Chapter 3 Immunity and Immunologic Oral Lesions · Type II Hypersensitivity Cytotoxic type...

Chapter 3

Immunity and Immunologic Oral Lesions

Copyright © 2014, 2009, 2004, 2000, 1996, 1992 by Saunders, an imprint of Elsevier Inc 1

� Outline Ø Acquired Immune ResponseØ AntigensØ Cellular Involvement in the Immune ResponseØ Major Divisions of the Immune ResponseØ Memory and ImmunityØ Types of ImmunityØ ImmunopathologyØ Oral Diseases with Immunologic PathogenesisØ Autoimmune Diseases that Affect the Oral Cavity


Acquired Immune Response

� Defends the body against injury

� Has memory capability

� Responds quicker than inflammatory response

� Involves complex network of white blood cells

� May result in increased level of tissue damage and disease as it fights


Antigens or Immunogens

� Foreign substances versus body� Components of self as antigen

Ø Tumor cellsØ Cells infected with virusesØ Organ transplantØ Tissue graftØ Incompatible blood transfusionØ Cells of own body: Autoimmune diseases

� Non-recognition of foreign material as antigen: Autoimmune disease

� Overreaction to antigens: Hypersensitivity


Cellular Involvement in the Immune Response

� Cytokines� Lymphocytes

Ø B-cell lymphocytesØ T-cell lymphocytesØ Natural killer cells

� Macrophages� Dendritic cells


Cellular Involvement in the Immune Response


B-Cell Lymphocytes

� Develop from stem cells in bone marrow� Mature and reside in lymphoid tissue

Ø Lymph nodes, tonsils, and other body tissue

� B cells travel to the site of injury when stimulated by antigen

� Two main types:Ø Plasma cell: Produces specific antibodiesØ B memory cell: Retains the memory of previously encountered

antigen and will clone itself in the presence of antigen


B-cell Lymphocytes: Plasma Cells

� Round, pinwheel-shaped nucleus with visible cytoplasm

� Produces and releases a protein (antibody) in response to presence of antigen

� Circulating antibodies: Immunoglobulins (Igs)


B-cell Lymphocytes: Plasma Cells

� Five different types of immunoglobulins:Ø IgAØ IgDØ IgEØ IgGØ IgM

� Antibody titer: Level of a specific antibody� Immune complex: Antibody + antigen


T-cell Lymphocytes� Develop from bone marrow stem cell� Travel to the thymus and mature� Types of T-cell lymphocytes:

Ø Memory cellsØ T-helper cells: Increase functioning of B cellsØ T-suppressor cells: Turn off functioning of B cellsØ T-cytotoxic cells: Attack virally infected cells or tumor cells


T-cell Lymphocytes


T-Cell Lymphocytes: Function Review

� Increase the function of B cells: Enhancing the antibody response

� Carry the CD8 marker

� Active in surveillance against virally infected cells

� Directly attack virally infected and neoplastic cells

� Start, regulate, and coordinate the overall immune response


Natural Killer (NK) Cells

� Destroy foreign cells

� Located within the microcirculation

� Active against viruses and cancer cells

� Activity can be abnormal as in HIV infection


Macrophages

� Accessory cells in immune response

� Located in connective tissue (CT) during inflammation

� Functions: Ø Phagocytosis Ø Assist B cells and T cells


Macrophages: Functions Continued

� Phagocytosis

� Messenger between inflammatory response and immune response

� Activating factor: Produce and secrete lysosomal enzymes

� Amplify the immune response but do not have memory of the encountered antigen


Dendritic Cells (DCs)

� Type of white blood cell found on skin, mucosa, and in blood

� Antigen-presenting cells (APCs): Process antigenic material and present it to other immune system cells

� Messenger between innate immunity and acquired immunity

� Langerhans’ cell: Specialized dendritic cell


Cytokines

� Immunomodulating agents: Alter the immune response� Communication system

Ø InterleukinsØ Macrophage chemotactic factorØ Migration inhibitory factorØ Macrophage-activating factorØ LymphotoxinØ InterferonsØ Tumor necrosis factor


Major Divisions of the Immune Response

� Humoral immunity � Cell-mediated immunity


Immune Response

� Humoral immunity� Antibody-mediated

immunityØ Production of antibodiesØ Protection against

bacteria and virusesØ B cells are the primary

cells

� Cell-mediated immunity� Cellular immunity

Ø T cells are the primary cellsØ Regulates both major immune

responses


Memory and Immunity

� The immune system has memory; the inflammatory system does notØ Some lymphocytes retain memory of an antigen after an initial

encounter

Ø This means the immune response will be faster and stronger the next time an antigen enters the body

Ø The retained memory is called immunity


Types of Immunity: Passive and Active

� Passive immunity: Using antibodies created by another person to prevent infectious diseaseØ Natural: Mother to fetusØ Acquired: Injection

� Active immunity: Antibodies created by the person himself or herselfØ Natural: Microorganism causes the diseaseØ Acquired: Immunization, vaccination, booster

• Killed-type vaccine• Live-attenuated vaccine


Immunopathology

� The study of immune reactions involved in disease; the study of diseases caused by the malfunctioning of the immune systemØ Hypersensitivity

Ø Autoimmune diseases

Ø Immunodeficiency


Hypersensitivity or Allergy

� Type I or anaphylactic type: Hay fever, asthma, anaphylaxis

� Type II or cytotoxic type: Autoimmune hemolytic anemia� Type III or immune complex type: Autoimmune diseases� Type IV or cell-mediated type: Granulomatous disease,

tuberculosis


Type I Hypersensitivity

� Immediate (anaphylactic type)Ø The reaction occurs within minutes of exposure to an antigenØ Plasma cells produce IgE

• IgE causes mast cells to release histamine, causing increased dilation and permeability of blood vessels and constricting smooth muscle in bronchioles of the lungs

Ø The reaction may range from hay fever to asthma and life-threatening anaphylaxis


Type II Hypersensitivity� Cytotoxic type

Ø Antibody combines with an antigen bound to the surface of tissue cells, usually a circulating red blood cell (RBC)

� Activated complement components, and IgG and IgM antibodies in blood, participate in this type of hypersensitivity reactionØ This destroys the tissue that has the antigens on the surface of its

cells (e.g., Rh incompatibility)


Type III Hypersensitivity

� Immune complex type (serum sickness)Ø Immune complexes are formed between microorganisms and

antibody in circulating blood• These complexes leave the blood and are deposited in body

tissues, where they cause an acute inflammatory response

Ø Tissue destruction occurs after phagocytosis by neutrophils


Type IV Hypersensitivity

� Cell-mediated type (delayed)Ø T cells that previously have been introduced to an antigen

cause damage to tissue cells or recruit other cellsØ Responsible for the rejection of tissue grafts and transplanted

organs


Hypersensitivity to Drugs

� Drugs can act as antigensØ Topical administration may cause a greater number of

reactions than oral or parenteral routesØ However, the parenteral route may cause a more

widespread and severe reaction


Autoimmune Diseases

� Immunologic toleranceØ The body learns to distinguish self from nonself

� Autoimmune disorderØ The recognition mechanism breaks down; some body cells are

not tolerated and are treated as foreign antigens


Immunodeficiency

� An immunopathologic conditionØ A deficiency in number, function, or interrelationships of the

involved white blood cells (WBCs) and their productsØ May be congenital or acquiredØ Infections and tumors may occur as a result of the deficiency


Oral Diseases with Immunologic Pathogenesis

� Aphthous ulcers� Urticaria and angioedema� Contact mucositis and contact dermatitis� Fixed drug eruptions� Erythema multiforme� Lichen planus� Reactive arthritis (Reiter syndrome)� Langerhans’ cell disease


Aphthous Ulcers

� Painful oral ulcers with an unclear causeØ Occur in about 20% of the populationØ Trauma is the most common precipitating factor

• May be caused by emotional stress or certain foodØ May be associated with certain systemic diseasesØ Thought to have an immunologic pathogenesisØ Occur in three forms: Minor, major, and herpetiform


Recurrent Aphthous Ulcers (Canker Sores, Aphthous Stomatitis)

� Trauma� Perceived food associations� Menstruation� Systemic diseases� Tobacco cessation� Stress


Minor Aphthous Ulcers� Discrete, round or oval ulcers � Occur on movable mucosa� Up to 1 cm in diameter� Erythematous halo surrounding a

yellowish-white fibrin surface� May have single or multiple lesions� May have a prodrome of 1 to 2

days


Major Aphthous Ulcers (Sutton Disease, Periadenitis Mucosa Necrotica Recurrens)

� Larger than minor aphthous ulcers (>1 cm)

� Deeper and longer lasting than minor aphthous ulcers

� Very painful� Occur in the posterior of the mouth

more often than do minor aphthous ulcers

� May require several weeks to heal� May require a biopsy


Major Aphthous Ulcers


Herpetiform Aphthous Ulcers

� Tiny (1-2 mm)� Resemble herpes simplex ulcers� Painful, generally occur in groups


Aphthous Ulcers and Systemic Disease

� Chronic gastrointestinal symptoms� Crohn disease� Gluten-sensitive enteropathy/celiac disease� Inflammatory bowel syndrome� Intestinal lymphoma� Ulcerative colitis� Arthritis� Skin lesions (Behçet syndrome)� Childhood periodic fevers


Aphthous Ulcers: Treatment

� Topical corticosteroids� Topical nonsteroidal antiinflammatory drugs � Pain relief: Lidocaine, benzocaine� Systemic steroids� Nicotine replacement therapy


Urticaria (Hives)

� Appears as multiple areas of well-demarcated swelling of skin

� May include itching (pruritus)� Lesions are caused by localized

areas of vascular permeability in superficial connective tissue


Angioedema

� Lesions caused by diffuse swelling as a result of increased permeability of deeper blood vesselsØ The skin covering the swelling

appears normalØ Usually do not itch


Urticaria and Angioedema

Causes:� Idiopathic� Infection� Trauma� Emotional stress � Systemic diseases� Ingested allergens

Treatment:� Antihistaminic drugs� Epinephrine


Contact Mucositis and Dermatitis� Lesions result from contact of an

allergen with skin or mucosa

� Involves T cells in a cell-mediated immune response

� Type IV hypersensitivity


Contact Mucositis and Contact Dermatitis

Possible causes:� Preservatives in local

anesthetics� Topical medications� Acrylics� Metal-based alloys� Epoxy resins� Flavoring agents� Gloves

Treatment:� Topical corticosteroids� Systemic corticosteroids


Fixed Drug Eruptions

� Lesions that appear in the same site each time a drug is introducedØ Generally appear suddenly after a latent period and subside when

the drug is discontinued� May be single or multiple, slightly raised, reddish patches

or clusters of macules on the skin, or sometimes the mucous membranes

� Occurrence may include pain or pruritus


Fixed Drug Eruptions

� A type of allergic reaction (type III)Ø Immune complexes are deposited along the endothelial walls of

blood vesselsØ Inflammation causes vasculitis with damage to the vessel wallØ This creates erythema and edema in superficial layers of the

skin or mucosa� Treatment

Ø The drug causing the reaction should be identified and discontinued


Erythema Multiforme

� Acute, self-limited disease that affects skin and mucous membranes

� Cause: Not clear; may be a hypersensitivity reaction

� Target or bull’s-eye lesionØ Concentric erythematous rings

alternating with normal skin color


Erythema Multiforme


Erythema Multiforme

� Stevens-Johnson syndromeØ The most severe form

Ø More extensive and painful oral lesions

Ø Genital mucosa and mucosa of eyes may be involved

Ø Lips generally are encrusted and bloody


Erythema Multiforme

� Diagnosis:Ø Based on clinical

features and by exclusion of other diseases

Ø Eye lesions may lead to blindness

� Treatment: Ø Remove cause, if possibleØ Topical or systemic

corticosteroidsØ Systemic antiviral medications


Lichen Planus

� A benign, chronic disease affecting the skin and oral mucosa

� Unknown cause� Lesions have characteristic

Wickham striae (lacelike)


Lichen Planus

� Most commonly on buccal mucosaØ Lesions may be on the tongue,

lips, floor of mouth, and gingiva� Present in about 1% of the

U.S. populationØ Most common in middle ageØ Slightly more common in women


Types of Lichen Planus

� Reticular lichen planusØ Most common form

� Erosive and bullous lichen planusØ Epithelium separates from

connective tissue


Types of Lichen Planus

� Desquamative gingivitis can be associated with lichen planus

� Skin lesionsØ Papules (2-4 mm) most

commonly in lumbar region, flexor surfaces of the wrist, anterior ankle


Diagnosis of Lichen Planus

� Epithelium is generally parakeratotic

� Either hyperplastic or atrophic� Degeneration of basal cell layer

of epithelium� Broad band of lymphocytes in

CT� Separation of epithelium from

CT = erosive areas� May be premalignant


Treatment and Prognosis for Lichen Planus

� Treated when symptomatic� Topical corticosteroid medications� Meticulous oral hygiene� Discontinuation of drugs causing condition� Regular oral examination � Biopsy of suspicious lesions is necessary because

these patients may be at increased risk of development of squamous cell carcinoma


Reactive Arthritis: Reiter Syndrome

� Classic syndrome includes arthritis, urethritis, and conjunctivitis

� An antigenic marker called HLA-B27 is present in most patients, meaning there may be a genetic influence

� Probably an abnormal immune response to a microbial antigen


Reactive Arthritis: Reiter Syndrome

� May see aphthous ulcers, erythematous lesions, and geographic tongue-like lesions


Langerhans’ Cell Histiocytosis (Histiocytosis X)

� Langerhans’ cells and eosinophils


Langerhans’ Cell Histiocytosis (LCH), Acute Disseminated Form:

Letterer-Siwe Disease

� Usually affects children younger than 3 years of age

� No significant oral involvement� Resembles a lymphoma� May respond to chemotherapy


Langerhans’ Cell Histiocytosis (LCH), Chronic Disseminated or Multifocal Form: Hand-Schüller-

Christian Disease

� Children younger than 5 years of age

� Radiolucent areas in the skull� Exophthalmos and diabetes

insipidus may be present

� Gingivitis� Halitosis� Unpleasant taste� Mobile and sensitive teeth� Early exfoliation� Nonhealing extraction sites� Bone loss


Langerhans’ Cell Histiocytosis (LCH): Eosinophilic Granuloma

� Affects older children and young adults

� Involves skull and mandible� May resemble periodontal

disease or periapical inflammatory disease

� Treatment:Ø Surgical excisionØ Radiation therapy


Autoimmune Diseases That Affect the Oral Cavity

� Sjögren syndrome� Systemic lupus erythematosus� Pemphigus vulgaris� Mucous membrane pemphigoid� Bullous pemphigoid� Behçet syndrome


Sjögren Syndrome

� Affects the salivary and lacrimal glands� Results in a decrease in saliva and tears,

causing a dry mouth (xerostomia) and dry eyes (xerophthalmia)

� Keratoconjunctivitis sicca: Damage to eyes


Sjögren Syndrome

� May be associated with other autoimmune disordersØ Primary Sjögren syndrome: When it

occurs aloneØ Secondary Sjögren syndrome:

When it occurs with other autoimmune disorders

� Affects both major and minor salivary glandsØ Parotid gland enlargement occurs in

about 50% of patients


Sjögren Syndrome

� Oral discomfort caused by dry mouth

� Lips: Cracked and dry

� May see loss of filiform and fungiform papillae on the dorsum of the tongue

� High risk for caries, periodontal disease, and oral candidiasis


Sjögren Syndrome

� Biopsy reveals a characteristic appearance:Ø Major salivary glands

• Replacement with lymphocytes and the presence of islands of epithelium called epimyoepithelial islands

Ø Minor salivary glands • Aggregates of lymphocytes

surrounding the salivary gland ducts


Sjögren Syndrome and Raynaud Phenomenon

� 20% of patients with Sjögren syndrome will have this disorder affecting the fingers and toes

� Initial pallor and subsequent cyanosis of skin caused by cold or stress

� Hyperemia when blood vessels are warmed� Myalgia� Arthralgia� Chronic fatigue


Sjögren Syndrome

� 90% of these patients have a positive response to rheumatoid factor, an antibody to IgG present in serumØ Rheumatoid factor is an antibody to an antibody

� Other autoantibodies, anti-Sjögren syndrome A and anti-Sjögren syndrome B, are also present


Diagnosis and Management of Sjögren Syndrome

� Diagnosis is made when two of three components are present:Ø Xerostomia

• Measurement of salivary flow and biopsy can helpØ Keratoconjunctivitis sicca

• Confirmed by eye examinationØ Rheumatoid arthritis

� For most patients, the course of the disease is chronic and benign, but these patients are at risk for the development of other, more serious diseases


Treatment of Sjögren Syndrome

� Treated symptomaticallyØ Nonsteroidal antiinflammatory agents for arthritis

• May need corticosteroids and immunosuppressive drugs for severe cases

Ø Saliva substitutes for xerostomia• Humidifier, sugarless gum, or lozenges• Pilocarpine

Ø Glasses and/or artificial tears to protect eyesØ Good oral hygieneØ FluorideØ Frequent recare appointments


Systemic Lupus Erythematosus (SLE)

� An acute and chronic inflammatory autoimmune diseaseØ No known cause

� Affects women eight times more frequently than men, predominantly during childbearing yearsØ Three times more frequent in black women than in white women



� A syndrome with a wide range of disease activityØ Usually chronic and progressive

• Periods of remission and exacerbation� Autoantibodies to DNA are present in serum� May have a genetic component


Clinical Features: Systemic Lupus Erythematosus (SLE)

� Skin lesions occur in 85% of individualsØ “Butterfly” rash on bridge of

noseØ There may be erythematous

lesions on fingertipsØ Arthritis and arthralgia are

common



� Oral lesions accompany skin lesions in about 25% of patients with discoid LEØ Erythematous plaques or erosions

• May have white striae; resemble lichen planus but are less symmetric

� Medical consultation may be needed before dental treatment!



Diagnosis:� Based on multiorgan

involvement and presence of anti-nuclear antibodies in serumØ Inflammatory infiltrate is

around blood vessels in connective tissue

Treatment:� Aspirin and

antiinflammatory drugs� Hydroxychloroquine and

corticosteroids along with immunosuppressive agents


Pemphigus Vulgaris

� A severe, progressive autoimmune disease affecting the skin and mucous membranesØ Characterized by intraepithelial

blister formation resulting from acantholysis, a breakdown of cellular adhesion between epithelial cells


Pemphigus Vulgaris

� The first signs of disease occur in the oral cavity in more than 50% of cases

� There may be shallow ulcers, to fragile vesicles, to bullae

� Nikolsky signØ Rubbing with a finger can

produce a bulla


Pemphigus Vulgaris

� Microscopic appearance:Ø Acantholytic cells

• The loss of attachment between epithelial cells leads to cells that appear rounded

Ø Tzanck cells


Treatment and Prognosis for Pemphigus Vulgaris

� High doses of corticosteroidsØ May include

immunosuppressive drugsØ Mortality rate of 8% to 10%

in 5 years is related to complications of corticosteroid treatment


Mucous Membrane Pemphigoid (Benign Mucous Membrane Pemphigoid;

Cicatricial Pemphigoid)

� A chronic autoimmune disease� Affects oral mucosa, conjunctiva, genital mucosa,

and skin� Not as severe as pemphigus vulgaris� Will see positive Nikolsky sign


Benign Mucous Membrane Pemphigoid; Cicatricial Pemphigoid

� Gingival lesions have been called desquamative gingivitis, but this may be seen with lichen planus and pemphigus as well

� Will see positive Nikolsky sign


Diagnosis of Mucous Membrane Pemphigoid

� Made by biopsy and histologic examinationØ No degeneration of

epithelium occurs Ø An inflammatory infiltrate,

usually with predominant plasma cells and eosinophils, is seen in connective tissue


Treatment and Prognosis for Mucous Membrane Pemphigoid

� A chronic disease with a benign courseØ Topical corticosteroid for mild casesØ Systemic corticosteroids may be required for more

severe casesØ Eye lesions can lead to eye damage


Bullous Pemphigoid

� Some investigators believe bullous and mucous membrane pemphigoid are variants of a single disease

� 80% of patients are older than 60 years� Oral lesions are less common than in cicatricial

pemphigoid� Treatment:

Ø Systemic corticosteroids and nonsteroidal antiinflammatory drugs


Behçet Syndrome

� A chronic, recurrent autoimmune diseaseØ Primarily oral ulcers, genital ulcers,

ocular inflammationØ No sex predilection; mean onset is

30 yearsØ Autoantibodies to human mucosa

may be found� Oral ulcers are similar in

appearance to aphthous ulcers


Behçet Syndrome

� Diagnosis requires that two of three types of lesions (oral, genital, and ocular) be present

� A pustular lesion after needle puncture suggests Behçet syndrome

� Treatment:Ø Systemic and topical corticosteroidsØ Chlorambucil is used for ocular lesions


Discussion Questions

� What is an autoimmune disorder?� What is the difference between an antigen and an

antibody?� What are the differences between active and passive

immunity?� What oral diseases have an immunologic pathogenesis?� What is an autoimmune disorder?� What are the oral symptoms of Sjögren syndrome?� What are differences between pemphigus and pemphigoid?


Chapter 3 Immunity and Immunologic Oral Lesions · Type II Hypersensitivity Cytotoxic type...

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