasia). Patients suffer from general susceptibility to infections since the absence of T lymphocytes impacts also on the ability of B cells to synthesize antibodies (see Lectures 3 and 5

Inherited B cell defects X-linked agammaglobulinemia: X-chromosome-linked inability to produce B lymphocytes, leads to absence of Ig. Patients suffer mainly from infectious diseases with bacteria and viruses that require antibodies for their disposal.

Mixed Immunodeficiencies Inherited mixed T and B cell defects: X-linked Severe combined immune deficiencies (SCID). Patients suffer from total susceptibility to infections since neither T nor B cells are generated. Inherited defects of phagocytic function. Inherited defects of complement: Loss of specific complement components. Inability to form the MAC and/or to produce anaphylatoxins.

Acquired immune deficiencies. Acquired immune deficiency syndrome (AIDS). The immune response becomes defective as a result of exposure to the Human Immunodeficiency Virus (HIV). The HIV infects selectively CD 4+ T cells and macrophages. The disease is usually lethal due to loss of CD 4+ T cells. B cell and T cell tumours (myelomas and lymphomas). The uncontrolled growth either B or T lymphocyte tumours encroaches on the ability of normal T and B cells to divide and perform their function.

Consequences of immunodeficiencies in dental patients Increased incidence of infections in the oral cavity (Herpes virus), even with organisms that are usually nonpathogenic such as Candida species (candidiasis): In AIDS patients In cancer patients undergoing chemotherapy, and in immunosuppressed transplant recipients: Increased plaque formation Ulcerations Xerostomia Sialadenitis Periodontal disease, bone loss Osteomyelitis Papillary atrophy of the tongue

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